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WO2023240920A1 - Sulfur-containing artemisinin analogue dimer, and preparation method therefor and use thereof - Google Patents

Sulfur-containing artemisinin analogue dimer, and preparation method therefor and use thereof Download PDF

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Publication number
WO2023240920A1
WO2023240920A1 PCT/CN2022/131906 CN2022131906W WO2023240920A1 WO 2023240920 A1 WO2023240920 A1 WO 2023240920A1 CN 2022131906 W CN2022131906 W CN 2022131906W WO 2023240920 A1 WO2023240920 A1 WO 2023240920A1
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WIPO (PCT)
Prior art keywords
compound
group
sulfur
acid
reaction
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PCT/CN2022/131906
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French (fr)
Chinese (zh)
Inventor
李剑峰
王小婷
坝德伟
周启心
孔迪
黄陈舟
王正学
余开波
熊伟
虎文华
李志强
王金龙
李明峰
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云南苏理生物医药科技有限公司
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Publication of WO2023240920A1 publication Critical patent/WO2023240920A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present invention relates to the technical field of medicinal chemistry, and in particular to a sulfur-containing artemisinin dimer, its preparation method and application.
  • artemisinin was extracted from Artemisia annua and proved to have powerful antimalarial effects in laboratories and clinical trials. Based on this structure, a series of anti-malarial products were successively synthesized and semi-synthesized. Derivatives with malarial activity, such as dihydroartemisinin, artesunate, artemether, arteether, etc.
  • the present invention provides a sulfur-containing artemisinin dimer, its preparation method and application.
  • the present invention provides a sulfur-containing artemisinin dimer, the chemical structural formula of which is a compound represented by formula I or a pharmaceutically acceptable salt thereof:
  • W represents: any one of S, SO and SO 2 ;
  • Z represents: any one of S, SO, SO 2 , O, NR 1 and CR 1 2 ;
  • Y represents: any one of single bond, alkyl group, aryl group, cyclic group, ether and ammonia;
  • R 1 represents: any one of hydrogen, halogen, alkyl, aryl, cyclic group, ether and ammonia;
  • n and m are each independently selected from: an integer from 0 to 15.
  • the beneficial effects of the present invention are: the sulfur-containing artemisinin dimer of the present invention has a selective inhibitory effect on the growth of human cancer cell lines.
  • the present invention can also make the following improvements.
  • sulfur-containing artemisinin dimer or the pharmaceutically acceptable salt of the sulfur-containing artemisinin dimer has any of the following structures:
  • Y represents: any one of single bond, alkyl group, aryl group, cyclic group, ether and ammonia;
  • R 1 represents: any one of hydrogen, halogen, alkyl, aryl, cyclic group, ether and ammonia;
  • n and m are each independently selected from: an integer from 0 to 15.
  • Y represents: single bond, NR 2 , O, S, SO, SO 2 , SR 2 x , PR 2 x , C1 ⁇ C5 heteroalkyl group, C1 ⁇ C5 heteroalkyl group substituted by 1 to 5 R 2 Alkyl group, C1 ⁇ C10 alkyl group, C1 ⁇ C10 alkyl group substituted by 1 ⁇ 5 R2 , aryl group, aryl group substituted by 1 ⁇ 5 R2 , 3 ⁇ 10 membered ring group, substituted by 1 ⁇ 5 In 3 to 10-membered ring groups substituted with R 2 , 3 to 10-membered heterocyclyl groups, 3 to 10-membered heterocyclyl groups substituted with 1 to 5 R 2s , ethers and ethers substituted with 1 to 5 R 2s any kind of;
  • R 2 represents: any one of H, F, O, Cl, Br, I, CN, C1-C5 alkyl, aryl, cyclic group, ether and ammonia;
  • the x is selected from an integer from 1 to 4.
  • the aryl group is selected from phenyl, pyridyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, naphthyl, pyrrolyl, furyl, indolyl, quinolyl, purinyl and biaryl. any kind of;
  • the 1 to 6 ring atoms in the 3 to 10 membered heterocyclic group are independently selected from any one of O, S and N.
  • the ring group includes a saturated monocyclic group, an unsaturated monocyclic group, a saturated polycyclic group system and an unsaturated polycyclic group system, and the polycyclic group system includes a spiro ring, a paracyclic ring, a bridged ring and a linked ring;
  • the heterocyclyl group includes a saturated monoheterocyclyl group, an unsaturated monoheterocyclyl group, a saturated polyheterocyclyl system and an unsaturated polyheterocyclyl system, and the polyheterocyclyl system includes a spiro ring, a paracyclic ring, and a bridged ring. and linked rings.
  • R 1 is represented by: H, F, Cl, Br, I, CN, NR 2 , S, SO, SO 2 , SR 2 x, PR 2 x, C1 to C5 heteroalkyl, 1 to 5 C1 ⁇ C5 heteroalkyl group substituted by R 2 , C1 ⁇ C10 alkyl group, C1 ⁇ C10 alkyl group substituted by 1 to 5 R 2 , aryl group, aryl group substituted by 1 to 5 R 2 , 3 ⁇ 10 1-membered ring group, 3-10-membered ring group substituted by 1-5 R 2 , 3-10-membered heterocyclic group, 3-10-membered heterocyclic group substituted with 1-5 R 2 , ether and 1-10 membered heterocyclic group. Any one of the 5 R 2 substituted ethers;
  • R 2 represents: any one of H, F, O, Cl, Br, I, CN, C1-C5 alkyl, aryl, cyclic group, ether and ammonia;
  • the x is selected from an integer from 1 to 4.
  • the aryl group is selected from phenyl, pyridyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, naphthyl, pyrrolyl, furyl, indolyl, quinolyl, purinyl and biaryl. any kind of;
  • the 1 to 6 ring atoms in the 3 to 10 membered heterocyclic group are independently selected from any one of O, S and N.
  • the cyclic groups include saturated cyclic groups and unsaturated cyclic groups, and also include single and polycyclic ring systems.
  • Polycyclic ring systems include spirocyclic rings, paracyclic rings, bridged rings and jointed rings;
  • the heterocyclyl group includes a saturated monoheterocyclyl group, an unsaturated monoheterocyclyl group, a saturated polyheterocyclyl system and an unsaturated polyheterocyclyl system, and the polyheterocyclyl system includes a spiro ring, a paracyclic ring, and a bridged ring. and linked rings.
  • sulfur-containing artemisinin dimer has any of the following structures:
  • W represents: any one of S, SO and SO 2 ;
  • Z represents: any one of S, SO, SO 2 , O, NR 1 and CR 1 2 ;
  • Y represents: any one of single bond, alkyl group, aryl group, cyclic group, ether and ammonia;
  • R 1 represents: any one of hydrogen, halogen, alkyl, aryl, cyclic group, ether and ammonia;
  • n and m are each independently selected from: integers from 0 to 15;
  • the acid is selected from: hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, boron trifluoride etherate complex, titanium tetrachloride, zinc chloride, aluminum trichloride, trimethyltrifluoromethanesulfonate Any one of silyl ester and p-toluenesulfonic acid;
  • reaction formula 1 the compound of formula II and dihydroartemisinin are dispersed in a solvent, and acid is added dropwise to react at -78°C to 25°C to obtain sulfur-containing artemisinin dimer.
  • W represents: any one of S, SO and SO 2 ;
  • Z represents: any one of S, SO, SO 2 , O, NR 1 and CR 1 2 ;
  • Y represents: any one of single bond, alkyl group, aryl group, cyclic group, ether and ammonia;
  • R 1 represents: any one of hydrogen, halogen, alkyl, aryl, cyclic group, ether and ammonia;
  • X represents: any one of halogen and halogen-like; the halogen is selected from: any one of F, Cl, Br and I; the halogen-like is selected from: methanesulfonyloxy, trifluoromethanesulfonate Any one of acyloxy group, p-toluenesulfonyloxy group, p-nitrobenzenesulfonyloxy group and acyloxy group;
  • n and m are each independently selected from: integers from 0 to 15;
  • dihydroartemisinin is thio-reacted to prepare thiodihydroartemisinin represented by formula III, and thiodihydroartemisinin is reacted with the compound represented by formula IV to obtain Sulfur-containing artemisinin dimers.
  • W represents: any one of S, SO and SO 2 ;
  • Z represents: any one of S, SO, SO 2 , O, NR 1 and CR 1 2 ;
  • Y represents: any one of single bond, alkyl group, aryl group, cyclic group, ether and ammonia;
  • R 1 represents: any one of hydrogen, halogen, alkyl, aryl, cyclic group, ether and ammonia;
  • TMS represents: trimethylsilyl group
  • n and m are each independently selected from: integers from 0 to 15;
  • the acid is selected from: hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, boron trifluoride etherate complex, titanium tetrachloride, zinc chloride, aluminum trichloride, trimethyltrifluoromethanesulfonate Any one of silyl ester and p-toluenesulfonic acid;
  • reaction formula 3 the compound represented by formula V and dihydroartemisinin are dissolved in a solvent, and acid is added dropwise to react at -78°C to 25°C to obtain sulfur-containing artemisinin dimers.
  • the sulfur-containing artemisinin dimer containing low oxidation state sulfur is oxidized with an oxidizing agent to obtain a high oxygen-containing artemisinin dimer.
  • the oxidant is selected from: ozone, urea peroxide, hydrogen peroxide, hypochlorous acid, hypochlorite, perchloric acid, perchlorate, perhydrogen persulfate, persulfate, permanganate, and dichromate , any one of periodic acid, periodate and peroxy organic acid;
  • the low oxidation state sulfur is expressed as: negative divalent sulfur
  • the highly oxidized sulfur is expressed as: SO or SO 2 .
  • the pathological state for which the anti-tumor drug is applied is cancer, including but not limited to leukemia, lung cancer, liver cancer, breast cancer, colon cancer, gastric cancer, ovarian cancer, cervical cancer, etc.
  • sulfur-containing artemisinin dimer of the present invention can be used in combination with known anti-cancer drugs, such as paclitaxel, etoposide, cisplatin, etc.
  • the sulfur-containing artemisinin dimers of the present invention can be used in combination with other cancer therapies, such as radiotherapy and bone marrow transplantation.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for contact with human or animal tissue. Suitable for use without undue toxicity, irritation, allergic reactions or other problems or complications and commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refers to salts of compounds of the present invention prepared from compounds having specific substituents found in the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a solvent.
  • Pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, ammonium, organic ammonia, magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a solvent.
  • Pharmaceutically acceptable acid addition salts include inorganic acid salts and organic acid salts.
  • Inorganic acids include but are not limited to hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, sulfurous acid, Phosphorous acid, etc.
  • organic acids include but are not limited to formic acid, acetic acid, propionic acid, butyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, butenedioic acid, lactic acid, mandelic acid, phthalic acid Dicarboxylic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid,
  • Certain specific compounds of the present invention contain both acidic and basic functional groups and thus can be converted into either base or acid addition salts.
  • the pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases. In general, such salts are prepared by reacting these compounds via the free acid or base formation with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
  • the compounds provided by the invention also exist in prodrug forms.
  • Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert them into compounds of the invention.
  • prodrugs can be converted to compounds of the invention by chemical or biochemical methods in the in vivo environment.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomeric or diastereomerically enriched mixtures, all of which are within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • enantiomers or “optical isomers” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomers or “geometric isomers” refers to the inability of the double bonds or single bonds of the carbon atoms in the ring to rotate freely.
  • diastereomer refers to stereoisomers whose molecules have two or more chiral centers and are in a non-mirror image relationship between the molecules.
  • wedge-shaped solid line keys and wedge-shaped dotted keys Represents the absolute configuration of a three-dimensional center
  • using straight solid line keys and straight dotted keys Represent the relative configuration of the three-dimensional center with a wavy line Indicates that the stereochemical configuration is uncertain or not fixed or that it is a mixture.
  • Optically active (R)- and (S)-isomers as well as D- and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliaries, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, and then the salt is formed by conventional methods known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereoisomers is usually accomplished by using chromatography with a chiral stationary phase, optionally combined with chemical derivatization (e.g. generated from amines). carbamate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • deuterated drugs can be replaced by heavy hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce side effects and increase drug stability. , enhance efficacy, extend drug biological half-life and other advantages. All variations in the isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • substituted means that any one or more hydrogens on a particular atom are replaced by a substituent, which may include deuterium and variants of hydrogen, as long as the valence state of the particular atom is normal and the substituted compound is stable.
  • oxygen it means that two hydrogen atoms are replaced.
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical achievability.
  • any variable eg, R1
  • its definition in each instance is independent.
  • R 1 When any variable (eg, R1 ) occurs more than once in the composition or structure of a compound, its definition in each instance is independent.
  • R 1 When any variable (eg, R1 ) occurs more than once in the composition or structure of a compound, its definition in each instance is independent.
  • a group is substituted by 0 to 2 R 1 , then said group may optionally be substituted with up to two R 1 s, with independent options for R 1 in each case.
  • substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CR 1 2 ) 0 -, it means that the linking group is a single bond.
  • the substituent can be bonded through any atom thereof.
  • a pyridyl group as a substituent can be bonded through any one of the pyridine rings.
  • the carbon atom is attached to the substituted group.
  • the listed linking groups do not specify the direction of attachment, the direction of attachment is arbitrary.
  • C1-C10 alkyl is used to represent a straight-chain or branched saturated hydrocarbon group consisting of 1 to 10 carbon atoms. It may be monovalent (eg methyl), divalent (eg methylene) or polyvalent (eg methine).
  • aryl refers to any functional group or substituent derived from a simple aromatic ring. Including but not limited to phenyl, biphenyl, pyridyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, naphthyl, pyrrolyl, furyl, indolyl, quinolyl, purinyl, etc., so When selecting an aryl group, two C atoms can be optionally connected to -(CR 1 2 ) n - in the main structure, and the remaining atoms can be optionally substituted by 1 to 5 R 1 ;
  • 3- to 10-membered cyclic group in the present invention refers to a saturated or unsaturated cyclic group composed of 3 to 10 carbon atoms; including monocyclic and polycyclic systems, and polycyclic systems include spirocyclic, paracyclic, and Bridge rings and linked rings. Except for the atoms connected to -(CR 1 2 ) n - in the main structure, the remaining atoms can be optionally substituted by 1 to 2 R 1 ; unsaturated cyclic group refers to a non-aryl group containing 1 to 3 unsaturated bonds. .
  • 3-10 membered heterocyclyl in the present invention refers to a saturated or unsaturated cyclic group composed of 3-10 carbon atoms, of which 1-6 ring atoms are independently selected from O, S and N. atoms, the remainder being carbon atoms, of which nitrogen atoms are optionally quaternized, and nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and SO t , t is 1 or 2). It includes single-ring and multi-ring systems, and the multi-ring system includes spiro ring, parallel ring, bridged ring and double ring.
  • a heteroatom may occupy the connection position between the heterocycloalkyl group and the rest of the molecule. Except for the atom connected to -(CR 1 2 ) n - in the main structure, the remaining carbon atoms can be optionally substituted by 1 to 2 R 1 ; unsaturated cyclic group refers to a non-aryl group containing 1 to 3 unsaturated bonds. group.
  • the spiro ring is two adjacent single rings sharing one atom; the merged ring is two or more single rings merged together. Among the two merged single rings, two adjacent atoms on one single ring are the same.
  • the bridged ring is a polycyclic structure that shares two or more atoms;
  • the linked ring is two or more single rings, and each of the atoms on the single ring is connected by a single bond or a double bond. key connected.
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and methods well known to those skilled in the art. Equivalent alternatives and preferred embodiments include, but are not limited to, embodiments of the present invention.
  • aq represents aqueous solution
  • eq represents equivalent, equal amount
  • M or N represents mol/L or mmol/mL
  • DHA represents dihydroartemisinin, that is, (3R, 5 ⁇ S, 6R, 8 ⁇ S, 9R,10S,12R,12 ⁇ R)-octahydro-3,6,9-trimethyl-3,12-oxo-12H-pyrano[4,3-j]-1,2-benzodithiane Ping-10(3H)-ol
  • SDHA-A stands for ⁇ -thiodihydroartemisin, that is, (3R,5 ⁇ S,6R,8 ⁇ S,9R,10R,12R,12 ⁇ R)-octahydro-3,6,9- Trimethyl-3,12-oxo-12H-pyrano[4,3-j]-1,2-benzodithiopin-10(3H)-thiol
  • 1,2-ethanedithiol (83 mg, 0.88 mmol, 0.50 eq) was used as the raw material to obtain 196 mg of compound 3A and 165 mg of compound 3B.
  • 1,8-octanediol (1.05g, 7.18mmol, 1.00eq) was used as the raw material to obtain 180 mg of compound 9A, 390 mg of compound 9B and 700 mg of compound 9C.
  • Compound 9A, compound 9B and compound 9C were all colorless. Oily substance.
  • 1,9-nonanediol (1.00g, 6.24mmol, 1.00eq) was used as the raw material to obtain 667 mg of compound 10A, 632 mg of compound 10B and 548 mg of compound 10C. The combined yield was 64%.
  • Compound 10A, compound 10B and Compound 10C was a white foamy solid.
  • 1,10-decanediol (1.00g, 5.74mmol, 1.00eq) was used as the raw material to obtain 382 mg of compound 11A and 481 mg of compound 11B. The combined yield was 36%. Both compound 11A and compound 11B were white solids.
  • Example 19 cis-cyclobutanediol (500 mg, 5.67 mmol, 1.00 eq) was used as the raw material, and 172 mg of compound 20A and 215 mg of compound 20B were obtained as white solids. The combined yield was 55%. Compound 20A and compound 20B were both white solids.
  • intermediate 30-1 (18.00g, 44.29mmol, 1.00eq) to 1.5L methanol, cool to -25°C, slowly add 97mL of 0.5M sodium methoxide methanol solution dropwise, and continue to - Stir for 30 minutes at 25°C, adjust the pH value to neutral using cation exchange resin, and purify to obtain 16.00g of intermediate 30-2;
  • Example 19 raw material 38 was used as the raw material, and 0.70 g of compound 38 was obtained with a yield of 36%.
  • Compound 38 was a white foam compound.
  • intermediate 40-1 (2.20g, 9.01mmoL, 1.00eq) was used to obtain 0.30g of compound 40A and 0.70g of compound 40B. Both compound 40A and compound 40B were in the form of white foam.
  • raw material 47 (1.00g, 5.98mmol, 1.00eq) was used to obtain 210 mg of compound 47A and 280 mg of compound 47B. Both compound 47A and compound 47B were white solids;
  • the nuclear magnetic structure of compound 47 is as follows:
  • raw material 49 500 mg, 2.90 mmol, 1.00 eq
  • compound 49A and compound 49B were foamy white solids.
  • raw material 41 (1.00g, 5.95mmol, 1.00eq), 312mg compound 51A and 286mg compound 51B were used. Both compound 51A and compound 51B were in the form of white foam.
  • raw material 53 (1.00g, 5.88mmol, 1.00eq) was used as the raw material, and 269 mg of compound 53A and 236 mg of compound 53B were obtained. Both compound 53A and compound 53B were in the form of white foam.
  • MTS is a new MTT analogue, whose full name is 3-(4,5-dimethylthiazol-2-yl)-5(3-carboxymethoxyphenyl)-2-(4-sulfopheny)-2H- Tetrazolium is a yellow dye.
  • Succinate dehydrogenase in the mitochondria of living cells can metabolize and reduce MTS to generate soluble formazan compounds.
  • the content of formazan can be measured at 490nm with a microplate reader. Under normal circumstances, the amount of formazan produced is directly proportional to the number of viable cells, so the number of viable cells can be estimated based on the optical density OD value.
  • Inoculated cells Use culture medium (DMEM or RMPI1640) containing 10% fetal calf serum to make a single cell suspension.
  • DMEM or RMPI1640 10% fetal calf serum
  • Adherent cells are inoculated and cultured 12 to 24 hours in advance.
  • Add the solution of the compound to be tested dissolve the compound in DMSO, and initially screen the compound at a concentration of 40uM. The final volume of each well is 200ul. Each treatment has 3 duplicate wells.
  • Colorimetry Select the wavelength of 492nm, read the light absorption value of each well with a multifunctional microplate reader (MULTISKAN FC), record the results, and finally take the average of the three results.
  • MULTISKAN FC multifunctional microplate reader
  • Positive control compounds Each experiment includes two positive compounds: cisplatin (DDP) and paclitaxel (Taxol).

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Abstract

The present invention relates to a sulfur-containing artemisinin analogue dimer, and a preparation method therefor and the use thereof, which belong to the technical field of pharmaceutical chemistry. The sulfur-containing artemisinin analogue dimer is a compound having a chemical structural formula represented by formula I or a pharmaceutically acceptable salt thereof, wherein W represents any one of S, SO and SO2; Z represents any one of S, SO, SO2, O, NR1 and CR1 2; Y represents any one of a single bond, an alkyl group, an aryl group, a cyclic group, ether and ammonia; R1 represents any one of hydrogen, halogen, an alkyl group, an aryl group, a cyclic group, ether and ammonia; and n and m are each independently selected from integers of 0-15. Further disclosed in the present invention is a method for preparing a sulfur-containing artemisinin analogue dimer. The sulfur-containing artemisinin analogue dimer of the present invention has a selective inhibition effect on the growth of human cancer cell strains.

Description

一种含硫类青蒿素二聚体、其制备方法和应用A kind of sulfur-containing artemisinin dimer, its preparation method and application 技术领域Technical field
本发明涉及药物化学技术领域，尤其涉及一种含硫类青蒿素二聚体、其制备方法及应用。The present invention relates to the technical field of medicinal chemistry, and in particular to a sulfur-containing artemisinin dimer, its preparation method and application.
背景技术Background technique
上世纪七十年代，从黄花蒿中提取出青蒿素，并在实验室和临床证实青蒿素具有强大的抗疟作用，并在此结构基础上又相继合成、半合成出一系列具有抗疟活性的衍生物，如双氢青蒿素、青蒿琥酯、蒿甲醚、蒿乙醚等。In the 1970s, artemisinin was extracted from Artemisia annua and proved to have powerful antimalarial effects in laboratories and clinical trials. Based on this structure, a series of anti-malarial products were successively synthesized and semi-synthesized. Derivatives with malarial activity, such as dihydroartemisinin, artesunate, artemether, arteether, etc.
在青蒿素类药物的抗疟作用被证实之后，其它生物活性如抗其它寄生虫、抗癌和免疫抑制的研究也随之开展。After the antimalarial effect of artemisinins was confirmed, research on other biological activities, such as antiparasitic, anticancer and immunosuppressive activities, was also carried out.
Woerdenbag HJ等报道青蒿素、蒿甲醚、蒿乙醚、青蒿琥酯对Ehrlich Ascites细胞株有一定的细胞毒性，11,13-脱氢青蒿素(Artemisitene)的作用更强，双氢青蒿素的二聚体则显示最强活性 [1]。 Woerdenbag HJ et al. reported that artemisinin, artemether, arteether, and artesunate have certain cytotoxicity to Ehrlich Ascites cell lines, 11,13-dehydroartemisitene (Artemisitene) has a stronger effect, and dihydrocyanin The dimer of artemisinin shows the strongest activity [1] .
为了寻找具有更高活性的化合物，数以百计的青蒿素类化合物被合成及筛选，特别是近十年以来，一些采用不同连接物组成的青蒿素二聚体和三聚体被大量报道，其中有不少化合物对人癌细胞株的生长具有强大的选择性抑制作用。In order to find compounds with higher activity, hundreds of artemisinin compounds have been synthesized and screened. Especially in the past decade, some artemisinin dimers and trimers composed of different linkers have been synthesized and screened in large quantities. It has been reported that many of these compounds have strong selective inhibitory effects on the growth of human cancer cell lines.
但是，含硫类青蒿素二聚体未见报道。However, sulfur-containing artemisinin dimers have not been reported.
发明内容Contents of the invention
本发明为了解决上述技术问题提供了一种含硫类青蒿素二聚体、其制备方法和应用。In order to solve the above technical problems, the present invention provides a sulfur-containing artemisinin dimer, its preparation method and application.
本发明解决上述技术问题的技术方案如下：The technical solutions of the present invention to solve the above technical problems are as follows:
本发明提供一种含硫类青蒿素二聚体，其化学结构式如式Ⅰ表示的化合物或其药学上可接受的盐：The present invention provides a sulfur-containing artemisinin dimer, the chemical structural formula of which is a compound represented by formula I or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022131906-appb-000001
Figure PCTCN2022131906-appb-000001
其中，W表示为：S、SO和SO 2中的任意一种； Among them, W represents: any one of S, SO and SO 2 ;
Z表示为：S、SO、SO 2、O、NR 1和CR 1 2中的任意一种； Z represents: any one of S, SO, SO 2 , O, NR 1 and CR 1 2 ;
Y表示为：单键、烷基、芳基、环基、醚和氨中的任意一种；Y represents: any one of single bond, alkyl group, aryl group, cyclic group, ether and ammonia;
R 1表示为：氢、卤素、烷基、芳基、环基、醚和氨中的任意一种； R 1 represents: any one of hydrogen, halogen, alkyl, aryl, cyclic group, ether and ammonia;
n和m各自独立的选自：0～15的整数。n and m are each independently selected from: an integer from 0 to 15.
本发明的有益效果是：本发明的含硫类青蒿素二聚体对人癌细胞株的生长具有选择性的抑制作用。The beneficial effects of the present invention are: the sulfur-containing artemisinin dimer of the present invention has a selective inhibitory effect on the growth of human cancer cell lines.
在上述技术方案的基础上，本发明还可以做如下改进。On the basis of the above technical solution, the present invention can also make the following improvements.
进一步，所述含硫类青蒿素二聚体或含硫类青蒿素二聚体在药学上可接受的盐具有以下任一的结构：Further, the sulfur-containing artemisinin dimer or the pharmaceutically acceptable salt of the sulfur-containing artemisinin dimer has any of the following structures:
Figure PCTCN2022131906-appb-000002
Figure PCTCN2022131906-appb-000002
Figure PCTCN2022131906-appb-000003
Figure PCTCN2022131906-appb-000003
Figure PCTCN2022131906-appb-000004
Figure PCTCN2022131906-appb-000004
其中，Y表示为：单键、烷基、芳基、环基、醚和氨中的任意一种；Among them, Y represents: any one of single bond, alkyl group, aryl group, cyclic group, ether and ammonia;
R 1表示为：氢、卤素、烷基、芳基、环基、醚和氨中的任意一种； R 1 represents: any one of hydrogen, halogen, alkyl, aryl, cyclic group, ether and ammonia;
n、m各自独立的选自：0～15的整数。n and m are each independently selected from: an integer from 0 to 15.
进一步的，Y表示为：单键、NR 2、O、S、SO、SO 2、SR 2 x、PR 2 x、C1～C5杂烷基、被1～5个R 2取代的C1～C5杂烷基、C1～C10烷基、被1～5个R 2取代的C1～C10烷基、芳基、被1～5个R 2取代的芳基、3～10元环基、被1～5个R 2取代的3～10元环基、3～10元杂环基、被1～5个R 2取代的3～10元杂环基、醚和被1～5个R 2取代的醚中的任意任意一种； Further, Y represents: single bond, NR 2 , O, S, SO, SO 2 , SR 2 x , PR 2 x , C1～C5 heteroalkyl group, C1～C5 heteroalkyl group substituted by 1 to 5 R 2 Alkyl group, C1~C10 alkyl group, C1~C10 alkyl group substituted by 1~5 R2 , aryl group, aryl group substituted by 1~5 R2 , 3~10 membered ring group, substituted by 1~5 In 3 to 10-membered ring groups substituted with R 2 , 3 to 10-membered heterocyclyl groups, 3 to 10-membered heterocyclyl groups substituted with 1 to 5 R 2s , ethers and ethers substituted with 1 to 5 R 2s any kind of;
其中，所述R 2表示为：H、F、O、Cl、Br、I、CN、C1～C5烷基、芳基、环基、醚和氨中的任意一种； Wherein, the R 2 represents: any one of H, F, O, Cl, Br, I, CN, C1-C5 alkyl, aryl, cyclic group, ether and ammonia;
所述x选自1～4的整数；The x is selected from an integer from 1 to 4;
所述芳基选自苯基、吡啶基、吡嗪基、哒嗪基、噻吩基、噻唑基、萘基、吡咯基、呋喃基、吲哚基、喹啉基、嘌呤基和联芳基中的任意一种；The aryl group is selected from phenyl, pyridyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, naphthyl, pyrrolyl, furyl, indolyl, quinolyl, purinyl and biaryl. any kind of;
所述3～10元杂环基中的1～6个环原子独立的选自O、S和N中的任意一种。The 1 to 6 ring atoms in the 3 to 10 membered heterocyclic group are independently selected from any one of O, S and N.
所述环基包括饱和单环基、不饱和单环基、饱和多环基体系和不饱和多环基体系，所述多环基体系包括螺环、并环、桥环和联环；The ring group includes a saturated monocyclic group, an unsaturated monocyclic group, a saturated polycyclic group system and an unsaturated polycyclic group system, and the polycyclic group system includes a spiro ring, a paracyclic ring, a bridged ring and a linked ring;
所述杂环基包括饱和单杂环基、不饱和单杂环基、饱和多杂环基体系和不饱和多杂环基体系，所述多杂环基体系包括螺环、并环、桥环和联环。The heterocyclyl group includes a saturated monoheterocyclyl group, an unsaturated monoheterocyclyl group, a saturated polyheterocyclyl system and an unsaturated polyheterocyclyl system, and the polyheterocyclyl system includes a spiro ring, a paracyclic ring, and a bridged ring. and linked rings.
采用上述进一步方案的有益效果是：能够丰富结构是中Y的选择。The beneficial effect of adopting the above further solution is that it can enrich the structure and is the best choice for Y.
进一步的，R 1表示为：H、F、Cl、Br、I、CN、NR 2、S、SO、SO 2、SR 2x、PR 2x、C1～C5杂烷基、被1～5个R 2取代的C1～C5杂烷基、C1～C10烷基、被1～5个R 2取代的C1～C10烷基、芳基、被1～5个R 2取代的芳基、3～10元环基、被1～5个R 2取代的3～10元环基、3～10元杂环基、被1～5个R 2取代的3～10元杂环基、醚和被1～5个R 2取代的醚中的任意任意一种； Further, R 1 is represented by: H, F, Cl, Br, I, CN, NR 2 , S, SO, SO 2 , SR 2 x, PR 2 x, C1 to C5 heteroalkyl, 1 to 5 C1～C5 heteroalkyl group substituted by R 2 , C1～C10 alkyl group, C1～C10 alkyl group substituted by 1 to 5 R 2 , aryl group, aryl group substituted by 1 to 5 R 2 , 3～10 1-membered ring group, 3-10-membered ring group substituted by 1-5 R 2 , 3-10-membered heterocyclic group, 3-10-membered heterocyclic group substituted with 1-5 R 2 , ether and 1-10 membered heterocyclic group. Any one of the 5 R 2 substituted ethers;
其中所述R 2表示为：H、F、O、Cl、Br、I、CN、C1～C5烷基、芳基、环基、醚和氨中的任意一种； Wherein R 2 represents: any one of H, F, O, Cl, Br, I, CN, C1-C5 alkyl, aryl, cyclic group, ether and ammonia;
所述x选自1～4的整数；The x is selected from an integer from 1 to 4;
所述芳基选自苯基、吡啶基、吡嗪基、哒嗪基、噻吩基、噻唑基、萘基、吡咯基、呋喃基、吲哚基、喹啉基、嘌呤基和联芳基中的任意一种；The aryl group is selected from phenyl, pyridyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, naphthyl, pyrrolyl, furyl, indolyl, quinolyl, purinyl and biaryl. any kind of;
所述3～10元杂环基中的1～6个环原子独立的选自O、S和N中的任意一种。The 1 to 6 ring atoms in the 3 to 10 membered heterocyclic group are independently selected from any one of O, S and N.
所述环基包括饱和环基和不饱和环基，还包括单环和多环体系，多环体系包括螺环、并环、桥环和联环；The cyclic groups include saturated cyclic groups and unsaturated cyclic groups, and also include single and polycyclic ring systems. Polycyclic ring systems include spirocyclic rings, paracyclic rings, bridged rings and jointed rings;
所述杂环基包括饱和单杂环基、不饱和单杂环基、饱和多杂环基体系和不饱和多杂环基体系，所述多杂环基体系包括螺环、并环、桥环和联环。The heterocyclyl group includes a saturated monoheterocyclyl group, an unsaturated monoheterocyclyl group, a saturated polyheterocyclyl system and an unsaturated polyheterocyclyl system, and the polyheterocyclyl system includes a spiro ring, a paracyclic ring, and a bridged ring. and linked rings.
进一步的，所述含硫类青蒿素二聚体具有以下任一的结构：Further, the sulfur-containing artemisinin dimer has any of the following structures:
Figure PCTCN2022131906-appb-000005
Figure PCTCN2022131906-appb-000005
Figure PCTCN2022131906-appb-000006
Figure PCTCN2022131906-appb-000006
Figure PCTCN2022131906-appb-000007
Figure PCTCN2022131906-appb-000007
Figure PCTCN2022131906-appb-000008
Figure PCTCN2022131906-appb-000008
一种上述的含硫类青蒿素二聚体的制备方法，反应式如下：A method for preparing the above-mentioned sulfur-containing artemisinin dimer, the reaction formula is as follows:
Figure PCTCN2022131906-appb-000009
Figure PCTCN2022131906-appb-000009
其中，W表示为：S、SO和SO 2中的任意一种； Among them, W represents: any one of S, SO and SO 2 ;
Z表示为：S、SO、SO 2、O、NR 1和CR 1 2中的任意一种； Z represents: any one of S, SO, SO 2 , O, NR 1 and CR 1 2 ;
Y表示为：单键、烷基、芳基、环基、醚和氨中的任意一种；Y represents: any one of single bond, alkyl group, aryl group, cyclic group, ether and ammonia;
R 1表示为：氢、卤素、烷基、芳基、环基、醚和氨中的任意一种； R 1 represents: any one of hydrogen, halogen, alkyl, aryl, cyclic group, ether and ammonia;
n和m各自独立的选自：0～15的整数；n and m are each independently selected from: integers from 0 to 15;
酸选自：盐酸、硫酸、硝酸、磷酸、甲酸、乙酸、三氟乙酸、三氟化硼乙醚络合物、四氯化钛、氯化锌、三氯化铝、三氟甲磺酸三甲基硅酯和对甲苯磺酸中的任意一种；The acid is selected from: hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, boron trifluoride etherate complex, titanium tetrachloride, zinc chloride, aluminum trichloride, trimethyltrifluoromethanesulfonate Any one of silyl ester and p-toluenesulfonic acid;
上述反应式的具体反应如下：The specific reactions of the above reaction formula are as follows:
如反应式一所示，将式Ⅱ的化合物与双氢青蒿素分散于溶剂中，-78℃～25℃下，滴加酸进行反应，即得到含硫类青蒿素二聚体。As shown in reaction formula 1, the compound of formula II and dihydroartemisinin are dispersed in a solvent, and acid is added dropwise to react at -78°C to 25°C to obtain sulfur-containing artemisinin dimer.
一种上述的含硫类青蒿素二聚体的制备方法，反应式如下：A method for preparing the above-mentioned sulfur-containing artemisinin dimer, the reaction formula is as follows:
Figure PCTCN2022131906-appb-000010
Figure PCTCN2022131906-appb-000010
其中，W表示为：S、SO和SO 2中的任意一种； Among them, W represents: any one of S, SO and SO 2 ;
Z表示为：S、SO、SO 2、O、NR 1和CR 1 2中的任意一种； Z represents: any one of S, SO, SO 2 , O, NR 1 and CR 1 2 ;
Y表示为：单键、烷基、芳基、环基、醚和氨中的任意一种；Y represents: any one of single bond, alkyl group, aryl group, cyclic group, ether and ammonia;
R 1表示为：氢、卤素、烷基、芳基、环基、醚和氨中的任意一种； R 1 represents: any one of hydrogen, halogen, alkyl, aryl, cyclic group, ether and ammonia;
X表示为：卤素和类卤素中的任意一种；所述卤素选自：F、Cl、Br和I中的任意一种；所述类卤素选自：甲磺酰氧基、三氟甲磺酰氧基、对甲苯磺酰氧基、对硝基苯磺酰氧基和酰氧基中的任意一种；X represents: any one of halogen and halogen-like; the halogen is selected from: any one of F, Cl, Br and I; the halogen-like is selected from: methanesulfonyloxy, trifluoromethanesulfonate Any one of acyloxy group, p-toluenesulfonyloxy group, p-nitrobenzenesulfonyloxy group and acyloxy group;
n和m各自独立的选自：0～15的整数；n and m are each independently selected from: integers from 0 to 15;
上述反应式的具体反应如下：The specific reactions of the above reaction formula are as follows:
如反应式二所示，将双氢青蒿素硫代反应制备成式Ⅲ所示的硫代双氢青蒿素，将硫代双氢青蒿素与式Ⅳ所示的化合物反应，即得到含硫类青蒿素二聚体。As shown in reaction formula 2, dihydroartemisinin is thio-reacted to prepare thiodihydroartemisinin represented by formula III, and thiodihydroartemisinin is reacted with the compound represented by formula IV to obtain Sulfur-containing artemisinin dimers.
一种上述的含硫类青蒿素二聚体的制备方法，反应式如下：A method for preparing the above-mentioned sulfur-containing artemisinin dimer, the reaction formula is as follows:
Figure PCTCN2022131906-appb-000011
Figure PCTCN2022131906-appb-000011
其中，W表示为：S、SO和SO 2中的任意一种； Among them, W represents: any one of S, SO and SO 2 ;
Z表示为：S、SO、SO 2、O、NR 1和CR 1 2中的任意一种； Z represents: any one of S, SO, SO 2 , O, NR 1 and CR 1 2 ;
Y表示为：单键、烷基、芳基、环基、醚和氨中的任意一种；Y represents: any one of single bond, alkyl group, aryl group, cyclic group, ether and ammonia;
R 1表示为：氢、卤素、烷基、芳基、环基、醚和氨中的任意一种； R 1 represents: any one of hydrogen, halogen, alkyl, aryl, cyclic group, ether and ammonia;
TMS表示为：三甲基硅基团；TMS represents: trimethylsilyl group;
n、m各自独立的选自：0～15的整数；n and m are each independently selected from: integers from 0 to 15;
酸选自：盐酸、硫酸、硝酸、磷酸、甲酸、乙酸、三氟乙酸、三氟化硼乙醚络合物、四氯化钛、氯化锌、三氯化铝、三氟甲磺酸三甲基硅酯和对甲苯磺酸中的任意一种；The acid is selected from: hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, boron trifluoride etherate complex, titanium tetrachloride, zinc chloride, aluminum trichloride, trimethyltrifluoromethanesulfonate Any one of silyl ester and p-toluenesulfonic acid;
上述反应式的具体反应如下：The specific reactions of the above reaction formula are as follows:
如反应式三所示，将式Ⅴ所示的化合物与双氢青蒿素溶解在溶剂中，-78℃～25℃下，滴加酸反应，得到含硫类青蒿素二聚体。As shown in reaction formula 3, the compound represented by formula V and dihydroartemisinin are dissolved in a solvent, and acid is added dropwise to react at -78°C to 25°C to obtain sulfur-containing artemisinin dimers.
一种上述的含硫类青蒿素二聚体的制备方法，其特征在于，在溶剂中，A method for preparing the above-mentioned sulfur-containing artemisinin dimer, characterized in that, in a solvent,
将含低氧化态硫的含硫类青蒿素二聚体用氧化剂氧化反应，即得含高氧The sulfur-containing artemisinin dimer containing low oxidation state sulfur is oxidized with an oxidizing agent to obtain a high oxygen-containing artemisinin dimer.
化态硫的含硫类青蒿素二聚体；Sulfur-containing artemisininoid dimers of chemical sulfur;
所述氧化剂选自：臭氧、过氧化脲、双氧水、次氯酸、次氯酸盐、高氯酸、高氯酸盐、过硫酸氢盐、过硫酸盐、高锰酸盐、重铬酸盐、高碘酸、高碘酸盐和过氧有机酸中的任意一种；The oxidant is selected from: ozone, urea peroxide, hydrogen peroxide, hypochlorous acid, hypochlorite, perchloric acid, perchlorate, perhydrogen persulfate, persulfate, permanganate, and dichromate , any one of periodic acid, periodate and peroxy organic acid;
所述低氧化态硫表示为：负二价硫；The low oxidation state sulfur is expressed as: negative divalent sulfur;
所述高氧化态硫表示为：SO或SO 2。 The highly oxidized sulfur is expressed as: SO or SO 2 .
一种上述的含硫类青蒿素二聚体在制备抗肿瘤药物中的应用。An application of the above-mentioned sulfur-containing artemisinin dimer in the preparation of anti-tumor drugs.
该抗肿瘤药物应用的病理状态是癌，包括但不限于白血病、肺癌、肝癌、乳腺癌、结肠癌、胃癌、卵巢癌、宫颈癌等The pathological state for which the anti-tumor drug is applied is cancer, including but not limited to leukemia, lung cancer, liver cancer, breast cancer, colon cancer, gastric cancer, ovarian cancer, cervical cancer, etc.
本发明上述的含硫类青蒿素二聚体可与已知抗癌药物联合使用，如紫杉醇、依托泊苷、顺铂等。The above-mentioned sulfur-containing artemisinin dimer of the present invention can be used in combination with known anti-cancer drugs, such as paclitaxel, etoposide, cisplatin, etc.
本发明所述的含硫类青蒿素二聚体可与其他癌症疗法联合使用，如放疗和骨髓移植。The sulfur-containing artemisinin dimers of the present invention can be used in combination with other cancer therapies, such as radiotherapy and bone marrow transplantation.
定义和说明：Definition and Description:
除非另有说明，本发明所用的下列术语和短语旨在具有下列含义；一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义取理解。Unless otherwise indicated, the following terms and phrases used in this invention are intended to have the following meanings; a particular term or phrase should not be considered uncertain or unclear in the absence of a particular definition, but should be treated in accordance with ordinary Meaning comes from understanding.
当本文中出现商品名时，意在指代其对用的商品或活性成分。Where a trade name appears herein, it is intended to refer to the trade name or active ingredient for which it is intended.
本文中用到的额术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于人或动物的组织接触适用，而没有过多的毒性、刺激性、过敏性反应或其他的问题或并发症，与合理的利益/风险比相称。The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for contact with human or animal tissue. Suitable for use without undue toxicity, irritation, allergic reactions or other problems or complications and commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。The term "pharmaceutically acceptable salts" refers to salts of compounds of the present invention prepared from compounds having specific substituents found in the present invention and relatively non-toxic acids or bases.
当本发明的化合物中含有相对酸性的官能团时，可以通过在溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括但不限于钠、钾、钙、铵、有机氨、镁盐或类似的盐。When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, ammonium, organic ammonia, magnesium salts or similar salts.
当本发明的化合物中含有相对碱性的官能团时，可以通过在溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐包括无机酸盐、有机酸盐。其中无机酸包括但不限于盐酸、氢溴酸、氢碘酸、氢氟酸、硝酸、碳酸、碳酸氢根、磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、亚硫酸、亚磷酸等；有机酸包括但不限于甲酸、乙 酸、丙酸、丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸、甲磺酸、乙磺酸、氨基酸、葡萄糖醛酸等类似的酸。When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a solvent. Pharmaceutically acceptable acid addition salts include inorganic acid salts and organic acid salts. Inorganic acids include but are not limited to hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, sulfurous acid, Phosphorous acid, etc.; organic acids include but are not limited to formic acid, acetic acid, propionic acid, butyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, butenedioic acid, lactic acid, mandelic acid, phthalic acid Dicarboxylic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, amino acids, glucuronic acid and other similar acids.
本发明的某些特定化合物含有酸性和碱性官能团，从而可以被转换成任一碱或酸加成的盐。Certain specific compounds of the present invention contain both acidic and basic functional groups and thus can be converted into either base or acid addition salts.
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形成这些化合物与化学计量的适当的碱或酸反应来制备。The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases. In general, such salts are prepared by reacting these compounds via the free acid or base formation with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
除了盐的形式，本发明所提供的化合物还存在前药形式。本发明所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。In addition to salt forms, the compounds provided by the invention also exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert them into compounds of the invention. In addition, prodrugs can be converted to compounds of the invention by chemical or biochemical methods in the in vivo environment.
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms. In general, solvated and unsolvated forms are equivalent to each other and are included within the scope of the present invention.
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomeric or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。Unless otherwise stated, the terms "enantiomers" or "optical isomers" refer to stereoisomers that are mirror images of each other.
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或 者成环碳原子单键不能自由旋转而引起。Unless otherwise stated, the term "cis-trans isomers" or "geometric isomers" refers to the inability of the double bonds or single bonds of the carbon atoms in the ring to rotate freely.
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。Unless otherwise stated, the term "diastereomer" refers to stereoisomers whose molecules have two or more chiral centers and are in a non-mirror image relationship between the molecules.
除非另有说明，“(D)”或者“(+)”表示右旋，“(L)”或者“(-)”表示左旋，“(DL)”或者“(±)”表示外消旋。Unless otherwise stated, "(D)" or "(+)" means dextrorotary, "(L)" or "(-)" means levorotary, and "(DL)" or "(±)" means racemic.
除非另有说明，用楔形实线键
Figure PCTCN2022131906-appb-000012
和楔形虚线键
Figure PCTCN2022131906-appb-000013
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2022131906-appb-000014
和直形虚线键
Figure PCTCN2022131906-appb-000015
表示立体中心的相对构型，用波浪线
Figure PCTCN2022131906-appb-000016
表示立体化学构型不确定或不固定或其为混合物。 Unless otherwise stated, use wedge-shaped solid line keys
Figure PCTCN2022131906-appb-000012
and wedge-shaped dotted keys
Figure PCTCN2022131906-appb-000013
Represents the absolute configuration of a three-dimensional center, using straight solid line keys
Figure PCTCN2022131906-appb-000014
and straight dotted keys
Figure PCTCN2022131906-appb-000015
Represent the relative configuration of the three-dimensional center with a wavy line
Figure PCTCN2022131906-appb-000016
Indicates that the stereochemical configuration is uncertain or not fixed or that it is a mixture.
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D-和L-异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通对使用色谱法完成的，所色谱法来用手性固定相，并任选地与化学衍生相结合(例如由胺生成氨基甲酸盐)。Optically active (R)- and (S)-isomers as well as D- and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliaries, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with a suitable optically active acid or base, and then the salt is formed by conventional methods known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereoisomers is usually accomplished by using chromatography with a chiral stationary phase, optionally combined with chemical derivatization (e.g. generated from amines). carbamate).
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。 The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C). For another example, deuterated drugs can be replaced by heavy hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce side effects and increase drug stability. , enhance efficacy, extend drug biological half-life and other advantages. All variations in the isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必 需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。The terms "optionally" or "optionally" mean that the subsequently described event or condition may, but need not, occur, and that the description includes instances in which the stated event or condition occurs and instances in which it does not. .
术语“被取代的”是指特定原子上的任意一个或多个氢原于被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。The term "substituted" means that any one or more hydrogens on a particular atom are replaced by a substituent, which may include deuterium and variants of hydrogen, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e. =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical achievability.
当任何变量(例如R 1)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0～2个R 1所取代，则所述基团可以任选地至多被两个R 1所取代，并且每种情况下的R 1都有独立的选项。此外，取代基和/或其变体的组合只有在这梯的组合会产生稳定的化合物的情况下才是被允许的。 When any variable (eg, R1 ) occurs more than once in the composition or structure of a compound, its definition in each instance is independent. Thus, for example, if a group is substituted by 0 to 2 R 1 , then said group may optionally be substituted with up to two R 1 s, with independent options for R 1 in each case. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
当一个连接基团的数量为0时，比如-(CR 1 2) 0-，表示该连接基团为单键。 When the number of a linking group is 0, such as -(CR 1 2 ) 0 -, it means that the linking group is a single bond.
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比A-L-B中L代表单键时表示该结构实际上是A-B。When one of the variables is selected from a single bond, it means that the two groups it is connected to are directly connected. Compared with A-L-B, when L represents a single bond, it means that the structure is actually A-B.
当一个取代基为空缺时，表示该取代基是不存在的，比如A-C中C为空缺时表示该结构实际上是A。When a substituent is vacant, it means that the substituent does not exist. For example, when C in A-C is vacant, it means that the structure is actually A.
当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。当所列举的连接基团没有指明其连接方向，其连接方向是任意的。When the listed substituent does not specify which atom it is connected to the substituted group through, the substituent can be bonded through any atom thereof. For example, a pyridyl group as a substituent can be bonded through any one of the pyridine rings. The carbon atom is attached to the substituted group. When the listed linking groups do not specify the direction of attachment, the direction of attachment is arbitrary.
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
除非另有规定，术语“C1～C10烷基”用于表示直链或支链的由1至10 个碳原子组成的饱和碳氢基团。其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。Unless otherwise specified, the term "C1-C10 alkyl" is used to represent a straight-chain or branched saturated hydrocarbon group consisting of 1 to 10 carbon atoms. It may be monovalent (eg methyl), divalent (eg methylene) or polyvalent (eg methine).
本发明中术语“芳基”指任何从简单芳香环衍生出的官能团或取代基。包括但不限于苯基、联苯基、吡啶基、吡嗪基、哒嗪基、噻吩基、噻唑基、萘基、吡咯基、呋喃基、吲哚基、喹啉基、嘌呤基等，所选芳基可任选两个C原子与主结构中-(CR 1 2) n-相连，其余原子可任选被1～5个R 1取代； The term "aryl" as used herein refers to any functional group or substituent derived from a simple aromatic ring. Including but not limited to phenyl, biphenyl, pyridyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, naphthyl, pyrrolyl, furyl, indolyl, quinolyl, purinyl, etc., so When selecting an aryl group, two C atoms can be optionally connected to -(CR 1 2 ) n - in the main structure, and the remaining atoms can be optionally substituted by 1 to 5 R 1 ;
本发明中术语“3～10元环基”指由3～10个碳原子组成的饱和或不饱和环状基团；其中包括单环和多环体系，多环体系包括螺环、并环、桥环和联环。除与主结构中-(CR 1 2) n-相连原子外，其余原子可任选被1～2个R 1取代；不饱和环基指含有1～3个不饱和键的非芳基基团。 The term "3- to 10-membered cyclic group" in the present invention refers to a saturated or unsaturated cyclic group composed of 3 to 10 carbon atoms; including monocyclic and polycyclic systems, and polycyclic systems include spirocyclic, paracyclic, and Bridge rings and linked rings. Except for the atoms connected to -(CR 1 2 ) n - in the main structure, the remaining atoms can be optionally substituted by 1 to 2 R 1 ; unsaturated cyclic group refers to a non-aryl group containing 1 to 3 unsaturated bonds. .
本发明中术语“3～10元杂环基”指由3～10个碳原子组成的饱和或不饱和环状基团，其1～6个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和SO t,t是1或2)。其包括单环和多环体系，其中多环体系包括螺环、并环、桥环和联环。此外，就该“3～10元杂环基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。除与主结构中-(CR 1 2) n-相连原子外，其余碳原子可任选被1～2个R 1取代；不饱和环基指含有1～3个不饱和键的非芳基基团。所述螺环为相邻两个单环共用一个原子；所述并环为两个以上单环并合在一起，所并合的两个单环中，一个单环上相邻两个原子与另一个单环的相邻两个原子共用；所述桥环为共用两个以上原子的多环结构；所述联环为两个以上的单环各一个单环上的原子以单键或双键相连。 The term "3-10 membered heterocyclyl" in the present invention refers to a saturated or unsaturated cyclic group composed of 3-10 carbon atoms, of which 1-6 ring atoms are independently selected from O, S and N. atoms, the remainder being carbon atoms, of which nitrogen atoms are optionally quaternized, and nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and SO t , t is 1 or 2). It includes single-ring and multi-ring systems, and the multi-ring system includes spiro ring, parallel ring, bridged ring and double ring. In addition, in the case of the "3- to 10-membered heterocyclic group", a heteroatom may occupy the connection position between the heterocycloalkyl group and the rest of the molecule. Except for the atom connected to -(CR 1 2 ) n - in the main structure, the remaining carbon atoms can be optionally substituted by 1 to 2 R 1 ; unsaturated cyclic group refers to a non-aryl group containing 1 to 3 unsaturated bonds. group. The spiro ring is two adjacent single rings sharing one atom; the merged ring is two or more single rings merged together. Among the two merged single rings, two adjacent atoms on one single ring are the same. Two adjacent atoms of another single ring are shared; the bridged ring is a polycyclic structure that shares two or more atoms; the linked ring is two or more single rings, and each of the atoms on the single ring is connected by a single bond or a double bond. key connected.
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。The structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制 备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and methods well known to those skilled in the art. Equivalent alternatives and preferred embodiments include, but are not limited to, embodiments of the present invention.
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水溶液；eq代表当量、等量；M或N代表mol/L或mmol/mL；DHA代表双氢青蒿素，即(3R,5αS,6R,8αS,9R,10S,12R,12αR)-八氢-3,6,9-三甲基-3,12-桥氧-12H-吡喃并[4,3-j]-1,2-苯并二噻平-10(3H)-醇；SDHA-A代表α硫代双氢青蒿素，即(3R,5αS,6R,8αS,9R,10R,12R,12αR)-八氢-3,6,9-三甲基-3,12-桥氧-12H-吡喃并[4,3-j]-1,2-苯并二噻平-10(3H)-硫醇；SDHA-B代表β硫代双氢青蒿素，即(3R,5αS,6R,8αS,9R,10S,12R,12αR)-八氢-3,6,9-三甲基-3,12-桥氧-12H-吡喃并[4,3-j]-1,2-苯并二噻平-10(3H)-硫醇；DCM代表二氯甲烷；PE代表石油醚；DMF代表N,N-二甲基甲酰胺；DMSO代表二甲基亚砜/氘代二甲基亚砜(即DMSO-d6)；EA代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；THF代表四氢呋喃；Et 2O代表乙醚；Et 3N代表三乙胺；CCl 4代表四氯化碳；CDCl 3代表氘代氯仿；MeOD代表氘代甲醇(即MeOH-d4)；DIAD代表偶氮二羧酸二异丙酯；SOCl 2代表氯化亚砜；Ts0H代表对甲苯磺酸；LiAlH 4代表四氢铝锂；AcOH代表乙酸；DMAP代表4-二甲氨基吡啶；Ac 2O代表乙酸酐；NaOH代表氢氧化钠；BF 3·Et 2O代表三氟化硼乙醚；AcSK代表硫代乙酸钾；MsCl代表甲磺酰氯；NaBH 4代表硼氢化钠；Cs 2CO 3代表碳酸铯；K 2CO 3代表碳酸钾；Na 2CO 3代表碳酸钠；DIBAH代表二异丁基氢化铝；AIBN代表偶氮二异丁腈；NBS代表溴代丁二酰亚胺；NaOCl代表次氯酸钠；TFAA代表三氟乙酸酐；UHP代表过氧化脲。 The solvent used in the present invention is commercially available. The present invention adopts the following abbreviations: aq represents aqueous solution; eq represents equivalent, equal amount; M or N represents mol/L or mmol/mL; DHA represents dihydroartemisinin, that is, (3R, 5αS, 6R, 8αS, 9R,10S,12R,12αR)-octahydro-3,6,9-trimethyl-3,12-oxo-12H-pyrano[4,3-j]-1,2-benzodithiane Ping-10(3H)-ol; SDHA-A stands for α-thiodihydroartemisinin, that is, (3R,5αS,6R,8αS,9R,10R,12R,12αR)-octahydro-3,6,9- Trimethyl-3,12-oxo-12H-pyrano[4,3-j]-1,2-benzodithiopin-10(3H)-thiol; SDHA-B stands for β-thiobis Hydroartemisinin, namely (3R,5αS,6R,8αS,9R,10S,12R,12αR)-octahydro-3,6,9-trimethyl-3,12-oxo-12H-pyrano[ 4,3-j]-1,2-Benzodithiopin-10(3H)-thiol; DCM represents dichloromethane; PE represents petroleum ether; DMF represents N,N-dimethylformamide; DMSO represents Dimethyl sulfoxide/deuterated dimethyl sulfoxide (i.e. DMSO-d6); EA represents ethyl acetate; EtOH represents ethanol; MeOH represents methanol; THF represents tetrahydrofuran; Et 2 O represents diethyl ether; Et 3 N represents triethyl Amine; CCl 4 represents carbon tetrachloride; CDCl 3 represents deuterated chloroform; MeOD represents deuterated methanol (MeOH-d4); DIAD represents diisopropyl azodicarboxylate; SOCl 2 represents sulfoxide chloride; TsOH represents p-toluenesulfonic acid; LiAlH 4 represents lithium aluminum tetrahydride; AcOH represents acetic acid; DMAP represents 4-dimethylaminopyridine; Ac 2 O represents acetic anhydride; NaOH represents sodium hydroxide; BF 3 ·Et 2 O represents trifluoride Boron ether; AcSK represents potassium thioacetate; MsCl represents methanesulfonyl chloride; NaBH 4 represents sodium borohydride; Cs 2 CO 3 represents cesium carbonate; K 2 CO 3 represents potassium carbonate; Na 2 CO 3 represents sodium carbonate; DIBAH represents dihydrogen Isobutylaluminum hydride; AIBN represents azobisisobutyronitrile; NBS represents bromosuccinimide; NaOCl represents sodium hypochlorite; TFAA represents trifluoroacetic anhydride; UHP represents urea peroxide.
化合物依据本领域常规命名原则命名,市售化合物采用供应商目录名称。Compounds were named according to conventional naming principles in this field, and commercially available compounds were named using supplier catalog names.
具体实施方式Detailed ways
以下对本发明的原理和特征进行描述，所举实例只用于解释本发明，并非用于限定本发明的范围。The principles and features of the present invention are described below. The examples cited are only used to explain the present invention and are not intended to limit the scope of the present invention.
实施例1：化合物1的制备Example 1: Preparation of Compound 1
Figure PCTCN2022131906-appb-000017
Figure PCTCN2022131906-appb-000017
1、将双氢青蒿素(100.00g，351.68mmol，1.00eq)和硫代乙酸(53.53g，703.35mmol，2.00eq)加入到1.2L的DCM中，降温至0℃，滴加三氟化硼乙醚(47.7mL，386.84mmol，1.10eq)，滴加完毕后，反应移至室温搅拌30min。TCL(20％EA/PE)显示原料消失，纯化得到12.00g的SDHA-A1和35.50g的SDHA-B1，合并收率为39％。1. Add dihydroartemisinin (100.00g, 351.68mmol, 1.00eq) and thioacetic acid (53.53g, 703.35mmol, 2.00eq) to 1.2L of DCM, cool to 0°C, and add trifluoride dropwise After the dropwise addition of boron ether (47.7 mL, 386.84 mmol, 1.10 eq) was completed, the reaction was moved to room temperature and stirred for 30 min. TCL (20% EA/PE) showed that the raw materials disappeared, and 12.00g of SDHA-A1 and 35.50g of SDHA-B1 were obtained after purification, with a combined yield of 39%.
2、将SDHA-A1(12.00g，35.04mmol，1.0eq)溶于120mL的95％乙醇中，降温至0℃，滴加26.3mL的2M氢氧化钠水溶液，反应在0℃下搅拌1.5h；反应液倒入500mL水中，滴加柠檬酸水溶液至体系呈弱酸性，纯化得到24.50g白色固体SDHA-A，收率80％。2. Dissolve SDHA-A1 (12.00g, 35.04mmol, 1.0eq) in 120mL of 95% ethanol, cool to 0°C, add 26.3mL of 2M sodium hydroxide aqueous solution dropwise, and stir the reaction at 0°C for 1.5h; The reaction solution was poured into 500 mL of water, and citric acid aqueous solution was added dropwise until the system became weakly acidic. After purification, 24.50 g of white solid SDHA-A was obtained with a yield of 80%.
3、将SDHA-B1(35.00g，102.20mmol，1.00eq)溶于350mL的95％乙醇中，降温至0℃，滴加76.7mL的2M氢氧化钠溶液，反应在0℃下搅拌1.5h；反应液倒入1500mL水中，滴加柠檬酸水溶液至体系呈弱酸性，纯化得到8.60g白色固体SDHA-B，收率82％。3. Dissolve SDHA-B1 (35.00g, 102.20mmol, 1.00eq) in 350mL of 95% ethanol, cool to 0°C, add 76.7mL of 2M sodium hydroxide solution dropwise, and stir the reaction at 0°C for 1.5h; The reaction solution was poured into 1500 mL of water, and citric acid aqueous solution was added dropwise until the system became weakly acidic. After purification, 8.60 g of white solid SDHA-B was obtained with a yield of 82%.
4、将SDHA-A(200mg，0.67mmol，1.00eq)或SDHA-A(200mg，0.67mmol，1.00eq)，和三乙胺(101mg，1.00mmol，1.50eq)加入到2mL的DCM中，降温至0℃；将I 2(85mg，0.33mmol，0.50eq)溶解在1mL的DCM中滴加至反应中， 反应在室温下搅拌2h。TCL(20％EA/PE)显示原料消失，纯化得到150mg化合物1A，收率为75％；得到162mg的化合物1B，收率81％。 4. Add SDHA-A (200mg, 0.67mmol, 1.00eq) or SDHA-A (200mg, 0.67mmol, 1.00eq) and triethylamine (101mg, 1.00mmol, 1.50eq) into 2mL of DCM and cool down. to 0°C; I 2 (85 mg, 0.33 mmol, 0.50 eq) was dissolved in 1 mL of DCM and added dropwise to the reaction, and the reaction was stirred at room temperature for 2 h. TCL (20% EA/PE) showed that the raw materials disappeared. After purification, 150 mg of compound 1A was obtained with a yield of 75%; 162 mg of compound 1B was obtained with a yield of 81%.
化合物1的核磁结果如下：The NMR results of compound 1 are as follows:
化合物1A: 1HNMR(500MHz,CDCl 3)δ5.29(s,2H),4.73(d,J＝10.8Hz,2H),2.75–2.67(m,2H),2.40–2.32(m,2H),2.04–1.97(m,2H),1.90–1.83(m,2H),1.73(d,J＝3.9Hz,2H),1.69–1.61(m,3H),1.48–1.44(m,1H),1.42–1.39(m,7H),1.36(d,J＝3.4Hz,1H),1.29–1.22(m,5H),0.97-0.91(m,15H). Compound 1A: 1 HNMR (500MHz, CDCl 3 ) δ5.29 (s, 2H), 4.73 (d, J = 10.8Hz, 2H), 2.75–2.67 (m, 2H), 2.40–2.32 (m, 2H), 2.04–1.97(m,2H),1.90–1.83(m,2H),1.73(d,J＝3.9Hz,2H),1.69–1.61(m,3H),1.48–1.44(m,1H),1.42– 1.39(m,7H),1.36(d,J＝3.4Hz,1H),1.29–1.22(m,5H),0.97-0.91(m,15H).
化合物1B: 1HNMR(500MHz,CDCl 3)δ5.56(s,2H),5.25(d,J＝5.3Hz,2H),3.04(d,J＝7.0Hz,2H),2.36(d,J＝3.8Hz,2H),2.05(s,2H),1.91–1.84(m,2H),1.76–1.66(m,4H),1.57(d,J＝3.0Hz,1H),1.50(dd,J＝7.0,4.9Hz,3H),1.44(s,5H),1.37(d,J＝3.6Hz,1H),1.25(d,J＝5.9Hz,7H),1.01(d,J＝7.3Hz,5H),0.95(d,J＝6.4Hz,6H),0.88–0.85(m,2H). Compound 1B: 1 HNMR (500MHz, CDCl 3 ) δ5.56 (s, 2H), 5.25 (d, J = 5.3Hz, 2H), 3.04 (d, J = 7.0Hz, 2H), 2.36 (d, J = 3.8Hz,2H),2.05(s,2H),1.91–1.84(m,2H),1.76–1.66(m,4H),1.57(d,J＝3.0Hz,1H),1.50(dd,J＝7.0 ,4.9Hz,3H),1.44(s,5H),1.37(d,J＝3.6Hz,1H),1.25(d,J＝5.9Hz,7H),1.01(d,J＝7.3Hz,5H), 0.95(d,J＝6.4Hz,6H),0.88–0.85(m,2H).
实施例2：化合物2的制备Example 2: Preparation of Compound 2
Figure PCTCN2022131906-appb-000018
Figure PCTCN2022131906-appb-000018
将DHA(500mg，0.76mmol，1.00eq)和二巯基甲烷(71mg，0.88mmol，0.50eq)加入到10mL乙醚中，降温至0℃，滴加三氟化硼乙醚(250mg，1.76mmol，1.00eq)，反应在0℃下搅拌1h后移至室温下搅拌过夜，TCL(20％EA/PE)显示原料消失，纯化得到108mg化合物2A和102mg化合物2B。Add DHA (500 mg, 0.76 mmol, 1.00 eq) and dimercaptomethane (71 mg, 0.88 mmol, 0.50 eq) into 10 mL of diethyl ether, cool to 0°C, and add boron trifluoride diethyl ether (250 mg, 1.76 mmol, 1.00 eq) dropwise. ), the reaction was stirred at 0°C for 1 h and then moved to room temperature and stirred overnight. TCL (20% EA/PE) showed that the raw materials disappeared, and 108 mg of compound 2A and 102 mg of compound 2B were obtained after purification.
化合物2的核磁结果如下：The NMR results of compound 2 are as follows:
化合物2A： 1HNMR(500MHz,CDCl 3)δ5.30(s,2H),4.72(d,J＝10.6Hz,2H),3.43(s,2H),2.77–2.63(m,2H),2.41–2.30(m,2H),2.14–1.99(m,2H),1.9 0–1.83(m,2H),1.76-1.71(m,2H),1.69–1.61(m,3H),1.48-1.36(m,9H),1.30–1.21(m,5H),0.97-0.84(m,15H). Compound 2A: 1 HNMR (500MHz, CDCl 3 ) δ5.30 (s, 2H), 4.72 (d, J = 10.6Hz, 2H), 3.43 (s, 2H), 2.77–2.63 (m, 2H), 2.41– 2.30(m,2H),2.14–1.99(m,2H),1.9 0–1.83(m,2H),1.76-1.71(m,2H),1.69–1.61(m,3H),1.48-1.36(m, 9H),1.30–1.21(m,5H),0.97-0.84(m,15H).
化合物2B： 1HNMR(500MHz,CDCl 3)δ5.57(s,2H),5.26(d,J＝5.4Hz,2H),3.44(s,2H),3.01(d,J＝7.0Hz,2H),2.31(d,J＝3.8Hz,2H),2.06(s,2H),1.90–1.84(m,2H),1.75–1.67(m,4H),1.56(d,J＝3.0Hz,1H),1.51(dd,J＝7.0,4.9Hz,3H),1.44-1.40(m,5H),1.38(d,J＝3.6Hz,1H),1.22(d,J＝5.8Hz,7H),1.01(d,J＝7.0Hz,5H),0.97(d,J＝6.6Hz,6H),0.90–0.85(m,2H). Compound 2B: 1 HNMR (500MHz, CDCl 3 ) δ5.57 (s, 2H), 5.26 (d, J = 5.4Hz, 2H), 3.44 (s, 2H), 3.01 (d, J = 7.0Hz, 2H) ,2.31(d,J＝3.8Hz,2H),2.06(s,2H),1.90–1.84(m,2H),1.75–1.67(m,4H),1.56(d,J＝3.0Hz,1H), 1.51(dd,J＝7.0,4.9Hz,3H),1.44-1.40(m,5H),1.38(d,J＝3.6Hz,1H),1.22(d,J＝5.8Hz,7H),1.01(d ,J＝7.0Hz,5H),0.97(d,J＝6.6Hz,6H),0.90–0.85(m,2H).
实施例3：化合物3的制备Example 3: Preparation of Compound 3
Figure PCTCN2022131906-appb-000019
Figure PCTCN2022131906-appb-000019
如实施例2，原料采用1,2-乙二硫醇(83mg，0.88mmol，0.50eq)，制得得到196mg化合物3A和165mg化合物3B。As in Example 2, 1,2-ethanedithiol (83 mg, 0.88 mmol, 0.50 eq) was used as the raw material to obtain 196 mg of compound 3A and 165 mg of compound 3B.
化合物3A和化合物3B的核磁结果如下：The NMR results of compound 3A and compound 3B are as follows:
化合物3A： 1HNMR(500MHz,CDCl 3)δ5.30(s,2H),4.72(d,J＝10.6Hz,2H),2.75–2.67(m,6H),2.41–2.32(m,2H),2.03–1.97(m,2H),1.90–1.83(m,2H),1.72(d,J＝3.9Hz,2H),1.69–1.63(m,3H),1.48–1.43(m,1H),1.41–1.39(m,7H),1.37(d,J＝3.4Hz,1H),1.28–1.22(m,5H),0.96-0.91(m,15H). Compound 3A: 1 HNMR (500MHz, CDCl 3 ) δ5.30 (s, 2H), 4.72 (d, J = 10.6Hz, 2H), 2.75–2.67 (m, 6H), 2.41–2.32 (m, 2H), 2.03–1.97(m,2H),1.90–1.83(m,2H),1.72(d,J＝3.9Hz,2H),1.69–1.63(m,3H),1.48–1.43(m,1H),1.41– 1.39(m,7H),1.37(d,J＝3.4Hz,1H),1.28–1.22(m,5H),0.96-0.91(m,15H).
化合物3B： 1HNMR(500MHz,CDCl 3)δ5.57(s,2H),5.24(d,J＝5.3Hz,2H),3.04(d,J＝7.0Hz,2H),2.71–2.68(m,4H),2.37(d,J＝3.8Hz,2H),2.05(s,2H),1.90–1.84(m,2H),1.74–1.68(m,4H),1.57(d,J＝3.0Hz,1H),1.51(dd,J＝7.0,4.9Hz,3H),1.43(s,5H),1.38(d,J＝3.6Hz,1H),1.25(d,J＝5.9Hz,7H),1.00(d,J＝7.3Hz,5H),0.94(d,J＝6.4Hz,6H),0.88–0.85(m,2H). Compound 3B: 1 HNMR (500MHz, CDCl 3 ) δ5.57 (s, 2H), 5.24 (d, J = 5.3Hz, 2H), 3.04 (d, J = 7.0Hz, 2H), 2.71–2.68 (m, 4H),2.37(d,J＝3.8Hz,2H),2.05(s,2H),1.90–1.84(m,2H),1.74–1.68(m,4H),1.57(d,J＝3.0Hz,1H ),1.51(dd,J＝7.0,4.9Hz,3H),1.43(s,5H),1.38(d,J＝3.6Hz,1H),1.25(d,J＝5.9Hz,7H),1.00(d ,J＝7.3Hz,5H),0.94(d,J＝6.4Hz,6H),0.88–0.85(m,2H).
实施例4：化合物4的制备Example 4: Preparation of Compound 4
Figure PCTCN2022131906-appb-000020
Figure PCTCN2022131906-appb-000020
如实施例2，原料采用1,3-丙二硫醇(1.00g，9.24mmol，1.00eq)，得到1.13g的化合物4A和2.51g的化合物4B，合并收率61％，化合物4A和化合物4B均为白色固体。As in Example 2, 1,3-propanedithiol (1.00g, 9.24mmol, 1.00eq) was used as the raw material to obtain 1.13g of compound 4A and 2.51g of compound 4B. The combined yield was 61%. Compound 4A and compound 4B All are white solids.
化合物4的核磁结果如下：The NMR results of compound 4 are as follows:
化合物4A： 1HNMR(600MHz,CDCl 3)δ5.27(s,2H),4.54(d,J＝10.7Hz,2H),2.96–2.86(m,2H),2.80–2.68(m,2H),2.64–2.55(m,2H),2.35(td,J＝14.0,3.9Hz,2H),2.08–1.98(m,4H),1.91–1.83(m,2H),1.76–1.67(m,4H),1.58(m,2H),1.51–1.29(m,12H),1.24(m,2H),1.07–0.98(m,2H),0.95(d,J＝6.3Hz,6H),0.92(d,J＝7.1Hz,6H). Compound 4A: 1 HNMR (600MHz, CDCl 3 ) δ5.27 (s, 2H), 4.54 (d, J = 10.7Hz, 2H), 2.96–2.86 (m, 2H), 2.80–2.68 (m, 2H), 2.64–2.55(m,2H),2.35(td,J＝14.0,3.9Hz,2H),2.08–1.98(m,4H),1.91–1.83(m,2H),1.76–1.67(m,4H), 1.58(m,2H),1.51–1.29(m,12H),1.24(m,2H),1.07–0.98(m,2H),0.95(d,J＝6.3Hz,6H),0.92(d,J＝ 7.1Hz,6H).
化合物4B： 1HNMR(600MHz,CDCl 3)δ5.61(s,2H),5.28–5.23(m,2H),3.03(dd,J＝12.0,5.2Hz,2H),2.83–2.72(m,4H),2.37(m,2H),2.07–1.93(m,4H),1.91–1.78(m,4H),1.75–1.63(m,6H),1.55–1.47(m,4H),1.47–1.37(m,8H),1.25(m,2H),1.00–0.90(m,12H). Compound 4B: 1 HNMR (600MHz, CDCl 3 ) δ5.61 (s, 2H), 5.28–5.23 (m, 2H), 3.03 (dd, J = 12.0, 5.2Hz, 2H), 2.83–2.72 (m, 4H) ),2.37(m,2H),2.07–1.93(m,4H),1.91–1.78(m,4H),1.75–1.63(m,6H),1.55–1.47(m,4H),1.47–1.37(m ,8H),1.25(m,2H),1.00–0.90(m,12H).
实施例5：化合物5的制备Example 5: Preparation of Compound 5
Figure PCTCN2022131906-appb-000021
Figure PCTCN2022131906-appb-000021
如实施例2，原料采用将1,4-丁二硫醇(1.00g，8.18mmol，1.00eq)， 得到1.08g化合物5A和2.33g化合物5B，合并收率65％，化合物5A和化合物5B均为白色固体。As in Example 2, 1,4-butanedithiol (1.00g, 8.18mmol, 1.00eq) was used as raw material to obtain 1.08g of compound 5A and 2.33g of compound 5B. The combined yield was 65%. Compound 5A and compound 5B were both It is a white solid.
化合物5的核磁结果如下：The NMR results of compound 5 are as follows:
化合物5A： 1HNMR(600MHz,CDCl 3)δ5.28(s,2H),4.53(d,J＝10.7Hz,2H),2.80(dd,J＝12.5,5.3Hz,2H),2.71–2.63(m,2H),2.59(ddd,J＝11.0,9.3,5.8Hz,2H),2.36(td,J＝14.0,3.8Hz,2H),2.01(d,J＝14.2Hz,2H),1.91–1.83(m,2H),1.82–1.75(m,4H),1.74–1.68(m,4H),1.58(dt,J＝13.5,4.0Hz,2H),1.52–1.30(m,12H),1.24(dt,J＝11.3,6.9Hz,2H),1.08–0.98(m,2H),0.95(d,J＝6.3Hz,6H),0.92(d,J＝7.1Hz,6H). Compound 5A: 1 HNMR (600MHz, CDCl 3 ) δ5.28 (s, 2H), 4.53 (d, J = 10.7Hz, 2H), 2.80 (dd, J = 12.5, 5.3Hz, 2H), 2.71–2.63 ( m,2H),2.59(ddd,J＝11.0,9.3,5.8Hz,2H),2.36(td,J＝14.0,3.8Hz,2H),2.01(d,J＝14.2Hz,2H),1.91–1.83 (m,2H),1.82–1.75(m,4H),1.74–1.68(m,4H),1.58(dt,J＝13.5,4.0Hz,2H),1.52–1.30(m,12H),1.24(dt ,J＝11.3,6.9Hz,2H),1.08–0.98(m,2H),0.95(d,J＝6.3Hz,6H),0.92(d,J＝7.1Hz,6H).
13CNMR(151MHz,CDCl 3)δ104.26,92.25,80.51,80.41,51.83,46.09,37.37,36.30,34.10,31.83,29.10,28.03,26.00,24.77,21.31,20.26,15.10. 13 CNMR (151MHz, CDCl 3 ) δ104.26,92.25,80.51,80.41,51.83,46.09,37.37,36.30,34.10,31.83,29.10,28.03,26.00,24.77,21.31,20.26,15.10.
化合物5B： 1HNMR(600MHz,CDCl 3)δ5.61(s,2H),5.27(d,J＝5.2Hz,2H),3.07–2.99(m,2H),2.69(m,4H),2.37(td,J＝14.1,3.6Hz,2H),2.04(dd,J＝14.6,2.9Hz,2H),1.92–1.79(m,4H),1.77–1.63(m,8H),1.55–1.47(m,4H),1.45–1.34(m,10H),1.25(m,2H),0.99–0.90(m,12H). Compound 5B: 1 HNMR (600MHz, CDCl 3 ) δ5.61 (s, 2H), 5.27 (d, J = 5.2Hz, 2H), 3.07–2.99 (m, 2H), 2.69 (m, 4H), 2.37 ( td,J＝14.1,3.6Hz,2H),2.04(dd,J＝14.6,2.9Hz,2H),1.92–1.79(m,4H),1.77–1.63(m,8H),1.55–1.47(m, 4H),1.45–1.34(m,10H),1.25(m,2H),0.99–0.90(m,12H).
13CNMR(151MHz,CDCl 3)δ104.19,92.25,88.01,86.70,81.17,80.56,80.39,52.71,45.19,37.21,36.44,34.4432.25,32.08,28.97,26.18,24.62,24.37,20.33,14.85. 13 CNMR (151MHz, CDCl 3 ) δ104.19,92.25,88.01,86.70,81.17,80.56,80.39,52.71,45.19,37.21,36.44,34.4432.25,32.08,28.97,26.18,24.62,24.3 7,20.33,14.85.
实施例6：化合物6的制备Example 6: Preparation of Compound 6
Figure PCTCN2022131906-appb-000022
Figure PCTCN2022131906-appb-000022
如实施例2，原料采用1,5-戊二硫醇(1.00g，7.34mmol，1.00eq)，得到0.90g的化合物6A、1.60g的化合物6B和1.20g的化合物6C，合并收率 75％，化合物6A、化合物6B和化合物6C均为白色固体。As in Example 2, 1,5-pentanedithiol (1.00g, 7.34mmol, 1.00eq) was used as the raw material to obtain 0.90g of compound 6A, 1.60g of compound 6B and 1.20g of compound 6C. The combined yield was 75%. , Compound 6A, Compound 6B and Compound 6C are all white solids.
化合物6的核磁结果如下：The NMR results of compound 6 are as follows:
化合物6A： 1HNMR(600MHz,CDCl 3)δ5.30(s,2H),4.51(d,J＝10.7Hz,2H),2.88–2.83(m,2H),2.71–2.62(m,4H),2.39-2.34(m,2H),2.18–2.03(m,2H),1.91–1.83(m,4H),1.74–1.68(m,4H),1.65-1.62(m,4H),1.56–1.46(m,6H),1.43(s,6H),1.38–1.33(m,2H),1.29–1.21(m,2H),1.08–0.90(m,14H). Compound 6A: 1 HNMR (600MHz, CDCl 3 ) δ5.30 (s, 2H), 4.51 (d, J = 10.7Hz, 2H), 2.88–2.83 (m, 2H), 2.71–2.62 (m, 4H), 2.39-2.34(m,2H),2.18–2.03(m,2H),1.91–1.83(m,4H),1.74–1.68(m,4H),1.65-1.62(m,4H),1.56–1.46(m ,6H),1.43(s,6H),1.38–1.33(m,2H),1.29–1.21(m,2H),1.08–0.90(m,14H).
化合物6B： 1HNMR(600MHz,CDCl 3)δ5.61(s,2H),5.27(d,J＝5.3Hz,2H),3.08–2.98(m,2H),2.71–2.62(m,4H),2.37(td,J＝14.1,3.8Hz,2H),2.08–1.98(m,2H),1.92–1.77(m,4H),1.69(ddd,J＝10.7,7.3,4.0Hz,4H),1.63–1.59(m,5H),1.56–1.46(m,7H),1.44(s,6H),1.40(dd,J＝6.3,3.3Hz,2H),1.29–1.21(m,2H),0.98–0.93(m,12H). Compound 6B: 1 HNMR (600MHz, CDCl 3 ) δ5.61 (s, 2H), 5.27 (d, J = 5.3Hz, 2H), 3.08–2.98 (m, 2H), 2.71–2.62 (m, 4H), 2.37(td,J＝14.1,3.8Hz,2H),2.08–1.98(m,2H),1.92–1.77(m,4H),1.69(ddd,J＝10.7,7.3,4.0Hz,4H),1.63– 1.59(m,5H),1.56–1.46(m,7H),1.44(s,6H),1.40(dd,J＝6.3,3.3Hz,2H),1.29–1.21(m,2H),0.98–0.93( m,12H).
化合物6C： 1HNMR(600MHz,CDCl 3)δ5.61(s,1H),5.31(s,1H),5.28(d,J＝5.4Hz,1H),4.50(d,J＝10.6Hz,2H),3.07–2.97(m,1H),2.88–2.82(m,1H),2.71–2.62(m,4H),2.37-2.28(m,2H),2.07–1.78(m,6H),1.68–1.60(m,9H),1.56–1.46(m,7H),1.44-1.38(m,8H),1.29–1.21(m,2H),1.08–0.94(m,12H). Compound 6C: 1 HNMR (600MHz, CDCl 3 ) δ5.61 (s, 1H), 5.31 (s, 1H), 5.28 (d, J = 5.4Hz, 1H), 4.50 (d, J = 10.6Hz, 2H) ,3.07–2.97(m,1H),2.88–2.82(m,1H),2.71–2.62(m,4H),2.37-2.28(m,2H),2.07–1.78(m,6H),1.68–1.60( m,9H),1.56–1.46(m,7H),1.44-1.38(m,8H),1.29–1.21(m,2H),1.08–0.94(m,12H).
实施例7Example 7
化合物7的制备：Preparation of compound 7:
Figure PCTCN2022131906-appb-000023
Figure PCTCN2022131906-appb-000023
如实施例2，原料采用1,6-丁二硫醇(1.00g，6.65mmol，1.00eq)，得到2.41g化合物7A和0.90g化合物7B，合并收率72％，化合物7A和化合物 7B均为白色固体。As in Example 2, 1,6-butanedithiol (1.00g, 6.65mmol, 1.00eq) was used as the raw material to obtain 2.41g of compound 7A and 0.90g of compound 7B. The combined yield was 72%. Both compound 7A and compound 7B were White solid.
化合物7的核磁结果如下：The NMR results of compound 7 are as follows:
化合物7A： 1HNMR(600MHz,CDCl 3)δ5.29(d,J＝13.3Hz,2H),4.29(d,J＝9.2Hz,2H),2.32(dt,J＝14.1,8.6Hz,4H),1.96(d,J＝14.4Hz,2H),1.85–1.79(m,2H),1.70(dd,J＝13.5,3.4Hz,2H),1.62(dd,J＝13.3,2.7Hz,2H),1.50–1.41(m,4H),1.38(s,6H),1.30–1.09(m,10H),0.95(dd,J＝20.1,7.6Hz,2H),0.89(d,J＝6.2Hz,6H),0.81(d,J＝7.1Hz,6H). Compound 7A: 1 HNMR (600MHz, CDCl 3 ) δ5.29 (d, J = 13.3 Hz, 2H), 4.29 (d, J = 9.2 Hz, 2H), 2.32 (dt, J = 14.1, 8.6 Hz, 4H) ,1.96(d,J＝14.4Hz,2H),1.85–1.79(m,2H),1.70(dd,J＝13.5,3.4Hz,2H),1.62(dd,J＝13.3,2.7Hz,2H), 1.50–1.41(m,4H),1.38(s,6H),1.30–1.09(m,10H),0.95(dd,J＝20.1,7.6Hz,2H),0.89(d,J＝6.2Hz,6H) ,0.81(d,J＝7.1Hz,6H).
化合物7B： 1HNMR(600MHz,CDCl 3)δ5.61(s,2H),5.27(d,J＝5.3Hz,2H),3.03(dd,J＝12.2,5.2Hz,2H),2.67(m,4H),2.37(td,J＝14.1,3.8Hz,2H),2.08–2.02(m,2H),1.93–1.79(m,4H),1.75–1.66(m,4H),1.62(s,4H),1.52(m,5H),1.44(s,6H),1.42–1.35(m,7H),1.25(td,J＝11.6,6.7Hz,2H),0.99–0.92(m,12H). Compound 7B: 1 HNMR (600MHz, CDCl 3 ) δ5.61 (s, 2H), 5.27 (d, J = 5.3Hz, 2H), 3.03 (dd, J = 12.2, 5.2Hz, 2H), 2.67 (m, 4H),2.37(td,J＝14.1,3.8Hz,2H),2.08–2.02(m,2H),1.93–1.79(m,4H),1.75–1.66(m,4H),1.62(s,4H) ,1.52(m,5H),1.44(s,6H),1.42–1.35(m,7H),1.25(td,J＝11.6,6.7Hz,2H),0.99–0.92(m,12H).
实施例8：化合物8的制备Example 8: Preparation of Compound 8
Figure PCTCN2022131906-appb-000024
Figure PCTCN2022131906-appb-000024
1、将1,7-庚二醇(1.00g，7.56mmol，1.00eq)、三乙胺(2.30g，22.69mmol，3.00eq)加入到20mL二氯甲烷中，反应降温至0℃，滴加甲磺酰氯(2.17g，18.91mmol，2.50eq)，反应在0℃搅拌1h，TLC(5％MeOH/DCM)显示反应完全，向反应液中加入20mL水，纯化得到2.16g中间体8-1；1. Add 1,7-heptanediol (1.00g, 7.56mmol, 1.00eq) and triethylamine (2.30g, 22.69mmol, 3.00eq) into 20mL dichloromethane, cool the reaction to 0°C, and add dropwise Methanesulfonyl chloride (2.17g, 18.91mmol, 2.50eq), the reaction was stirred at 0°C for 1h, TLC (5% MeOH/DCM) showed that the reaction was complete, 20mL of water was added to the reaction solution, and 2.16g of intermediate 8-1 was obtained after purification. ;
2、将中间体8-1(2.16g，7.49mmol，1.00eq)加入25mL的DMF中，加入 硫代乙酸钾(1.88g，16.48mmol，2.20eq)，反应升温至60℃并搅拌过夜。TLC(5％EA/PE)显示反应完全，纯化得到410mg中间体8-2；2. Add intermediate 8-1 (2.16g, 7.49mmol, 1.00eq) to 25mL of DMF, add potassium thioacetate (1.88g, 16.48mmol, 2.20eq), heat the reaction to 60°C and stir overnight. TLC (5% EA/PE) showed that the reaction was complete, and 410 mg of intermediate 8-2 was obtained after purification;
3、将中间体8-2(400mg，1.61mmol，1.00eq)加入到8mL的乙醇中，反应降温至0℃，滴加2mL的2M氢氧化钠水溶液，反应在0℃下搅拌0.5h。TLC(5％EA/PE)显示反应完全，反应液用1N盐酸调节pH值至中性，纯化得到250mg中间体8-3，收率95％，；3. Add intermediate 8-2 (400 mg, 1.61 mmol, 1.00 eq) to 8 mL of ethanol, cool the reaction to 0°C, add 2 mL of 2M aqueous sodium hydroxide solution dropwise, and stir the reaction at 0°C for 0.5 h. TLC (5% EA/PE) showed that the reaction was complete. The pH value of the reaction solution was adjusted to neutral with 1N hydrochloric acid, and 250 mg of intermediate 8-3 was purified with a yield of 95%;
4、将中间体8-3(210mg，1.28mmol，1.00eq)和DHA(727mg，2.56mmol，2.00eq)加入到15mL乙醚中，降温至0℃，滴加三氟化硼乙醚(320mg，2.81mmol，2.20eq)；反应在0℃下搅拌30min后移至室温搅拌2h。TLC(20％EA/PE)显示反应完全，反应用20mL饱和碳酸氢钠溶液淬灭，分液，纯化得到172mg的化合物8A和190mg的化合物8B，收率48％，化合物8A和化合物8B均为白色固体。4. Add intermediate 8-3 (210mg, 1.28mmol, 1.00eq) and DHA (727mg, 2.56mmol, 2.00eq) into 15mL ether, cool to 0°C, and add boron trifluoride ether (320mg, 2.81 mmol, 2.20eq); the reaction was stirred at 0°C for 30min and then moved to room temperature and stirred for 2h. TLC (20% EA/PE) showed that the reaction was complete. The reaction was quenched with 20 mL of saturated sodium bicarbonate solution, separated, and purified to obtain 172 mg of compound 8A and 190 mg of compound 8B. The yield was 48%. Compound 8A and compound 8B were both White solid.
化合物8的核磁结果如下：The NMR results of compound 8 are as follows:
化合物8A: 1HNMR(500MHz,CDCl 3)δ5.27(s,2H),4.52(d,J＝10.7Hz,2H),2.76(d,J＝7.0Hz,2H),2.61(d,J＝11.7Hz,2H),2.37(m,2H),2.03(m,2H),1.82(d,J＝10.5Hz,4H),1.76–1.58(m,6H),1.50(m,4H),1.46–1.19(m,20H),1.01–0.81(m,14H). Compound 8A: 1 HNMR (500MHz, CDCl 3 ) δ5.27 (s, 2H), 4.52 (d, J = 10.7Hz, 2H), 2.76 (d, J = 7.0Hz, 2H), 2.61 (d, J = 11.7Hz,2H),2.37(m,2H),2.03(m,2H),1.82(d,J＝10.5Hz,4H),1.76–1.58(m,6H),1.50(m,4H),1.46– 1.19(m,20H),1.01–0.81(m,14H).
化合物8B: 1HNMR(500MHz,CDCl 3)δ5.61(s,2H),5.26(d,J＝5.0Hz,2H),3.03(d,J＝5.8Hz,2H),2.66(s,4H),2.37(t,J＝14.1Hz,2H),2.04(d,J＝14.7Hz,2H),1.84(dd,J＝26.4,11.8Hz,4H),1.74–1.65(m,5H),1.52(dd,J＝27.8,15.5Hz,4H),1.46–1.22(m,19H),0.99–0.85(m,14H). Compound 8B: 1 HNMR (500MHz, CDCl 3 ) δ5.61 (s, 2H), 5.26 (d, J = 5.0Hz, 2H), 3.03 (d, J = 5.8Hz, 2H), 2.66 (s, 4H) ,2.37(t,J＝14.1Hz,2H),2.04(d,J＝14.7Hz,2H),1.84(dd,J＝26.4,11.8Hz,4H),1.74–1.65(m,5H),1.52( dd,J＝27.8,15.5Hz,4H),1.46–1.22(m,19H),0.99–0.85(m,14H).
13CNMR(126MHz,CDCl 3)δ104.21,88.03,86.75,52.71,45.20,37.21,36.43,34.44,32.09,29.64,26.19,24.37,20.34,14.86. 13 CNMR (126MHz, CDCl 3 ) δ104.21,88.03,86.75,52.71,45.20,37.21,36.43,34.44,32.09,29.64,26.19,24.37,20.34,14.86.
实施例9：化合物9的制备Example 9: Preparation of Compound 9
Figure PCTCN2022131906-appb-000025
Figure PCTCN2022131906-appb-000025
如实施例8，原料采用1,8-辛二醇(1.05g，7.18mmol，1.00eq)，得到180mg化合物9A、390mg化合物9B和700mg化合物9C，化合物9A、化合物9B和化合物9C均为无色油状物。As in Example 8, 1,8-octanediol (1.05g, 7.18mmol, 1.00eq) was used as the raw material to obtain 180 mg of compound 9A, 390 mg of compound 9B and 700 mg of compound 9C. Compound 9A, compound 9B and compound 9C were all colorless. Oily substance.
化合物9的核磁结果如下：The NMR results of compound 9 are as follows:
化合物9A： 1HNMR(500MHz,CDCl 3)δ5.31(s,2H),4.52(d,J＝10.7Hz,2H),2.79–2.68(m,2H),2.73–2.54(m,4H),2.37(dd,J＝19.4,8.5Hz,2H),2.01(d,J＝14.1Hz,2H),1.87(dd,J＝8.5,5.1Hz,2H),1.77–1.54(m,12H),1.51–1.18(m,20H),0.98(m,14H). Compound 9A: 1 HNMR (500MHz, CDCl 3 ) δ5.31 (s, 2H), 4.52 (d, J = 10.7Hz, 2H), 2.79–2.68 (m, 2H), 2.73–2.54 (m, 4H), 2.37(dd,J＝19.4,8.5Hz,2H),2.01(d,J＝14.1Hz,2H),1.87(dd,J＝8.5,5.1Hz,2H),1.77–1.54(m,12H),1.51 –1.18(m,20H),0.98(m,14H).
13CNMR(126MHz,CDCl 3)δ104.24,92.25,80.58,80.40,51.82,46.07,37.37,36.29,34.10,31.74,29.86,29.15,29.02,28.38,25.97,24.76,21.30,20.25,15.10. 13 CNMR (126MHz, CDCl 3 ) δ104.24,92.25,80.58,80.40,51.82,46.07,37.37,36.29,34.10,31.74,29.86,29.15,29.02,28.38,25.97,24.76,21.30,20. 25,15.10.
化合物9B： 1HNMR(500MHz,CDCl 3)δ5.61(s,2H),5.26(d,J＝4.8Hz,2H),3.03(d,J＝6.2Hz,2H),2.74–2.58(m,4H),2.38(dd,J＝19.5,8.2Hz,2H),2.04(d,J＝14.3Hz,2H),1.85(dd,J＝25.8,12.3Hz,4H),1.70(dd,J＝19.7,7.8Hz,5H),1.60(td,J＝14.2,6.9Hz,5H),1.50(t,J＝14.9Hz,4H),1.44(s,6H),1.37(s,6H),1.33–1.21(m,6H),0.95(m,14H). Compound 9B: 1 HNMR (500MHz, CDCl 3 ) δ5.61 (s, 2H), 5.26 (d, J = 4.8Hz, 2H), 3.03 (d, J = 6.2Hz, 2H), 2.74–2.58 (m, 4H),2.38(dd,J＝19.5,8.2Hz,2H),2.04(d,J＝14.3Hz,2H),1.85(dd,J＝25.8,12.3Hz,4H),1.70(dd,J＝19.7 ,7.8Hz,5H),1.60(td,J＝14.2,6.9Hz,5H),1.50(t,J＝14.9Hz,4H),1.44(s,6H),1.37(s,6H),1.33–1.21 (m,6H),0.95(m,14H).
13CNMR(126MHz,CDCl 3)δ104.16,88.01,86.73,52.71,45.21,37.21,36.4 3,34.45,32.71,32.08,29.69,29.10,28.83,26.18,24.63,24.37,20.34,14.85. 13 CNMR (126MHz, CDCl 3 ) δ104.16,88.01,86.73,52.71,45.21,37.21,36.4 3,34.45,32.71,32.08,29.69,29.10,28.83,26.18,24.63,24.37,20.34,14 .85.
化合物9C： 1HNMR(500MHz,CDCl 3)δ5.61(s,1H),5.28(s,1H),5.26(d,J＝5.0Hz,1H),4.52(d,J＝10.7Hz,1H),3.03(d,J＝6.3Hz,1H),2.83–2.73(m,1H),2.75–2.54(m,4H),2.37(t,J＝13.5Hz,2H),2.03(t,J＝14.0Hz,2H),1.85(m,3H),1.77–1.55(m,10H),1.53–1.47(m,2H),1.33(m,19H),1.10–1.00(m,1H),1.01–0.88(m,13H). Compound 9C: 1 HNMR (500MHz, CDCl 3 ) δ5.61 (s, 1H), 5.28 (s, 1H), 5.26 (d, J = 5.0Hz, 1H), 4.52 (d, J = 10.7Hz, 1H) ,3.03(d,J＝6.3Hz,1H),2.83–2.73(m,1H),2.75–2.54(m,4H),2.37(t,J＝13.5Hz,2H),2.03(t,J＝14.0 Hz,2H),1.85(m,3H),1.77–1.55(m,10H),1.53–1.47(m,2H),1.33(m,19H),1.10–1.00(m,1H),1.01–0.88( m,13H).
13CNMR(126MHz,CDCl 3)δ104.23,104.16,92.24,88.01,86.72,52.71,51.81,46.07,45.21,37.37,37.20,36.44,36.28,34.45,34.09,32.71,32.08,31.73,29.86,29.70,29.13,28.99,28.87,28.34,26.18,25.96,24.76,24.62,24.37,21.30,20.34,20.25,15.10,14.85. 13 CNMR (126MHz, CDCl 3 ) δ104.23,104.16,92.24,88.01,86.72,52.71,51.81,46.07,45.21,37.37,37.20,36.44,36.28,34.45,34.09,32.71,32.08,31 .73,29.86,29.70,29.13, 28.99,28.87,28.34,26.18,25.96,24.76,24.62,24.37,21.30,20.34,20.25,15.10,14.85.
实施例10：化合物10的制备：Example 10: Preparation of Compound 10:
Figure PCTCN2022131906-appb-000026
Figure PCTCN2022131906-appb-000026
如实施例8，原料采用1,9-壬二醇(1.00g，6.24mmol，1.00eq)，得到667mg化合物10A、632mg化合物10B和548mg化合物10C，合并收率64％，化合物10A、化合物10B和化合物10C均为白色泡末状固体。As in Example 8, 1,9-nonanediol (1.00g, 6.24mmol, 1.00eq) was used as the raw material to obtain 667 mg of compound 10A, 632 mg of compound 10B and 548 mg of compound 10C. The combined yield was 64%. Compound 10A, compound 10B and Compound 10C was a white foamy solid.
化合物10的核磁结果如下:The NMR results of compound 10 are as follows:
化合物10A： 1HNMR(500MHz,CDCl 3)δ5.29(s,2H),4.52(d,J＝10.6Hz,2H),2.80–2.71(m,2H),2.65–2.59(m,4H),2.36(t,J＝12.6Hz,2H),2.03(t,J＝13 .5Hz,2H),1.93–1.78(m,4H),1.75–1.54(m,8H),1.50–1.46(m,4H),1.48–1.37(m,12H),1.28(s,8H),1.08–1.00(m,2H),0.96–0.92(m,12H). Compound 10A: 1 HNMR (500MHz, CDCl 3 ) δ5.29 (s, 2H), 4.52 (d, J = 10.6Hz, 2H), 2.80–2.71 (m, 2H), 2.65–2.59 (m, 4H), 2.36(t,J＝12.6Hz,2H),2.03(t,J＝13.5Hz,2H),1.93–1.78(m,4H),1.75–1.54(m,8H),1.50–1.46(m,4H ),1.48–1.37(m,12H),1.28(s,8H),1.08–1.00(m,2H),0.96–0.92(m,12H).
13CNMR(126MHz,CDCl 3)δ104.25,92.25,80.58,80.40,51.82,46.06,37.39,36.44,34.10,32.06,31.73,29.86,29.38,29.04,28.36,25.95,24.77,21.30,20.25,15.10. 13 CNMR (126MHz, CDCl 3 ) δ104.25,92.25,80.58,80.40,51.82,46.06,37.39,36.44,34.10,32.06,31.73,29.86,29.38,29.04,28.36,25.95,24.77,21. 30,20.25,15.10.
化合物10B： 1HNMR(500MHz,CDCl 3)δ5.62(s,2H),5.27(d,J＝5.1Hz,2H),3.03(dd,J＝11.4,5.3Hz,2H),2.66(t,J＝6.4Hz,4H),2.37(td,J＝14.0,3.1Hz,2H),2.04(d,J＝14.4Hz,2H),1.95–1.78(m,4H),1.69(t,J＝12.8Hz,4H),1.60(dd,J＝14.9,7.6Hz,4H),1.55–1.46(m,4H),1.44(s,6H),1.39–1.36(m,6H),1.32–1.23(m,8H),0.96–0.90(m,14H). Compound 10B: 1 HNMR (500MHz, CDCl 3 ) δ5.62 (s, 2H), 5.27 (d, J = 5.1Hz, 2H), 3.03 (dd, J = 11.4, 5.3Hz, 2H), 2.66 (t, J＝6.4Hz,4H),2.37(td,J＝14.0,3.1Hz,2H),2.04(d,J＝14.4Hz,2H),1.95–1.78(m,4H),1.69(t,J＝12.8 Hz,4H),1.60(dd,J＝14.9,7.6Hz,4H),1.55–1.46(m,4H),1.44(s,6H),1.39–1.36(m,6H),1.32–1.23(m, 8H),0.96–0.90(m,14H).
13CNMR(126MHz,CDCl 3)δ104.18,88.02,86.73,81.20,52.71,45.21,37.21,36.44,34.45,32.72,32.08,29.72,29.38,29.18,28.90,26.19,24.63,24.37,20.35,14.86. 13 CNMR (126MHz, CDCl 3 ) δ104.18,88.02,86.73,81.20,52.71,45.21,37.21,36.44,34.45,32.72,32.08,29.72,29.38,29.18,28.90,26.19,24.63,24. 37,20.35,14.86.
化合物10C： 1HNMR(500MHz,CDCl 3)δ5.61(s,1H),5.28(s,1H),5.26(d,J＝5.3Hz,1H),4.52(d,J＝10.6Hz,1H),3.03(s,1H),2.81–2.72(m,1H),2.66–2.60(m,4H),2.36(t,J＝13.1Hz,2H),2.03(t,J＝13.1Hz,2H),1.93–1.78(m,3H),1.75–1.54(m,10H),1.50(dd,J＝17.2,8.4Hz,3H),1.48–1.37(m,12H),1.28(s,8H),1.08–1.00(m,1H),0.96–0.92(m,13H). Compound 10C: 1 HNMR (500MHz, CDCl 3 ) δ5.61 (s, 1H), 5.28 (s, 1H), 5.26 (d, J = 5.3Hz, 1H), 4.52 (d, J = 10.6Hz, 1H) ,3.03(s,1H),2.81–2.72(m,1H),2.66–2.60(m,4H),2.36(t,J＝13.1Hz,2H),2.03(t,J＝13.1Hz,2H), 1.93–1.78(m,3H),1.75–1.54(m,10H),1.50(dd,J＝17.2,8.4Hz,3H),1.48–1.37(m,12H),1.28(s,8H),1.08– 1.00(m,1H),0.96–0.92(m,13H).
13CNMR(126MHz,CDCl 3)δ104.24,104.17,92.25,88.02,86.73,81.20,80.58,80.41,52.72,51.82,46.07,45.21,37.38,37.21,36.44,36.29,34.45,34.10,32.73,32.08,31.73,29.87,29.72,29.40,29.21,29.04,28.90,28.35,26.19,25.96,24.77,24.63,24.37,21.30,20.34,20.25,15.10,14.86. 13 CNMR (126MHz, CDCl 3 ) δ104.24,104.17,92.25,88.02,86.73,81.20,80.58,80.41,52.72,51.82,46.07,45.21,37.38,37.21,36.44,36.29,34.45,34 .10,32.73,32.08,31.73, 29.87,29.72,29.40,29.21,29.04,28.90,28.35,26.19,25.96,24.77,24.63,24.37,21.30,20.34,20.25,15.10,14.86.
实施例11：化合物11的制备：Example 11: Preparation of Compound 11:
Figure PCTCN2022131906-appb-000027
Figure PCTCN2022131906-appb-000027
如实施例8，原料采用1,10-癸二醇(1.00g，5.74mmol，1.00eq)，得到382mg化合物11A和481mg化合物11B，合并收率36％，化合物11A和化合物11B均为白色固体。As in Example 8, 1,10-decanediol (1.00g, 5.74mmol, 1.00eq) was used as the raw material to obtain 382 mg of compound 11A and 481 mg of compound 11B. The combined yield was 36%. Both compound 11A and compound 11B were white solids.
化合物11的核磁结果如下：The NMR results of compound 11 are as follows:
化合物11A: 1HNMR(500MHz,CDCl 3)δ5.26(s,2H),4.52(d,J＝10.7Hz,2H),2.81–2.71(m,2H),2.61(d,J＝11.4Hz,2H),2.37(t,J＝13.7Hz,2H),2.03(t,J＝14.6Hz,2H),1.88–1.79(m,4H),1.77–1.54(m,5H),1.50(t,J＝12.9Hz,4H),1.44-1.37(m,16H),1.27-1.24(m,11H),1.01-0.83(m,14H) Compound 11A: 1 HNMR (500MHz, CDCl 3 ) δ5.26 (s, 2H), 4.52 (d, J = 10.7Hz, 2H), 2.81–2.71 (m, 2H), 2.61 (d, J = 11.4Hz, 2H),2.37(t,J＝13.7Hz,2H),2.03(t,J＝14.6Hz,2H),1.88–1.79(m,4H),1.77–1.54(m,5H),1.50(t,J ＝12.9Hz,4H),1.44-1.37(m,16H),1.27-1.24(m,11H),1.01-0.83(m,14H)
化合物11B: 1HNMR(500MHz,CDCl 3)δ5.62(s,2H),5.27(d,J＝5.1Hz,2H),3.03(d,J＝5.5Hz,2H),2.66(t,J＝6.9Hz,4H),2.35(dd,J＝9.0,4.6Hz,2H),2.07–1.98(m,2H),1.84(td,J＝13.9,3.4Hz,4H),1.69(t,J＝14.1Hz,4H),1.61(dd,J＝14.1,7.5Hz,5H),1.50(dd,J＝17.0,8.3Hz,4H),1.40(d,J＝34.2Hz,11H),1.27(s,10H),1.06-0.86(m,14H). Compound 11B: 1 HNMR (500MHz, CDCl 3 ) δ5.62 (s, 2H), 5.27 (d, J = 5.1Hz, 2H), 3.03 (d, J = 5.5Hz, 2H), 2.66 (t, J = 6.9Hz,4H),2.35(dd,J＝9.0,4.6Hz,2H),2.07–1.98(m,2H),1.84(td,J＝13.9,3.4Hz,4H),1.69(t,J＝14.1 Hz,4H),1.61(dd,J＝14.1,7.5Hz,5H),1.50(dd,J＝17.0,8.3Hz,4H),1.40(d,J＝34.2Hz,11H),1.27(s,10H ),1.06-0.86(m,14H).
13CNMR(126MHz,CDCl 3)δ104.18,88.02,86.73,81.20,52.72,45.21,37.21,36.44,34.45,32.72,32.08,29.73,29.45,29.23,28.92,26.19,24.63,24.37,20.34,14.86. 13 CNMR (126MHz, CDCl 3 ) δ104.18,88.02,86.73,81.20,52.72,45.21,37.21,36.44,34.45,32.72,32.08,29.73,29.45,29.23,28.92,26.19,24.63,24. 37,20.34,14.86.
实施例12：化合物12的制备Example 12: Preparation of Compound 12
Figure PCTCN2022131906-appb-000028
Figure PCTCN2022131906-appb-000028
1、将2,5-己二醇(600mg，5.08mmol，1.00eq)和三乙胺(3.08g，30.46mmol，6.00eq)加入到25mL的DCM中，降温至0℃，滴加甲磺酰氯(2.33g，20.31mmol，4.00eq)，反应搅拌15min后移至室温搅拌1h，TCL(40％EA/PE)显示原料消失，向反应中加入50mL水，纯化得到1.20g中间体12-1，收率86％；1. Add 2,5-hexanediol (600mg, 5.08mmol, 1.00eq) and triethylamine (3.08g, 30.46mmol, 6.00eq) to 25mL of DCM, cool to 0°C, and add methanesulfonyl chloride dropwise. (2.33g, 20.31mmol, 4.00eq), the reaction was stirred for 15min and then moved to room temperature and stirred for 1h. TCL (40% EA/PE) showed that the raw materials disappeared. 50mL of water was added to the reaction, and 1.20g of intermediate 12-1 was obtained after purification. Yield 86%;
2、将中间体12-1(0.50g，1.82mmol，1.00eq)和实施例1制得的SDHA-A(1.10g，3.65mmol，3.00eq)加入到10mL的DMF中，加入碳酸钾(756mg，5.47mmol，3.00eq)，反应室温下搅拌20h。TCL(15％EA/PE)显示原料消失，向反应中加入30mL水，纯化得到510mg化合物12A，收率41％；2. Add intermediate 12-1 (0.50g, 1.82mmol, 1.00eq) and SDHA-A (1.10g, 3.65mmol, 3.00eq) prepared in Example 1 to 10mL of DMF, and add potassium carbonate (756mg , 5.47mmol, 3.00eq), the reaction was stirred at room temperature for 20h. TCL (15% EA/PE) showed that the raw materials disappeared, 30 mL of water was added to the reaction, and 510 mg of compound 12A was purified, with a yield of 41%;
3、将中间体12-1(0.50g，1.82mmol，1.00eq)和实施例1制得的SDHA-B(1.10g，3.65mmol，3.00eq)加入到10mL的DMF中，加入碳酸钾(756mg，5.47mmol，3.00eq)，反应室温下搅拌20h。TCL(15％EA/PE)显示原料消失，向反应中加入30mL水，纯化得到560mg化合物12B，收率45％。3. Add intermediate 12-1 (0.50g, 1.82mmol, 1.00eq) and SDHA-B (1.10g, 3.65mmol, 3.00eq) prepared in Example 1 to 10mL of DMF, and add potassium carbonate (756mg , 5.47mmol, 3.00eq), the reaction was stirred at room temperature for 20h. TCL (15% EA/PE) showed that the raw materials disappeared, 30 mL of water was added to the reaction, and 560 mg of compound 12B was purified, with a yield of 45%.
化合物12的核磁结果如下：The NMR results of compound 12 are as follows:
化合物12A： 1HNMR(500MHz,CDCl 3)δ5.26(s,2H),4.52(d,J＝10.6Hz,2H),3.11–2.96(m,2H),2.45-2.36(m,2H),2.07(t,J＝14.9Hz,2H),1.89-1.65(m,12H),1.59–1.23(m,22H),1.03–0.86(m,14H). Compound 12A: 1 HNMR (500MHz, CDCl 3 ) δ5.26 (s, 2H), 4.52 (d, J = 10.6Hz, 2H), 3.11–2.96 (m, 2H), 2.45-2.36 (m, 2H), 2.07(t,J＝14.9Hz,2H),1.89-1.65(m,12H),1.59–1.23(m,22H),1.03–0.86(m,14H).
化合物12B： 1HNMR(500MHz,CDCl 3)δ5.61(s,2H),5.33(d,J＝5.2Hz,2H), 3.10–2.97(m,2H),2.40-2.35(m,2H),2.02(t,J＝14.9Hz,2H),1.86–1.63(m,13H),1.57–1.23(m,21H),1.06–0.84(m,14H). Compound 12B: 1 HNMR (500MHz, CDCl 3 ) δ5.61 (s, 2H), 5.33 (d, J = 5.2Hz, 2H), 3.10–2.97 (m, 2H), 2.40-2.35 (m, 2H), 2.02(t,J＝14.9Hz,2H),1.86–1.63(m,13H),1.57–1.23(m,21H),1.06–0.84(m,14H).
13CNMR(126MHz,CDCl 3)δ104.17,92.15,88.06,84.85,81.18,80.58,80.40,52.73,45.25,40.81,37.22,36.45,34.47,34.22,32.10,26.16,24.63,24.42,21.64,20.33,14.93. 13 CNMR (126MHz, CDCl 3 ) δ104.17,92.15,88.06,84.85,81.18,80.58,80.40,52.73,45.25,40.81,37.22,36.45,34.47,34.22,32.10,26.16,24.63,24. 42,21.64,20.33, 14.93.
实施例13：Example 13:
化合物13的制备：Preparation of compound 13:
Figure PCTCN2022131906-appb-000029
Figure PCTCN2022131906-appb-000029
将13-1(100mg，0.31mmol，1.00eq)和DHA(192mg，0.68mmol，2.20eq)加入到10mL乙醚中，降温至0℃，滴加三氟化硼乙醚(77mg，0.68mmol，2.20eq)；反应在0℃下搅拌30min后移至室温搅拌2h；TLC(20％EA/PE)显示反应完全，反应用20mL饱和碳酸氢钠溶液淬灭，分液，纯化得到69mg化合物13A和91mg化合物13B，收率61％，化合物13A和化合物13B均为白色固体。Add 13-1 (100 mg, 0.31 mmol, 1.00 eq) and DHA (192 mg, 0.68 mmol, 2.20 eq) to 10 mL of diethyl ether, cool to 0°C, and add boron trifluoride diethyl ether (77 mg, 0.68 mmol, 2.20 eq) dropwise. ); the reaction was stirred at 0°C for 30 min and then moved to room temperature for 2 h; TLC (20% EA/PE) showed that the reaction was complete. The reaction was quenched with 20 mL of saturated sodium bicarbonate solution, separated, and purified to obtain 69 mg of compound 13A and 91 mg of compound 13A. 13B, the yield is 61%. Compound 13A and compound 13B are both white solids.
化合物13的核磁结果如下：The NMR results of compound 13 are as follows:
化合物13A: 1HNMR(500MHz,CDCl 3)δ5.61(s,2H),5.26(d,J＝5.2Hz,2H),3.05-3.18(m,2H),2.67(s,6H),2.37(t,J＝13.8Hz,2H),2.04(d,J＝12.2Hz,2H),1.89–1.80(m,4H),1.74–1.58(m,13H),1.57(s,6H),1.50(t,J＝12.4Hz,4H),1.45–1.22(m,27H),0.98–0.88(m,14H). Compound 13A: 1 HNMR (500MHz, CDCl 3 ) δ5.61 (s, 2H), 5.26 (d, J = 5.2Hz, 2H), 3.05-3.18 (m, 2H), 2.67 (s, 6H), 2.37 ( t,J＝13.8Hz,2H),2.04(d,J＝12.2Hz,2H),1.89–1.80(m,4H),1.74–1.58(m,13H),1.57(s,6H),1.50(t ,J＝12.4Hz,4H),1.45–1.22(m,27H),0.98–0.88(m,14H).
化合物13B: 1HNMR(500MHz,CDCl 3)δ5.26(s,2H),4.36(d,J＝10.6Hz,2H),2.88-2.85(m,2H),2.67(s,2H),2.38(t,J＝13.8Hz,2H),2.05(d,J＝12.2Hz,2H),1.84(d,J＝14.4Hz,4H),1.74–1.58(m,13H),1.57(s,6H),1.50(t,J＝12.4Hz,4H),1.45–1.22(m,23H),0.98–0.88(m,12H). Compound 13B: 1 HNMR (500MHz, CDCl 3 ) δ5.26 (s, 2H), 4.36 (d, J = 10.6Hz, 2H), 2.88-2.85 (m, 2H), 2.67 (s, 2H), 2.38 ( t,J＝13.8Hz,2H),2.05(d,J＝12.2Hz,2H),1.84(d,J＝14.4Hz,4H),1.74–1.58(m,13H),1.57(s,6H), 1.50(t,J＝12.4Hz,4H),1.45–1.22(m,23H),0.98–0.88(m,12H).
实施例14：化合物14的制备：Example 14: Preparation of compound 14:
Figure PCTCN2022131906-appb-000030
Figure PCTCN2022131906-appb-000030
制备过程：Preparation Process:
将14-1(0.50g，2.74mmol，1.00eq)和双氢青蒿素(1.72g，6.03mmol，2.20eq)加入27mL的Et 2O中，置换Ar，置于-5℃下搅拌，缓慢滴加三氟化硼乙醚(0.85g，6.03mmol，2.20eq)，加完后移至室温搅拌3h。反应液倾倒入100mL饱和碳酸氢钠溶液中淬灭，用80mL的EA萃取3次，纯化白色泡沫状0.90g化合物14，收率45％，化合物14为白色泡沫。 Add 14-1 (0.50g, 2.74mmol, 1.00eq) and dihydroartemisinin (1.72g, 6.03mmol, 2.20eq) into 27mL of Et 2 O, replace Ar, and stir slowly at -5°C. Boron trifluoride ether (0.85g, 6.03mmol, 2.20eq) was added dropwise. After the addition was completed, the mixture was moved to room temperature and stirred for 3 hours. The reaction solution was poured into 100 mL of saturated sodium bicarbonate solution to quench, and extracted three times with 80 mL of EA to purify 0.90 g of compound 14 as a white foam, with a yield of 45%. Compound 14 was a white foam.
化合物14的核磁结果如下：The NMR results of compound 14 are as follows:
1HNMR(500MHz,CDCl 3)δ5.60(s,2H),5.31(d,J＝4.4Hz,2H),3.80–3.71(m,2H),3.67–3.57(m,6H),3.03(d,J＝4.8Hz,2H),2.92(dd,J＝13.4,6.6Hz,2H),2.83(dd,J＝12.9,6.7Hz,2H),2.37(t,J＝13.9Hz,2H),2.04(d,J＝14.5Hz,2H),1.94–1.76(m,4H),1.68(dd,J＝28.1,12.9Hz,6H),1.51–1.48(m,4H),1.43(s,6H),1.32–1.19(m,4H),0.96–0.86(m,12H). 1 HNMR (500MHz, CDCl 3 ) δ5.60 (s, 2H), 5.31 (d, J = 4.4Hz, 2H), 3.80–3.71 (m, 2H), 3.67–3.57 (m, 6H), 3.03 (d ,J＝4.8Hz,2H),2.92(dd,J＝13.4,6.6Hz,2H),2.83(dd,J＝12.9,6.7Hz,2H),2.37(t,J＝13.9Hz,2H),2.04 (d,J＝14.5Hz,2H),1.94–1.76(m,4H),1.68(dd,J＝28.1,12.9Hz,6H),1.51–1.48(m,4H),1.43(s,6H), 1.32–1.19(m,4H),0.96–0.86(m,12H).
13CNMR(126MHz,CDCl 3)δ104.21,87.95,87.25,81.17,70.86,70.24,52.67,45.12,37.21,36.40,34.42,32.18,26.16,24.63,24.37,20.36,14.85. 13 CNMR (126MHz, CDCl 3 ) δ104.21,87.95,87.25,81.17,70.86,70.24,52.67,45.12,37.21,36.40,34.42,32.18,26.16,24.63,24.37,20.36,14.85.
实施例15：化合物15的制备:Example 15: Preparation of compound 15:
Figure PCTCN2022131906-appb-000031
Figure PCTCN2022131906-appb-000031
1、将DHA(2.00g，7.03mmol，1.00eq)加入到15mL1,4-丁二醇和15mL的DCM中，降温至0℃，滴加三氟化硼乙醚(1.05g，7.39mmol，1.05eq)；反应在0℃下搅拌30min后移至室温搅拌2h。TLC(20％EA/PE)显示反应完全，反应用100mL饱和碳酸氢钠溶液淬灭，分液，纯化得到2.32g中间体15-1，收率93％，中间体15-1为无色油状液体；1. Add DHA (2.00g, 7.03mmol, 1.00eq) to 15mL of 1,4-butanediol and 15mL of DCM, cool to 0°C, and add boron trifluoride ether (1.05g, 7.39mmol, 1.05eq) dropwise. ; The reaction was stirred at 0°C for 30min and then moved to room temperature and stirred for 2h. TLC (20% EA/PE) showed that the reaction was complete. The reaction was quenched with 100 mL of saturated sodium bicarbonate solution, separated, and purified to obtain 2.32 g of intermediate 15-1 with a yield of 93%. Intermediate 15-1 was a colorless oil. liquid;
2、将中间体15-1(2.32g，8.61mmol，1.0eq)溶于50mL无水二氯甲烷中，降温0℃，加入三乙胺(1.65g，16.27mmol，2.50eq)，搅拌10min后滴加甲基磺酰氯(895mg，7.81mmol，1.20eq)；加完后反应移至室温搅拌2h；待反应完成后将反应液倒入150mL饱和碳酸氢钠溶液中，充分搅拌；纯化得到0.53g中间体15-2和2.02g中间体15-3，收率90％，中间体15-2和中间体16-3均为白色固体；2. Dissolve intermediate 15-1 (2.32g, 8.61mmol, 1.0eq) in 50 mL anhydrous dichloromethane, lower the temperature to 0°C, add triethylamine (1.65g, 16.27mmol, 2.50eq), and stir for 10 minutes. Methanesulfonyl chloride (895mg, 7.81mmol, 1.20eq) was added dropwise; after the addition was completed, the reaction was moved to room temperature and stirred for 2 hours; after the reaction was completed, the reaction solution was poured into 150mL saturated sodium bicarbonate solution and stirred fully; purification yielded 0.53g Intermediate 15-2 and 2.02g of intermediate 15-3, yield 90%, both intermediate 15-2 and intermediate 16-3 are white solids;
3、将15-2(200mg，0.46mmol，1.00eq)和SDHA-A(139mg，0.46mmol，1.00eq)加入到5mL的DMF中，加入碳酸钾(128mg，0.92mmol，2.00eq)，反应室温下搅拌20h。TCL(20％EA/PE)显示原料消失，纯化得到163mg化合物15A，收率55％。3. Add 15-2 (200mg, 0.46mmol, 1.00eq) and SDHA-A (139mg, 0.46mmol, 1.00eq) to 5mL of DMF, add potassium carbonate (128mg, 0.92mmol, 2.00eq), and react at room temperature. Stir for 20h. TCL (20% EA/PE) showed that the starting material disappeared, and 163 mg of compound 15A was obtained after purification, with a yield of 55%.
4、将15-2(200mg，0.46mmol，1.00eq)和SDHA-B(139mg，0.46mmol，1.00eq)加入到5mLDMF中，加入碳酸钾(128mg，0.92mmol，2.00eq)，反应 室温下搅拌20h。TCL(20％EA/PE)显示原料消失，纯化得到143mg化合物15C，收率49％。4. Add 15-2 (200mg, 0.46mmol, 1.00eq) and SDHA-B (139mg, 0.46mmol, 1.00eq) to 5mLDMF, add potassium carbonate (128mg, 0.92mmol, 2.00eq), and stir at room temperature. 20h. TCL (20% EA/PE) showed that the starting material disappeared, and 143 mg of compound 15C was obtained after purification, with a yield of 49%.
5、将15-3(500mg，1.15mmol，1.00eq)和实施例1的SDHA-A(346mg，1.15mmol，1.00eq)加入到10mL的DMF中，加入碳酸钾(318mg，2.30mmol，2.00eq)，反应室温下搅拌20h。TCL(20％EA/PE)显示原料消失，纯化得到465mg化合物15D，收率63％。5. Add 15-3 (500 mg, 1.15 mmol, 1.00 eq) and SDHA-A (346 mg, 1.15 mmol, 1.00 eq) of Example 1 to 10 mL of DMF, and add potassium carbonate (318 mg, 2.30 mmol, 2.00 eq) ), the reaction was stirred at room temperature for 20 h. TCL (20% EA/PE) showed that the starting material disappeared, and 465 mg of compound 15D was obtained after purification, with a yield of 63%.
6、将15-3(500mg，1.15mmol，1.00eq)和实施例1的SDHA-B(346mg，1.15mmol，1.00eq)加入到10mL的DMF中，加入碳酸钾(318mg，2.30mmol，2.00eq)，反应室温下搅拌20h。TCL(20％EA/PE)显示原料消失，纯化得到432mg化合物15B，收率59％。6. Add 15-3 (500 mg, 1.15 mmol, 1.00 eq) and SDHA-B of Example 1 (346 mg, 1.15 mmol, 1.00 eq) to 10 mL of DMF, and add potassium carbonate (318 mg, 2.30 mmol, 2.00 eq) ), the reaction was stirred at room temperature for 20 h. TCL (20% EA/PE) showed that the starting material disappeared, and 432 mg of compound 15B was obtained after purification, with a yield of 59%.
化合物15的核磁结果如下：The NMR results of compound 15 are as follows:
化合物15A： 1HNMR(600MHz,CDCl 3)δ5.38(s,1H),5.34(s,1H),4.52(d,J＝10.7Hz,1H),4.42(d,J＝9.2Hz,1H),3.87-3.85(m,1H),3.40-3.37(m,1H),2.83–2.78(m,1H),2.71–2.66(m,2H),2.64-2.56(m,2H),2.37–2.24(m,2H),2.13-2.02(m,2H),1.95–1.60(m,11H),1.58–1.12(m,14H),1.05–0.81(m,14H). Compound 15A: 1 HNMR (600MHz, CDCl 3 ) δ5.38 (s, 1H), 5.34 (s, 1H), 4.52 (d, J = 10.7Hz, 1H), 4.42 (d, J = 9.2Hz, 1H) ,3.87-3.85(m,1H),3.40-3.37(m,1H),2.83–2.78(m,1H),2.71–2.66(m,2H),2.64-2.56(m,2H),2.37–2.24( m,2H),2.13-2.02(m,2H),1.95–1.60(m,11H),1.58–1.12(m,14H),1.05–0.81(m,14H).
化合物15B： 1HNMR(600MHz,CDCl 3)δ5.61(s,1.0H),5.39(s,1H),5.26(d,J＝5.3Hz,1H),4.79(d,J＝3.0Hz,1H),3.87-3.85(m,1H),3.40-3.37(m,1H),3.04–3.02(m,1H),2.72–2.65(m,2H),2.65-2.56(m,2H),2.37–2.24(m,2H),2.13-2.04(m,2H),1.93–1.58(m,11H),1.53–1.18(m,14H),1.02–0.81(m,14H). Compound 15B: 1 HNMR (600MHz, CDCl 3 ) δ5.61 (s, 1.0H), 5.39 (s, 1H), 5.26 (d, J = 5.3Hz, 1H), 4.79 (d, J = 3.0Hz, 1H ),3.87-3.85(m,1H),3.40-3.37(m,1H),3.04–3.02(m,1H),2.72–2.65(m,2H),2.65-2.56(m,2H),2.37–2.24 (m,2H),2.13-2.04(m,2H),1.93–1.58(m,11H),1.53–1.18(m,14H),1.02–0.81(m,14H).
化合物15C： 1HNMR(600MHz,CDCl 3)δ5.61(s,1.0H),5.34(s,1H),5.26(d,J＝5.3Hz,1H),4.42(d,J＝9.2Hz,1H),3.88-3.86(m,1H),3.41-3.38(m,1H),3.04–3.02(m,1H),2.72–2.66(m,2H),2.64-2.55(m,2H),2.37–2.28(m,2H),2.15-2.03(m,2H),1.94–1.59(m,11H),1.53–1.18(m,14H),1.01–0.81(m, 14H). Compound 15C: 1 HNMR (600MHz, CDCl 3 ) δ5.61 (s, 1.0H), 5.34 (s, 1H), 5.26 (d, J = 5.3Hz, 1H), 4.42 (d, J = 9.2Hz, 1H ),3.88-3.86(m,1H),3.41-3.38(m,1H),3.04–3.02(m,1H),2.72–2.66(m,2H),2.64-2.55(m,2H),2.37–2.28 (m,2H),2.15-2.03(m,2H),1.94–1.59(m,11H),1.53–1.18(m,14H),1.01–0.81(m, 14H).
化合物15D； 1HNMR(600MHz,CDCl 3)δ5.39(s,1H),5.28(s,1H),4.79(d,J＝3.0Hz,1H),4.52(d,J＝10.7Hz,1H),3.87-3.85(m,1H),3.40-3.37(m,1H),2.83–2.78(m,1H),2.71–2.66(m,2H),2.64-2.56(m,2H),2.37–2.24(m,2H),2.13-2.02(m,2H),1.95–1.60(m,11H),1.58–1.12(m,14H),1.05–0.81(m,14H). Compound 15D; 1 HNMR (600MHz, CDCl 3 ) δ5.39 (s, 1H), 5.28 (s, 1H), 4.79 (d, J = 3.0Hz, 1H), 4.52 (d, J = 10.7Hz, 1H) ,3.87-3.85(m,1H),3.40-3.37(m,1H),2.83–2.78(m,1H),2.71–2.66(m,2H),2.64-2.56(m,2H),2.37–2.24( m,2H),2.13-2.02(m,2H),1.95–1.60(m,11H),1.58–1.12(m,14H),1.05–0.81(m,14H).
实施例16：化合物16的制备Example 16: Preparation of Compound 16
Figure PCTCN2022131906-appb-000032
Figure PCTCN2022131906-appb-000032
如实施例2，原料采用4-氨基丁烷-1-硫醇(174mg，1.66mmol，0.50eq)，得到114mg化合物16A和131mg化合物16B，合并收率23％，化合物16A和化合物16B均为白色固体。As in Example 2, 4-aminobutane-1-thiol (174 mg, 1.66 mmol, 0.50 eq) was used as the raw material to obtain 114 mg of compound 16A and 131 mg of compound 16B. The combined yield was 23%. Both compound 16A and compound 16B were white. solid.
化合物16的核磁结果如下：The NMR results of compound 16 are as follows:
化合物16A：1HNMR(600MHz,CDCl3)δ5.31(s,1H),5.28(s,1H),4.53(d,J＝10.7Hz,1H),4.13(d,J＝9.8Hz,1H),2.95(ddd,J＝11.4,8.07,6.55Hz,1H),2.80(dd,J＝12.5,5.3Hz,1H),2.71–2.61(m,2H),2.59–2.56(m,2H),2.36–2.30(m,2H),2.07–2.01(m,2H),1.91–1.83(m,2H),1.83–1.75(m,4H),1.73–1.66(m,4H),1.59–1.54(m,2H),1.52–1.30(m,12H),1.24-1.18(m,2H),1.08–0.98(m,2H),0.95–0.89(m,12H).Compound 16A: 1HNMR (600MHz, CDCl3) δ5.31 (s, 1H), 5.28 (s, 1H), 4.53 (d, J = 10.7Hz, 1H), 4.13 (d, J = 9.8Hz, 1H), 2.95 (ddd,J＝11.4,8.07,6.55Hz,1H),2.80(dd,J＝12.5,5.3Hz,1H),2.71–2.61(m,2H),2.59–2.56(m,2H),2.36–2.30 (m,2H),2.07–2.01(m,2H),1.91–1.83(m,2H),1.83–1.75(m,4H),1.73–1.66(m,4H),1.59–1.54(m,2H) ,1.52–1.30(m,12H),1.24-1.18(m,2H),1.08–0.98(m,2H),0.95–0.89(m,12H).
化合物16B： 1HNMR(600MHz,CDCl 3)δ5.61(s,1H),5.59(s,1H),5.27(d,J＝5.2Hz,1H),5.20(d,J＝4.6Hz,1H),3.07–2.99(m,2H),2.69–2.60(m,4H),2.37-2.31(m,2H),2.08–2.01(m,2H),1.94–1.79(m,4H),1.75–1.61(m,8H),1.55–1.47(m,4H),1.45–1.34(m,10H),1.25(m,2H),0.99–0.86(m,12H). Compound 16B: 1 HNMR (600MHz, CDCl 3 ) δ5.61 (s, 1H), 5.59 (s, 1H), 5.27 (d, J = 5.2Hz, 1H), 5.20 (d, J = 4.6Hz, 1H) ,3.07–2.99(m,2H),2.69–2.60(m,4H),2.37-2.31(m,2H),2.08–2.01(m,2H),1.94–1.79(m,4H),1.75–1.61( m,8H),1.55–1.47(m,4H),1.45–1.34(m,10H),1.25(m,2H),0.99–0.86(m,12H).
实施例17：化合物17的制备Example 17: Preparation of Compound 17
Figure PCTCN2022131906-appb-000033
Figure PCTCN2022131906-appb-000033
1、将DHA(20.00g，70.34mmol，1.00eq)和烯丙基三甲基氯硅烷(20.09g，175.84mmol，2.50eq)加入到200mL二氯甲烷中，反应降温至-50℃，滴加三氟化硼乙醚(9.61g，84.40mmol，1.20eq)反应，纯化得到8.60g中间体17-1；1. Add DHA (20.00g, 70.34mmol, 1.00eq) and allyltrimethylsilyl chloride (20.09g, 175.84mmol, 2.50eq) into 200mL dichloromethane, cool the reaction to -50°C, and add dropwise React boron trifluoride ether (9.61g, 84.40mmol, 1.20eq) and purify to obtain 8.60g of intermediate 17-1;
2、将中间体17-1(10.00g，32.42mmol，1.00eq)加入500mL的DCM中，降温至-78℃，通入臭氧1.5h，反应液变成蓝色，停止通入臭氧，继续通入空气30min，浓缩除去溶剂；向反应瓶中加入80mL的THF和20mL的MeOH，降温至0℃，分批加入NaBH 4(7.36g，194.54mmol，6.00eq)，反应在0℃下搅拌4h后移至室温搅拌过夜；反应用50mL水淬灭，分液，纯化得到6.39g中间体17-2； 2. Add intermediate 17-1 (10.00g, 32.42mmol, 1.00eq) to 500mL of DCM, cool to -78°C, and add ozone for 1.5 hours. If the reaction solution turns blue, stop adding ozone and continue to add ozone. Add air for 30 minutes, concentrate and remove the solvent; add 80 mL of THF and 20 mL of MeOH to the reaction flask, cool to 0°C, add NaBH 4 (7.36g, 194.54mmol, 6.00eq) in batches, and stir the reaction for 4 hours at 0°C. Move to room temperature and stir overnight; the reaction is quenched with 50 mL of water, separated, and purified to obtain 6.39 g of intermediate 17-2;
3、将中间体17-2(1.00g，3.20mmol，1.00eq)和三乙胺(972mg，9.60mmol，3.00eq)加入到20mL的DCM中，反应降温至0℃，滴加甲磺酰氯(440mg，3.84mmol，1.20eq)，反应在0℃下搅拌2h后移至室温过夜，TLC(40％EA/PE)显示反应完全，纯化得到10.05g中间体17-3；3. Add intermediate 17-2 (1.00g, 3.20mmol, 1.00eq) and triethylamine (972mg, 9.60mmol, 3.00eq) into 20mL of DCM, cool the reaction to 0°C, and add methanesulfonyl chloride ( 440mg, 3.84mmol, 1.20eq), the reaction was stirred at 0°C for 2h and then moved to room temperature overnight. TLC (40% EA/PE) showed that the reaction was complete, and 10.05g of intermediate 17-3 was obtained after purification;
4、将中间体17-3(560mg，1.43mmol，1.00eq)和硫代乙酸钾(246mg，2.15mmol，1.50eq)加入到10mL的DMF中，反应升温至60℃并搅拌过夜，纯化得到370mg中间体17-4，收率70％。4. Add intermediate 17-3 (560 mg, 1.43 mmol, 1.00 eq) and potassium thioacetate (246 mg, 2.15 mmol, 1.50 eq) into 10 mL of DMF. The reaction is heated to 60°C and stirred overnight. Purify to obtain 370 mg. Intermediate 17-4, yield 70%.
5、将中间体17-4(370mg，1.00mmol，1.00eq)加入10mLEtOH中，降温至0℃，滴加0.75mL的2M氢氧化钠溶液，反应在0℃下搅拌1h，TLC(20％EA/PE)显示反应完成，反应液用2M盐酸调节值中性，纯化得到300mg中间体17-5，收率91％。5. Add intermediate 17-4 (370 mg, 1.00 mmol, 1.00 eq) to 10 mL EtOH, cool to 0°C, add dropwise 0.75 mL of 2M sodium hydroxide solution, stir the reaction at 0°C for 1 h, and perform TLC (20% EA /PE) showed that the reaction was completed, the reaction solution was adjusted to neutrality with 2M hydrochloric acid, and 300 mg of intermediate 17-5 was obtained after purification, with a yield of 91%.
6、将中间体17-5(300mg，0.81mmol，1.00eq)和DHA(346mg，1.21mmol，1.50eq)加入到20mL乙醚中，反应降温至0℃，滴加三氟化硼乙醚(173mg，1.21mmol，1.50eq)，反应在0℃下搅拌10min后逐渐升至室温搅拌3h，TLC(20％EA/PE)显示反应完全，纯化得到280mg化合物18，收率52％，化合物17为白色固体。6. Add intermediate 17-5 (300 mg, 0.81 mmol, 1.00 eq) and DHA (346 mg, 1.21 mmol, 1.50 eq) into 20 mL of diethyl ether, cool the reaction to 0°C, and add boron trifluoride diethyl ether (173 mg, 1.21mmol, 1.50eq), the reaction was stirred at 0°C for 10min and then gradually raised to room temperature and stirred for 3h. TLC (20% EA/PE) showed that the reaction was complete. 280mg of compound 18 was obtained after purification, with a yield of 52%. Compound 17 was a white solid. .
化合物17的核磁结果如下：The NMR results of compound 17 are as follows:
1HNMR(500MHz,CDCl 3)δ5.79(s,1H),5.41(s,1H),5.01(s,1H),4.73(d,J＝9.2Hz,1H),2.63(s,1H),2.44(s,1H),2.35(t,J＝13.7Hz,2H),2.02(t,J＝13.9Hz,3H),1.87(d,J＝14.9Hz,3H),1.70(dd,J＝35.7,14.2Hz,4H),1.56–1.42(m,7H),1.39–1.22(m,11H),0.96–0.85(m,14H). 1 HNMR (500MHz, CDCl 3 ) δ5.79 (s, 1H), 5.41 (s, 1H), 5.01 (s, 1H), 4.73 (d, J = 9.2Hz, 1H), 2.63 (s, 1H), 2.44(s,1H),2.35(t,J＝13.7Hz,2H),2.02(t,J＝13.9Hz,3H),1.87(d,J＝14.9Hz,3H),1.70(dd,J＝35.7 ,14.2Hz,4H),1.56–1.42(m,7H),1.39–1.22(m,11H),0.96–0.85(m,14H).
13CNMR(126MHz,CDCl 3)δ103.85,103.82,101.59,98.79,90.63,88.56,81.17,80.04,52.75,51.56,45.43,44.59,37.41,37.37,36.56,36.26,34.85,34.30,32.97,31.17,26.20,25.90,24.79,24.69,24.21,21.99,20.34,20.30,13.09,12.66. 13 CNMR (126MHz, CDCl 3 ) δ103.85,103.82,101.59,98.79,90.63,88.56,81.17,80.04,52.75,51.56,45.43,44.59,37.41,37.37,36.56,36.26,34.85,3 4.30,32.97,31.17,26.20, 25.90,24.79,24.69,24.21,21.99,20.34,20.30,13.09,12.66.
实施例18：化合物18的制备Example 18: Preparation of Compound 18
Figure PCTCN2022131906-appb-000034
Figure PCTCN2022131906-appb-000034
1、将1,4-环己二酮(18-1：4.00g，35.67mmol，1.00eq)溶解在71mL甲醇中，降温至0℃，分批加入NaBH 4(2.70g，71.35mmol，2.00eq)，加完后反应在0℃搅拌20min，移至室温搅拌1h；TLC(10％MeOH/DCM)显示原料消失，加水淬灭反应，纯化得到3.20g中间体18-1。 1. Dissolve 1,4-cyclohexanedione (18-1: 4.00g, 35.67mmol, 1.00eq) in 71mL methanol, cool to 0°C, and add NaBH 4 (2.70g, 71.35mmol, 2.00eq) in batches ), after the addition, the reaction was stirred at 0°C for 20 min, moved to room temperature and stirred for 1 h; TLC (10% MeOH/DCM) showed that the raw materials disappeared, water was added to quench the reaction, and 3.20 g of intermediate 18-1 was obtained after purification.
2、将中间体18-1(3.00g，25.83mmol，1.00eq)和三乙胺(6.53g，64.57mmol，2.50eq)加入到50mL的DCM中，反应降温至0℃，缓慢滴加甲磺酰氯(6.51g，56.82mmol，2.20eq)，反应在0℃下搅拌10min后移至室温搅拌1h；TLC(2.5％MeOH/DCM)显示原料消失，加冰水淬灭反应，纯化得到2.08g中间体18-2和1.12g中间体18-3；2. Add intermediate 18-1 (3.00g, 25.83mmol, 1.00eq) and triethylamine (6.53g, 64.57mmol, 2.50eq) into 50mL of DCM, cool the reaction to 0°C, and slowly add methanesulfonate dropwise. Acid chloride (6.51g, 56.82mmol, 2.20eq), the reaction was stirred at 0°C for 10min and then moved to room temperature and stirred for 1h; TLC (2.5% MeOH/DCM) showed that the raw material disappeared, ice water was added to quench the reaction, and 2.08g of intermediate was obtained after purification Body 18-2 and 1.12 g of intermediate 18-3;
3、将中间体18-2(3.00g，11.02mmol，1.00eq)溶解在55mL的DMF中，加入硫代乙酸钾(3.77g，33.05mmol，3.00eq)，反应升温至80℃并搅拌3h。TLC(5％EA/PE)显示反应完全，纯化得到0.90g中间体18-4；3. Dissolve intermediate 18-2 (3.00g, 11.02mmol, 1.00eq) in 55mL of DMF, add potassium thioacetate (3.77g, 33.05mmol, 3.00eq), heat the reaction to 80°C and stir for 3 hours. TLC (5% EA/PE) showed that the reaction was complete, and 0.90g of intermediate 18-4 was obtained after purification;
4、将中间体18-4(900mg，3.87mmol，1.00eq)溶解在25mL95％EtOH中，降温至0℃，滴加5.8mL2M氢氧化钠水溶液，反应在0℃下搅拌0.5h。TLC(3％EA/PE)显示反应完全，向反应中加入100mL水，用1M盐酸调节pH值至3～4，纯化得到500mg中间体18-5；4. Dissolve intermediate 18-4 (900 mg, 3.87 mmol, 1.00 eq) in 25 mL 95% EtOH, cool to 0°C, add dropwise 5.8 mL 2M sodium hydroxide aqueous solution, and stir the reaction at 0°C for 0.5 h. TLC (3% EA/PE) showed that the reaction was complete. 100 mL of water was added to the reaction, the pH value was adjusted to 3-4 with 1M hydrochloric acid, and 500 mg of intermediate 18-5 was obtained after purification;
5、将DHA(844mg，2.97mmol，2.20eq)溶解在20mL乙醚中，降温至0℃， 搅拌10min，滴加三氟化硼乙醚(574mg，4.05mmol，3.00eq)，滴完后加入中间体18-5(200mg，1.35mmol，1.00eq)，反应在0℃下搅拌10min后移至室温搅拌2h。TLC(20％EA/PE)显示反应完全，纯化得到184mg化合物18B和242mg化合物18C，合并收率47％，化合物18B和化合物18C均为白色固体；5. Dissolve DHA (844mg, 2.97mmol, 2.20eq) in 20mL ether, cool to 0°C, stir for 10 minutes, add boron trifluoride ether (574mg, 4.05mmol, 3.00eq) dropwise, and add the intermediate after the drops are completed. 18-5 (200 mg, 1.35 mmol, 1.00 eq), the reaction was stirred at 0°C for 10 min and then moved to room temperature and stirred for 2 h. TLC (20% EA/PE) showed that the reaction was complete, and 184 mg of compound 18B and 242 mg of compound 18C were obtained after purification. The combined yield was 47%. Compound 18B and compound 18C were both white solids;
6、将18-3(1.20g，4.41mmol，1.00eq)溶解在40mL的DMF中，加入硫代乙酸钾(1.51g，13.22mmol，3.00eq)，反应升温至80℃并搅拌3h。TLC(5％EA/PE)显示反应完全，纯化得到0.60g中间体18-6；6. Dissolve 18-3 (1.20g, 4.41mmol, 1.00eq) in 40mL of DMF, add potassium thioacetate (1.51g, 13.22mmol, 3.00eq), heat the reaction to 80°C and stir for 3 hours. TLC (5% EA/PE) showed that the reaction was complete, and 0.60g of intermediate 18-6 was obtained after purification;
7、将18-6(600mg，2.58mmol，1.00eq)溶解在25mL的95％乙醇中，降温至0℃，滴加3.9mL的2M氢氧化钠水溶液，反应在0℃下搅拌0.5h。TLC(3％EA/PE)显示反应完全，纯化得到280mg中间体18-7；7. Dissolve 18-6 (600 mg, 2.58 mmol, 1.00 eq) in 25 mL of 95% ethanol, cool to 0°C, add dropwise 3.9 mL of 2M sodium hydroxide aqueous solution, and stir the reaction at 0°C for 0.5 h. TLC (3% EA/PE) showed that the reaction was complete, and 280 mg of intermediate 18-7 was obtained after purification;
8、将DHA(1.05g，3.71mmol，2.20eq)溶解在20mL乙醚中，降温至0℃，搅拌10min，滴加三氟化硼乙醚(717mg，5.06mmol，3.00eq)，滴完后加入18-7(250mg，1.69mmol，1.00eq)，反应在0℃下搅拌10min后移至室温搅拌2h。TLC(20％EA/PE)显示反应完全，纯化得到白色固体800mg化合物18A，收率70％，化合物18A为白色固体。8. Dissolve DHA (1.05g, 3.71mmol, 2.20eq) in 20mL ether, cool to 0°C, stir for 10 minutes, add boron trifluoride ether (717mg, 5.06mmol, 3.00eq) dropwise, add 18 -7 (250 mg, 1.69 mmol, 1.00 eq), the reaction was stirred at 0°C for 10 min and then moved to room temperature and stirred for 2 h. TLC (20% EA/PE) showed that the reaction was complete, and 800 mg of compound 18A was obtained as a white solid after purification, with a yield of 70%. Compound 18A was a white solid.
化合物18的核磁结果如下：The NMR results of compound 18 are as follows:
化合物18A： 1HNMR(600MHz,CDCl 3)δ5.61(s,1H),5.39(s,1H),5.31(d,J＝6.0Hz,1H),4.79–4.72(m,1H),3.24(s,1H),2.99(s,1H),2.69–2.57(m,1H),2.43–2.26(m,3H),2.04(ddd,J＝14.3,7.7,4.6Hz,2H),1.94–1.75(m,6H),1.74–1.62(m,3H),1.59–1.46(m,4H),1.42(t,J＝10.5Hz,6H),1.41–1.16(m,7H),1.07–0.77(m,16H). Compound 18A: 1 HNMR (600MHz, CDCl 3 ) δ5.61 (s, 1H), 5.39 (s, 1H), 5.31 (d, J = 6.0Hz, 1H), 4.79–4.72 (m, 1H), 3.24 ( s,1H),2.99(s,1H),2.69–2.57(m,1H),2.43–2.26(m,3H),2.04(ddd,J＝14.3,7.7,4.6Hz,2H),1.94–1.75( m,6H),1.74–1.62(m,3H),1.59–1.46(m,4H),1.42(t,J＝10.5Hz,6H),1.41–1.16(m,7H),1.07–0.77(m, 16H).
化合物18B： 1HNMR(600MHz,CDCl 3)δ5.62(s,2H),5.35(t,J＝6.0Hz,2H),3.03(dd,J＝12.1,5.1Hz,2H),2.81(s,2H),2.37(td,J＝14.2,3.7Hz,2H),2.17–2.12(m,4H),2.08–2.02(m,2H),1.91–1.85(m,2H),1.80–1.72(m,2H),1.68–1.66(m,4H),1.51–1.34(m,15H),1.25(td,J＝11.3,6.8Hz,3H),0.94-0 .88(m,14H). Compound 18B: 1 HNMR (600MHz, CDCl 3 ) δ5.62 (s, 2H), 5.35 (t, J = 6.0Hz, 2H), 3.03 (dd, J = 12.1, 5.1Hz, 2H), 2.81 (s, 2H),2.37(td,J＝14.2,3.7Hz,2H),2.17–2.12(m,4H),2.08–2.02(m,2H),1.91–1.85(m,2H),1.80–1.72(m, 2H),1.68–1.66(m,4H),1.51–1.34(m,15H),1.25(td,J＝11.3,6.8Hz,3H),0.94-0.88(m,14H).
13CNMR(151MHz,CDCl 3)δ104.22,88.07,85.49,81.16,52.67,45.18,43.69,37.18,36.43,34.42,34.14,33.63,32.10,26.20,24.61,24.35,20.33,14.97. 13 CNMR (151MHz, CDCl 3 ) δ104.22,88.07,85.49,81.16,52.67,45.18,43.69,37.18,36.43,34.42,34.14,33.63,32.10,26.20,24.61,24.35,20.33,14. 97.
化合物18C： 1HNMR(600MHz,CDCl3)δ5.62(s,1H),5.35(d,J＝5.4Hz,1H),5.26(d,J＝6.1Hz,1H),4.61(d,J＝10.8Hz,1H),3.02(dt,J＝17.3,7.9Hz,2H),2.83(t,J＝10.8Hz,1H),2.65–2.54(m,1H),2.37(tt,J＝14.3,3.8Hz,2H),2.26(d,J＝9.4Hz,1H),2.14(dd,J＝10.8,4.9Hz,2H),2.10–1.98(m,3H),1.92–1.84(m,2H),1.78–1.66(m,5H),1.58(dt,J＝13.3,4.0Hz,1H),1.51–1.33(m,16H),1.24(dd,J＝17.9,9.5Hz,3H),1.08–1.00(m,1H),0.94(ddd,J＝18.7,8.8,4.6Hz,12H). Compound 18C: 1 HNMR (600MHz, CDCl3) δ5.62 (s, 1H), 5.35 (d, J = 5.4Hz, 1H), 5.26 (d, J = 6.1Hz, 1H), 4.61 (d, J = 10.8 Hz,1H),3.02(dt,J＝17.3,7.9Hz,2H),2.83(t,J＝10.8Hz,1H),2.65–2.54(m,1H),2.37(tt,J＝14.3,3.8Hz ,2H),2.26(d,J＝9.4Hz,1H),2.14(dd,J＝10.8,4.9Hz,2H),2.10–1.98(m,3H),1.92–1.84(m,2H),1.78– 1.66(m,5H),1.58(dt,J＝13.3,4.0Hz,1H),1.51–1.33(m,16H),1.24(dd,J＝17.9,9.5Hz,3H),1.08–1.00(m, 1H),0.94(ddd,J＝18.7,8.8,4.6Hz,12H).
13CNMR(151MHz,CDCl 3)δ104.26,104.21,92.13,88.10,85.41,81.16,80.37,79.92,52.67,51.82,46.13,45.20,43.70,40.33,37.37,37.20,36.44,36.28,34.58,34.43,34.07,33.84,33.37,32.09,26.19,25.97,24.77,24.63,24.36,21.28,20.33,20.26,15.28,14.97. 13 CNMR (151MHz, CDCl 3 ) δ104.26,104.21,92.13,88.10,85.41,81.16,80.37,79.92,52.67,51.82,46.13,45.20,43.70,40.33,37.37,37.20,36.44,36 .28,34.58,34.43,34.07, 33.84,33.37,32.09,26.19,25.97,24.77,24.63,24.36,21.28,20.33,20.26,15.28,14.97.
实施例19：化合物19的制备Example 19: Preparation of Compound 19
Figure PCTCN2022131906-appb-000035
Figure PCTCN2022131906-appb-000035
1、将顺式1,3-环戊二醇(500mg，3.73mmol，1.00eq)、三乙胺(1.88g，18.63mmol，5.00eq)加入到10mL二氯甲烷中，反应降温至0℃，滴加甲磺酰氯(1.28g，11.18mmol，3.00eq)，反应在0℃搅拌1h，TLC(5％MeOH/DCM)显 示反应完全，纯化得到976mg中间体19-1；1. Add cis-1,3-cyclopentanediol (500mg, 3.73mmol, 1.00eq) and triethylamine (1.88g, 18.63mmol, 5.00eq) into 10mL dichloromethane, and cool the reaction to 0°C. Methanesulfonyl chloride (1.28g, 11.18mmol, 3.00eq) was added dropwise, and the reaction was stirred at 0°C for 1 hour. TLC (5% MeOH/DCM) showed that the reaction was complete, and 976 mg of intermediate 19-1 was obtained after purification;
2、将中间体19-1(972mg，3.36mmol，1.00eq)加入25mL的DMF中，加入硫代乙酸钾(1.15g，10.08mmol，3.00eq)，反应升温至60℃并搅拌过夜。TLC(10％EA/PE)显示反应完全，纯化得到312mg中间体19-2，收率37％；2. Add intermediate 19-1 (972 mg, 3.36 mmol, 1.00 eq) to 25 mL of DMF, add potassium thioacetate (1.15 g, 10.08 mmol, 3.00 eq), heat the reaction to 60°C and stir overnight. TLC (10% EA/PE) showed that the reaction was complete, and 312 mg of intermediate 19-2 was obtained after purification, with a yield of 37%;
3、将中间体19-2(300mg，1.20mmol，1.00eq)加入到10mL95％乙醇中，反应降温至0℃，滴加1.5mL的2M氢氧化钠水溶液，反应在0℃下搅拌0.5h。TLC(10％EA/PE)显示反应完全，反应液用1NHCl调节pH值至中性，纯化得到154mg中间体19-3；3. Add intermediate 19-2 (300 mg, 1.20 mmol, 1.00 eq) to 10 mL of 95% ethanol, cool the reaction to 0°C, add 1.5 mL of 2M aqueous sodium hydroxide solution dropwise, and stir the reaction at 0°C for 0.5 h. TLC (10% EA/PE) showed that the reaction was complete. The pH value of the reaction solution was adjusted to neutral with 1NHCl, and 154 mg of intermediate 19-3 was obtained after purification;
4、将中间体19-3(154mg，0.93mmol，1.00eq)和DHA(580mg，2.04mmol，2.20eq)加入到15mL乙醚中，降温至0℃，滴加三氟化硼乙醚(290mg，2.04mmol，2.20eq)；反应在0℃下搅拌30min后移至室温搅拌2h。TLC(20％EA/PE)显示反应完全，纯化得到白色固体164mg化合物19A和188mg化合物19B，合并收率57％，化合物19A和化合物19B均为宝色固体。4. Add intermediate 19-3 (154 mg, 0.93 mmol, 1.00 eq) and DHA (580 mg, 2.04 mmol, 2.20 eq) into 15 mL of diethyl ether, cool to 0°C, and dropwise add boron trifluoride diethyl ether (290 mg, 2.04 mmol, 2.20eq); the reaction was stirred at 0°C for 30min and then moved to room temperature and stirred for 2h. TLC (20% EA/PE) showed that the reaction was complete. After purification, 164 mg of compound 19A and 188 mg of compound 19B were obtained as white solids. The combined yield was 57%. Compound 19A and compound 19B were both solid solids.
化合物19的核磁结果如下：The NMR results of compound 19 are as follows:
化合物19A: 1HNMR(500MHz,CDCl 3)δ5.27(s,2H),4.56(d,J＝10.7Hz,2H),4.01-3.96(m,2H),2.75–2.67(m,2H),2.40–2.32(m,2H),2.05–1.97(m,3H),1.90–1.83(m,2H),1.73(d,J＝3.9Hz,2H),1.69–1.59(m,5H),1.58–1.50(m,2H),1.48–1.39(m,8H),1.36-1.22(m,7H),0.97-0.90(m,15H). Compound 19A: 1 HNMR (500MHz, CDCl 3 ) δ5.27 (s, 2H), 4.56 (d, J = 10.7Hz, 2H), 4.01-3.96 (m, 2H), 2.75–2.67 (m, 2H), 2.40–2.32(m,2H),2.05–1.97(m,3H),1.90–1.83(m,2H),1.73(d,J＝3.9Hz,2H),1.69–1.59(m,5H),1.58– 1.50(m,2H),1.48–1.39(m,8H),1.36-1.22(m,7H),0.97-0.90(m,15H).
化合物19B: 1HNMR(500MHz,CDCl 3)δ5.58(s,2H),5.26(d,J＝5.3Hz,2H),4.01-3.96(m,2H),3.04(d,J＝7.0Hz,2H),2.36(d,J＝3.8Hz,2H),2.08-2.03(s,3H),1.91–1.84(m,2H),1.76–1.69(m,6H),1.65-1.55(m,3H),1.51(dd,J＝7.0,4.9Hz,3H),1.44(s,5H),1.37–1.29(m,2H),1.25-1.01(d,J＝7.3Hz,12H),0.95–0.85(m,8H). Compound 19B: 1 HNMR (500MHz, CDCl 3 ) δ5.58 (s, 2H), 5.26 (d, J = 5.3Hz, 2H), 4.01-3.96 (m, 2H), 3.04 (d, J = 7.0Hz, 2H),2.36(d,J＝3.8Hz,2H),2.08-2.03(s,3H),1.91–1.84(m,2H),1.76–1.69(m,6H),1.65-1.55(m,3H) ,1.51(dd,J＝7.0,4.9Hz,3H),1.44(s,5H),1.37–1.29(m,2H),1.25-1.01(d,J＝7.3Hz,12H),0.95–0.85(m ,8H).
实施例20：化合物20的制备Example 20: Preparation of Compound 20
Figure PCTCN2022131906-appb-000036
Figure PCTCN2022131906-appb-000036
如实施例19，原料采用顺式环丁二醇(500mg，5.67mmol，1.00eq)，得到172mg化合物白色固体20A和215mg化合物20B，合并收率55％，化合物20A和化合物20B均为白色固体。As in Example 19, cis-cyclobutanediol (500 mg, 5.67 mmol, 1.00 eq) was used as the raw material, and 172 mg of compound 20A and 215 mg of compound 20B were obtained as white solids. The combined yield was 55%. Compound 20A and compound 20B were both white solids.
化合物20的核磁结果如下：The NMR results of compound 20 are as follows:
化合物20A: 1HNMR(500MHz,CDCl 3)δ5.27(s,2H),4.53(d,J＝10.8Hz,2H),4.42-4.38(m,2H),2.73–2.60(m,4H),2.38–2.30(m,4H),2.05–1.97(m,2H),1.91–1.83(m,2H),1.74(d,J＝3.9Hz,2H),1.69–1.62(m,3H),1.48–1.44(m,1H),1.43–1.38(m,7H),1.36(d,J＝3.4Hz,1H),1.28–1.21(m,6H),0.98-0.90(m,14H). Compound 20A: 1 HNMR (500MHz, CDCl 3 ) δ5.27 (s, 2H), 4.53 (d, J = 10.8Hz, 2H), 4.42-4.38 (m, 2H), 2.73–2.60 (m, 4H), 2.38–2.30(m,4H),2.05–1.97(m,2H),1.91–1.83(m,2H),1.74(d,J＝3.9Hz,2H),1.69–1.62(m,3H),1.48– 1.44(m,1H),1.43–1.38(m,7H),1.36(d,J＝3.4Hz,1H),1.28–1.21(m,6H),0.98-0.90(m,14H).
化合物20B: 1HNMR(500MHz,CDCl 3)δ5.56(s,2H),5.25(d,J＝5.3Hz,2H),4.42–4.38(m,2H),3.04(d,J＝7.1Hz,2H),2.68–2.60(m,2H),2.36–2.29(m,4H),2.04(s,2H),1.92–1.86(m,2H),1.77–1.66(m,4H),1.56(d,J＝3.0Hz,1H),1.51(dd,J＝7.0,4.9Hz,3H),1.46(s,5H),1.38(d,J＝3.6Hz,1H),1.28–1.20(m,7H),1.04-1.00(m,6H),0.94–0.85(m,7H). Compound 20B: 1 HNMR (500MHz, CDCl 3 ) δ5.56 (s, 2H), 5.25 (d, J = 5.3Hz, 2H), 4.42–4.38 (m, 2H), 3.04 (d, J = 7.1Hz, 2H),2.68–2.60(m,2H),2.36–2.29(m,4H),2.04(s,2H),1.92–1.86(m,2H),1.77–1.66(m,4H),1.56(d, J＝3.0Hz,1H),1.51(dd,J＝7.0,4.9Hz,3H),1.46(s,5H),1.38(d,J＝3.6Hz,1H),1.28–1.20(m,7H), 1.04-1.00(m,6H),0.94–0.85(m,7H).
实施例21：化合物21的制备Example 21: Preparation of Compound 21
Figure PCTCN2022131906-appb-000037
Figure PCTCN2022131906-appb-000037
如实施例19，原料采用顺式环辛二醇(500mg，3.84mmol，1.00eq)，得到159mg化合物21A和190mg化合物21B，合并收率46％，化合物21A和化合物21B均为白色固体。As in Example 19, cis-cyclooctanediol (500 mg, 3.84 mmol, 1.00 eq) was used as the raw material, and 159 mg of compound 21A and 190 mg of compound 21B were obtained. The combined yield was 46%. Compound 21A and compound 21B were both white solids.
化合物21的核磁结果如下：The NMR results of compound 21 are as follows:
化合物21A： 1HNMR(500MHz,CDCl 3)δ5.33–5.24(m,4H),4.53(d,J＝10.8Hz,1H),4.51(d,J＝10.8Hz,1H),2.75–2.67(m,2H),2.40–2.32(m,2H),2.22–2.13(m,2H),2.13–2.05(m,2H),2.04–1.97(m,2H),1.90–1.61(m,13H),1.48–1.32(m,9H),1.29–1.22(m,6H),0.97-0.91(m,14H). Compound 21A: 1 HNMR (500MHz, CDCl 3 ) δ5.33–5.24 (m, 4H), 4.53 (d, J = 10.8Hz, 1H), 4.51 (d, J = 10.8Hz, 1H), 2.75–2.67 ( m,2H),2.40–2.32(m,2H),2.22–2.13(m,2H),2.13–2.05(m,2H),2.04–1.97(m,2H),1.90–1.61(m,13H), 1.48–1.32(m,9H),1.29–1.22(m,6H),0.97-0.91(m,14H).
化合物21B： 1HNMR(500MHz,CDCl 3)δ5.58(s,1H),5.56(s,1H),5.34–5.20(m,4H),3.04(d,J＝7.0Hz,2H),2.36(d,J＝3.8Hz,2H),2.22–2.13(m,2H),2.10-2.05(m,4H),1.91–1.84(m,6H),1.80–1.66(m,6H),1.57(d,J＝3.0Hz,1H),1.50(dd,J＝7.0,4.9Hz,3H),1.44(s,5H),1.37(d,J＝3.6Hz,1H),1.25-1.20(m,7H),1.01(d,J＝7.3Hz,6H),0.95-0.85(m,7H). Compound 21B: 1 HNMR (500MHz, CDCl 3 ) δ5.58 (s, 1H), 5.56 (s, 1H), 5.34–5.20 (m, 4H), 3.04 (d, J = 7.0Hz, 2H), 2.36 ( d,J＝3.8Hz,2H),2.22–2.13(m,2H),2.10-2.05(m,4H),1.91–1.84(m,6H),1.80–1.66(m,6H),1.57(d, J＝3.0Hz,1H),1.50(dd,J＝7.0,4.9Hz,3H),1.44(s,5H),1.37(d,J＝3.6Hz,1H),1.25-1.20(m,7H), 1.01(d,J＝7.3Hz,6H),0.95-0.85(m,7H).
实施例22：化合物22的制备Example 22: Preparation of Compound 22
Figure PCTCN2022131906-appb-000038
Figure PCTCN2022131906-appb-000038
如实施例19，原料采用将原料22(5.00g，34.67mmol，1.00eq)，得到1.93g化合物22，收率57％，化合物22为泡沫状白色固体。As in Example 19, raw material 22 (5.00g, 34.67mmol, 1.00eq) was used to obtain 1.93g of compound 22, with a yield of 57%. Compound 22 was a foamy white solid.
化合物22的核磁结果如下：The NMR results of compound 22 are as follows:
1HNMR(500MHz,CDCl 3)δ5.57(s,1H),5.24–5.20(m,2H),4.46(d,J＝10.6Hz,1H),2.99(s,1H),2.66–2.45(m,5H),2.34(t,J＝13.5Hz,2H),2.05–1.76(m,9H),1.66(t,J＝14.2Hz,4H),1.58–1.26(m,15H),1.26–1.17(m,2H),1.02–0.84(m,18H). 1 HNMR (500MHz, CDCl 3 ) δ5.57 (s, 1H), 5.24–5.20 (m, 2H), 4.46 (d, J = 10.6Hz, 1H), 2.99 (s, 1H), 2.66–2.45 (m ,5H),2.34(t,J＝13.5Hz,2H),2.05–1.76(m,9H),1.66(t,J＝14.2Hz,4H),1.58–1.26(m,15H),1.26–1.17( m,2H),1.02–0.84(m,18H).
13CNMR(126MHz,CDCl 3)δ104.21,104.16,92.22,88.02,87.08,81.17,80.83,80.38,52.69,51.78,46.03,45.19,39.83,38.23,37.99,37.36,37.19,36.43,36.27,35.38,35.32,34.44,34.09,32.75,32.69,32.51,32.36,32.26,32.12,31.73,26.19,25.97,24.76,24.61,24.39,21.30,20.34,20.25,15.08,14.84. 13 CNMR (126MHz, CDCl 3 ) δ104.21,104.16,92.22,88.02,87.08,81.17,80.83,80.38,52.69,51.78,46.03,45.19,39.83,38.23,37.99,37.36,37.19,36 .43,36.27,35.38,35.32, 34.44,34.09,32.75,32.69,32.51,32.36,32.26,32.12,31.73,26.19,25.97,24.76,24.61,24.39,21.30,20.34,20.25,15.08,14.84.
实施例23：化合物23的制备Example 23: Preparation of Compound 23
Figure PCTCN2022131906-appb-000039
Figure PCTCN2022131906-appb-000039
如实施例19，原料采用原料23(2.00g，13.87mmol，1.00eq)，得到210mg化合物23，收率12％，化合物23为白色泡沫状固体。As in Example 19, raw material 23 (2.00g, 13.87mmol, 1.00eq) was used to obtain 210 mg of compound 23, with a yield of 12%. Compound 23 was a white foamy solid.
化合物23的核磁结果如下：The NMR results of compound 23 are as follows:
1HNMR(500MHz,CDCl 3)δ5.58(s,2H),5.22(d,J＝4.5Hz,2H),3.03(d,J＝11.8Hz,4H),2.60–2.51(m,2H),2.36(t,J＝13.8Hz,2H),2.03(d,J＝12.9Hz,2H),1.86(d,J＝9.8Hz,7H),1.73–1.64(m,6H),1.51(dd,J＝31.7,11.4Hz,6H),1.42(m,9H),1.23-1.16(m,6H),0.95(d,J＝3.0Hz,12H). 1 HNMR (500MHz, CDCl 3 ) δ5.58 (s, 2H), 5.22 (d, J = 4.5Hz, 2H), 3.03 (d, J = 11.8Hz, 4H), 2.60–2.51 (m, 2H), 2.36(t,J＝13.8Hz,2H),2.03(d,J＝12.9Hz,2H),1.86(d,J＝9.8Hz,7H),1.73–1.64(m,6H),1.51(dd,J ＝31.7,11.4Hz,6H),1.42(m,9H),1.23-1.16(m,6H),0.95(d,J＝3.0Hz,12H).
13CNMR(126MHz,CDCl 3)δ104.16,88.04,87.78,81.19,52.71,45.22,41.28,37.78,37.21,36.45,34.46,32.27,31.37,26.18,25.70,24.62,24.44,20.35,14.89. 13 CNMR (126MHz, CDCl 3 ) δ104.16,88.04,87.78,81.19,52.71,45.22,41.28,37.78,37.21,36.45,34.46,32.27,31.37,26.18,25.70,24.62,24.44,20. 35,14.89.
实施例24：化合物24的制备Example 24: Preparation of Compound 24
Figure PCTCN2022131906-appb-000040
Figure PCTCN2022131906-appb-000040
如实施例19，原料采用原料24(1.00g，6.93mmol，1.00eq)，得到2.60g化合物24，收率82％，化合物24为白色泡沫状固体25。As in Example 19, raw material 24 (1.00g, 6.93mmol, 1.00eq) was used to obtain 2.60g of compound 24 with a yield of 82%. Compound 24 was a white foamy solid 25.
化合物24的核磁结果如下：The NMR results of compound 24 are as follows:
1HNMR(500MHz,CDCl 3)δ5.60(s,2H),5.24(d,J＝5.7Hz,2H),3.02(d,J＝4.8Hz,2H),2.74–2.71(m,2H),2.64–2.54(m,2H),2.36(t,J＝13.9Hz,2H),2.04(d,J＝14.4Hz,2H),1.97–1.80(m,6H),1.72–1.69(m6H),1.58–1.20(m,18H),0.96–0.90(m,16H). 1 HNMR (500MHz, CDCl 3 ) δ5.60 (s, 2H), 5.24 (d, J = 5.7Hz, 2H), 3.02 (d, J = 4.8Hz, 2H), 2.74–2.71 (m, 2H), 2.64–2.54(m,2H),2.36(t,J＝13.9Hz,2H),2.04(d,J＝14.4Hz,2H),1.97–1.80(m,6H),1.72–1.69(m6H),1.58 –1.20(m,18H),0.96–0.90(m,16H).
13CNMR(126MHz,CDCl 3)δ104.14,88.06,88.01,87.27,81.15,81.12,52.70,45.20,39.38,38.63,37.20,37.18,36.44,34.46,34.11,32.20,32.13,28.18,28.12,26.17,26.15,24.61,24.58,24.43,24.40,20.35,14.88. 13 CNMR (126MHz, CDCl 3 ) δ104.14,88.06,88.01,87.27,81.15,81.12,52.70,45.20,39.38,38.63,37.20,37.18,36.44,34.46,34.11,32.20,32.13,28. 18,28.12,26.17, 26.15,24.61,24.58,24.43,24.40,20.35,14.88.
实施例25：化合物25的制备Example 25: Preparation of Compound 25
Figure PCTCN2022131906-appb-000041
Figure PCTCN2022131906-appb-000041
1、将原料25(1.50g，10.41mmol，1.00eq)溶于55mL的MeOH中，缓慢加入H 2SO 4(4.1g，41.63mmol，4.00eq)，加完后反应升温至回流下搅拌3h；反应冷却至0℃，加入碳酸氢钠调节PH至中性，纯化得到1.70g中间体25-1； 1. Dissolve raw material 25 (1.50g, 10.41mmol, 1.00eq) in 55mL of MeOH, slowly add H 2 SO 4 (4.1g, 41.63mmol, 4.00eq). After the addition is completed, the reaction is heated to reflux and stirred for 3 hours; The reaction was cooled to 0°C, sodium bicarbonate was added to adjust the pH to neutral, and 1.70 g of intermediate 25-1 was obtained after purification;
2、将LiAlH 4(1.45g，38.33mmol，4.00eq)加入到96mL的THF中，降温至0℃并搅拌10min；将中间体25-1(1.65g，95.83mmol，1.00eq)溶于20mL的THF滴加至反应中，加完后移至室温搅拌2h；待反应完成后，反应降温至0℃，纯化得到840mg中间体25-2； 2. Add LiAlH 4 (1.45g, 38.33mmol, 4.00eq) to 96mL of THF, cool to 0°C and stir for 10min; dissolve intermediate 25-1 (1.65g, 95.83mmol, 1.00eq) in 20mL of THF. THF was added dropwise to the reaction, and after the addition was completed, it was moved to room temperature and stirred for 2 hours; after the reaction was completed, the reaction was cooled to 0°C and purified to obtain 840 mg of intermediate 25-2;
3、如实施例19，采用中间体25-2(800mg，6.89mmol，1.00eq)，得到320mg化合物25，收率23％，化合物25为白色泡沫状固体。3. As in Example 19, using intermediate 25-2 (800 mg, 6.89 mmol, 1.00 eq), 320 mg of compound 25 was obtained with a yield of 23%. Compound 25 was a white foamy solid.
化合物25的核磁结果如下：The NMR results of compound 25 are as follows:
1HNMR(600MHz,CDCl 3)δ5.63(s,2H),5.28(d,J＝4.3Hz,2H),3.11(d,J＝12 .3Hz,2H),3.01(s,2H),2.86(d,J＝12.5Hz,2H),2.35(d,J＝13.8Hz,2H),2.03(d,J＝14.0Hz,2H),1.88(d,J＝12.3Hz,9H),1.73–1.65(m,4H),1.50(dd,J＝22.3,14.2Hz,4H),1.43(s,6H),1.23(dd,J＝25.9,8.9Hz,4H),1.01–0.88(m,15H). 1 HNMR (600MHz, CDCl 3 ) δ5.63 (s, 2H), 5.28 (d, J = 4.3Hz, 2H), 3.11 (d, J = 12.3Hz, 2H), 3.01 (s, 2H), 2.86 (d,J＝12.5Hz,2H),2.35(d,J＝13.8Hz,2H),2.03(d,J＝14.0Hz,2H),1.88(d,J＝12.3Hz,9H),1.73–1.65 (m,4H),1.50(dd,J＝22.3,14.2Hz,4H),1.43(s,6H),1.23(dd,J＝25.9,8.9Hz,4H),1.01–0.88(m,15H).
13CNMR(151MHz,CDCl 3)δ104.15,88.04,87.97,81.21,52.70,45.21,42.49,42.41,37.17,36.45,34.46,32.33,31.14,26.22,24.62,24.44,20.37,14.96. 13 CNMR (151MHz, CDCl 3 ) δ104.15,88.04,87.97,81.21,52.70,45.21,42.49,42.41,37.17,36.45,34.46,32.33,31.14,26.22,24.62,24.44,20.37,14. 96.
实施例26：化合物26的制备Example 26: Preparation of Compound 26
Figure PCTCN2022131906-appb-000042
Figure PCTCN2022131906-appb-000042
如实施例19，原料采用将原料26(1.00g，8.61mmol，1.00eq)，得到910mg化合物26，收率66％，化合物26为白色泡沫状固体。As in Example 19, raw material 26 (1.00g, 8.61mmol, 1.00eq) was used to obtain 910 mg of compound 26, with a yield of 66%. Compound 26 was a white foamy solid.
化合物26的核磁结果如下：The NMR results of compound 26 are as follows:
1HNMR(500MHz,CH 3CN)δ5.52(m,2H),5.13(m,2H),3.08–2.47(m,10H),2.49–2.25(m,2H),1.97(m,4H),1.90–1.57(m,10H),1.58–1.17(m,14H),0.98-0.94(m,12H). 1 HNMR(500MHz,CH 3 CN)δ5.52(m,2H),5.13(m,2H),3.08–2.47(m,10H),2.49–2.25(m,2H),1.97(m,4H), 1.90–1.57(m,10H),1.58–1.17(m,14H),0.98-0.94(m,12H).
13CNMR(126MHz,CH 3CN)δ104.18,92.18,88.05,88.01,87.41,86.79,81.16,52.70,46.06,45.19,37.35,37.19,36.87,36.44,34.44,34.18,34.06,32.21,32.09,26.18,24.62,24.38,24.30,20.33,20.25,14.89. 13 CNMR (126MHz, CH 3 CN) δ104.18,92.18,88.05,88.01,87.41,86.79,81.16,52.70,46.06,45.19,37.35,37.19,36.87,36.44,34.44,34.18,34.06,32 .21,32.09,26.18 ,24.62,24.38,24.30,20.33,20.25,14.89.
实施例27：化合物27的制备Example 27: Preparation of Compound 27
Figure PCTCN2022131906-appb-000043
Figure PCTCN2022131906-appb-000043
1、将甲基三苯基溴化磷(41.17g，115.25mmol，1.20eq)加入到400mL的THF中，置换氩气，降温至0℃，分批加入叔丁醇钾(12.93mg，115.25mmol，1.20eq)，反应在0℃下搅拌30min后移至室温搅拌3h，反应降温至0℃；将原料27(15.00g，96.04mmol，1.00eq)溶解在50mL放入THF中滴加至反应中，反应在0℃下搅拌1h后移至室温搅拌过夜，纯化得到12.5g中间体27-1；1. Add methyltriphenylphosphonium bromide (41.17g, 115.25mmol, 1.20eq) to 400mL of THF, replace the argon gas, cool to 0°C, and add potassium tert-butoxide (12.93mg, 115.25mmol) in batches , 1.20eq), the reaction was stirred at 0°C for 30min and then moved to room temperature and stirred for 3h. The reaction was cooled to 0°C; raw material 27 (15.00g, 96.04mmol, 1.00eq) was dissolved in 50mL and put into THF and added dropwise to the reaction. , the reaction was stirred at 0°C for 1 h, then moved to room temperature and stirred overnight, and 12.5 g of intermediate 27-1 was obtained after purification;
2、将中间体27-1(10.00g，64.85mmol，1.00eq)、Zn(8.48g，129.69mmol，2.00eq)和Cu(OAc) 2(1.18g，6.48mmol，0.10eq)加入到300mL乙醚中，置换氩气，室温下搅拌3h；将三氯乙酰氯(23.58g，129.69mmol，2.00eq)溶解在200mL乙醚中滴加至反应中，反应在室温下搅拌过夜，纯化得到10.50g中间体27-2； 2. Add intermediate 27-1 (10.00g, 64.85mmol, 1.00eq), Zn (8.48g, 129.69mmol, 2.00eq) and Cu(OAc) 2 (1.18g, 6.48mmol, 0.10eq) into 300mL diethyl ether in, replace the argon gas, and stir at room temperature for 3 hours; dissolve trichloroacetyl chloride (23.58g, 129.69mmol, 2.00eq) in 200mL of diethyl ether and add it dropwise to the reaction. The reaction is stirred at room temperature overnight, and 10.50g of the intermediate is obtained after purification. 27-2;
3、将中间体27-2(10.00g，37.72mmol，1.00eq)和Zn(12.33g，188.59mmol，5.00eq)加入到100mL甲醇中，搅拌下分批加入氯化铵(20.17g，377.17mmol，10.00eq)，反应在室温下搅拌5h，纯化得到6.6g中间体27-3；3. Add intermediate 27-2 (10.00g, 37.72mmol, 1.00eq) and Zn (12.33g, 188.59mmol, 5.00eq) into 100mL methanol, and add ammonium chloride (20.17g, 377.17mmol) in batches while stirring. , 10.00eq), the reaction was stirred at room temperature for 5h, and 6.6g of intermediate 27-3 was obtained after purification;
4、将中间体27-3(2.20g，11.21mmol，1.00eq)加入到30mL的6N盐酸中，室温下搅拌3h，纯化得到1.66g中间体27-4；4. Add intermediate 27-3 (2.20g, 11.21mmol, 1.00eq) to 30mL of 6N hydrochloric acid, stir at room temperature for 3h, and purify to obtain 1.66g of intermediate 27-4;
5、将中间体27-4(600mg，3.94mmol，1.00eq)加入到10mL甲醇中，降温至0℃，分批加入NaBH 4(448mg，11.83mmol，3.00eq)，反应在0℃下搅拌 3h后移至室温搅拌3h，纯化得到316mg中间体27-5； 5. Add intermediate 27-4 (600mg, 3.94mmol, 1.00eq) to 10mL methanol, cool to 0°C, add NaBH 4 (448mg, 11.83mmol, 3.00eq) in batches, and stir the reaction at 0°C for 3 hours. Then it was moved to room temperature and stirred for 3 hours, and then purified to obtain 316 mg of intermediate 27-5;
6、如实施例19，采用中间体27-5(300mg，1.92mmol，1.00eq)，得到57mg化合物27A和73mg化合物27B，合并收率42％，化合物27A和化合物27B均为白色固体。6. As in Example 19, using intermediate 27-5 (300 mg, 1.92 mmol, 1.00 eq), 57 mg of compound 27A and 73 mg of compound 27B were obtained. The combined yield was 42%. Compound 27A and compound 27B were both white solids.
化合物27的核磁结果如下：The NMR results of compound 27 are as follows:
化合物27A： 1HNMR(500MHz,CDCl 3)δ5.29(s,2H),4.73(d,J＝10.8Hz,2H),4.20–4.09(m,1H),3.48(s,1H),2.75–2.67(m,2H),2.40–2.32(m,2H),2.23(s,1H),2.07(s,1H),2.04–1.97(m,2H),1.90–1.83(m,2H),1.7–1.61(m,11H),1.48–1.39(m,8H),1.36–1.22(m,10H),0.97-0.91(m,15H). Compound 27A: 1 HNMR (500MHz, CDCl 3 ) δ5.29 (s, 2H), 4.73 (d, J = 10.8Hz, 2H), 4.20–4.09 (m, 1H), 3.48 (s, 1H), 2.75– 2.67(m,2H),2.40–2.32(m,2H),2.23(s,1H),2.07(s,1H),2.04–1.97(m,2H),1.90–1.83(m,2H),1.7– 1.61(m,11H),1.48–1.39(m,8H),1.36–1.22(m,10H),0.97-0.91(m,15H).
化合物27B： 1HNMR(500MHz,CDCl 3)δ5.56(s,2H),5.25(d,J＝5.3Hz,2H),4.20–4.09(m,1H),3.48(s,1H),3.04(d,J＝7.0Hz,2H),2.36(d,J＝3.8Hz,2H),2.23(s,1H),2.09–2.04(m,3H),1.91–1.84(m,2H),1.76–1.57(m,11H),1.51(dd,J＝7.0,4.9Hz,3H),1.44(s,5H),1.37-1.25(m,12H),1.01(d,J＝7.3Hz,5H),0.96(d,J＝6.4Hz,6H),0.89–0.85(m,2H). Compound 27B: 1 HNMR (500MHz, CDCl 3 ) δ5.56 (s, 2H), 5.25 (d, J = 5.3Hz, 2H), 4.20–4.09 (m, 1H), 3.48 (s, 1H), 3.04 ( d,J＝7.0Hz,2H),2.36(d,J＝3.8Hz,2H),2.23(s,1H),2.09–2.04(m,3H),1.91–1.84(m,2H),1.76–1.57 (m,11H),1.51(dd,J＝7.0,4.9Hz,3H),1.44(s,5H),1.37-1.25(m,12H),1.01(d,J＝7.3Hz,5H),0.96( d,J＝6.4Hz,6H),0.89–0.85(m,2H).
实施例28：化合物28的制备Example 28: Preparation of Compound 28
Figure PCTCN2022131906-appb-000044
Figure PCTCN2022131906-appb-000044
1、将LiAlH 4(403mg，10.62mmol，2.70eq)加入到30mLTHF中，降温至0℃，将原料28(1.00g，3.93mmol，1.00eq)用9mLTHF溶解并滴加到反应中，反应在0℃下搅拌20min后移至室温搅拌12h；TLC(50％EA/PE)显示原料消失，纯化得到600mg中间体28-1； 1. Add LiAlH 4 (403mg, 10.62mmol, 2.70eq) to 30mLTHF, cool to 0°C, dissolve raw material 28 (1.00g, 3.93mmol, 1.00eq) with 9mLTHF and add it dropwise to the reaction. The reaction is at 0 Stir at ℃ for 20 minutes, then move to room temperature and stir for 12 hours; TLC (50% EA/PE) shows that the raw material disappears, and 600 mg of intermediate 28-1 is obtained after purification;
2、将中间体28-1(690mg，4.05mmol，1.00eq)溶解在20mL甲苯中，依次加入咪唑(820mg，12.04mmol，2.97eq)、三苯基膦(3.16g，12.04mmol，2.97eq)和碘(3.06g，12.04mmol，2.97eq)，反应升温至60℃并搅拌12h；TLC(40％EA/PE)显示原料消失，纯化得到400mg中间体28-2；2. Dissolve intermediate 28-1 (690mg, 4.05mmol, 1.00eq) in 20mL toluene, and add imidazole (820mg, 12.04mmol, 2.97eq) and triphenylphosphine (3.16g, 12.04mmol, 2.97eq) in sequence. and iodine (3.06g, 12.04mmol, 2.97eq), the reaction was heated to 60°C and stirred for 12h; TLC (40% EA/PE) showed that the raw material disappeared, and 400mg of intermediate 28-2 was obtained after purification;
3、将中间体28-2(400mg，1.03mmol，1.00eq)溶解在4mLDMF中，加入硫代乙酸钾(352mg，3.08mmol，3.00eq)，反应升温至60℃搅拌2h；TLC(40％EA/PE)显示原料消失，纯化得到250mg中间体28-3；3. Dissolve intermediate 28-2 (400mg, 1.03mmol, 1.00eq) in 4mLDMF, add potassium thioacetate (352mg, 3.08mmol, 3.00eq), heat the reaction to 60°C and stir for 2h; TLC (40% EA /PE) showed that the raw materials disappeared, and 250 mg of intermediate 28-3 was obtained after purification;
4、将中间体28-3(150mg，0.52mmol，1.00eq)溶解在5mL的95％乙醇中，降温至0℃，缓慢滴加0.78mL的2M氢氧化钠水溶液，反应继续在0℃下搅拌15min；TLC(10％EA/PE)显示原料消失，纯化得到100mg中间体28-4；4. Dissolve intermediate 28-3 (150 mg, 0.52 mmol, 1.00 eq) in 5 mL of 95% ethanol, cool to 0°C, slowly add 0.78 mL of 2M sodium hydroxide aqueous solution dropwise, and continue stirring at 0°C. 15min; TLC (10% EA/PE) showed that the raw material disappeared, and 100 mg of intermediate 28-4 was obtained after purification;
5、将中间体28-4(100mg，0.49mmol，1.00eq)和DHA(351mg，1.24mmol，2.50eq)溶解在5mL乙醚中，降温至0℃，缓慢滴加三氟化硼乙醚(210mg，1.48mmol，3.00eq)，反应在0℃下搅拌30min后移至室温搅拌2h；TLC(40％EA/PE)显示原料消失，纯化得到91mg化合物28A和109mg化合物28B，收率55％，化合物28A和化合物28B均为白色固体。5. Dissolve intermediate 28-4 (100 mg, 0.49 mmol, 1.00 eq) and DHA (351 mg, 1.24 mmol, 2.50 eq) in 5 mL of diethyl ether, cool to 0°C, and slowly add boron trifluoride diethyl ether (210 mg, 1.48mmol, 3.00eq), the reaction was stirred at 0°C for 30min and then moved to room temperature and stirred for 2h; TLC (40% EA/PE) showed that the raw materials disappeared, and purification gave 91mg of compound 28A and 109mg of compound 28B, with a yield of 55%, compound 28A and compound 28B are both white solids.
化合物28的核磁结果如下：The NMR results of compound 28 are as follows:
化合物28A： 1HNMR(600MHz,CDCl 3)δ5.58(s,2H),5.16(d,J＝5.2Hz,2H),3.01(d,J＝7.0Hz,2H),2.64(d,J＝12.5Hz,2H),2.57(d,J＝6.8Hz,1H),2.45(d,J＝12.5Hz,2H),2.40–2.31(m,2H),2.06-2.02(m,2H),1.90–1.83(m,4H),1.73–1.67(m,4H),1.58–1.33(m,21H),1.27–1.20(m,4H),1.00–0.85(m,14H). Compound 28A: 1 HNMR (600MHz, CDCl 3 ) δ5.58 (s, 2H), 5.16 (d, J = 5.2 Hz, 2H), 3.01 (d, J = 7.0 Hz, 2H), 2.64 (d, J = 12.5Hz,2H),2.57(d,J＝6.8Hz,1H),2.45(d,J＝12.5Hz,2H),2.40–2.31(m,2H),2.06-2.02(m,2H),1.90– 1.83(m,4H),1.73–1.67(m,4H),1.58–1.33(m,21H),1.27–1.20(m,4H),1.00–0.85(m,14H).
化合物28B： 1HNMR(600MHz,CDCl 3)δ5.25(s,2H),4.49–4.43(d,J＝10.7Hz,2H),3.04-2.98(m,2H),2.63(d,J＝12.0Hz,2H),2.58(d,J＝7.0Hz,1H),2.46(d,J＝12.4Hz,2H),2.41–2.30(m,2H),2.04-2.00(m,2H),1.93–1.85(m,4H),1.72-1.66(m,4H),1.58–1.33(m,22H),1.25-1.20(m,3H),1.15-1. 04(m,2H),1.00–0.85(m,12H). Compound 28B: 1 HNMR (600MHz, CDCl 3 ) δ5.25 (s, 2H), 4.49–4.43 (d, J = 10.7Hz, 2H), 3.04-2.98 (m, 2H), 2.63 (d, J = 12.0 Hz,2H),2.58(d,J＝7.0Hz,1H),2.46(d,J＝12.4Hz,2H),2.41–2.30(m,2H),2.04-2.00(m,2H),1.93–1.85 (m,4H),1.72-1.66(m,4H),1.58–1.33(m,22H),1.25-1.20(m,3H),1.15-1. 04(m,2H),1.00–0.85(m, 12H).
实施例29：化合物29的制备Example 29: Preparation of Compound 29
Figure PCTCN2022131906-appb-000045
Figure PCTCN2022131906-appb-000045
1、将LiAlH 4(279mg，7.35mmol，2.50eq)加入到20mL的THF中，降温至0℃，将29(500mg，2.94mmol，1.00eq)用9mL的THF溶解并滴加到反应中，反应在0℃下搅拌20min后移至室温搅拌1h，纯化得到300mg中间体29-1； 1. Add LiAlH 4 (279 mg, 7.35 mmol, 2.50 eq) to 20 mL of THF, cool to 0°C, dissolve 29 (500 mg, 2.94 mmol, 1.00 eq) in 9 mL of THF and add it dropwise to the reaction. Stir at 0°C for 20 min, then move to room temperature and stir for 1 h, and purify to obtain 300 mg of intermediate 29-1;
2、将中间体29-1(740mg，5.77mmol，1.00eq)溶解在58mL的DCM中，降温至0℃，依次加入咪唑(1.14g，16.74mmol，2.97eq)、三苯基膦(4.39g，16.74mmol，2.97eq)和碘(4.25g，16.74mmol，2.97eq)，反应在0℃下搅拌10min后移至室温搅拌2h，纯化得到1.50g中间体29-2；2. Dissolve intermediate 29-1 (740mg, 5.77mmol, 1.00eq) in 58mL of DCM, cool to 0°C, and add imidazole (1.14g, 16.74mmol, 2.97eq) and triphenylphosphine (4.39g) in sequence. , 16.74mmol, 2.97eq) and iodine (4.25g, 16.74mmol, 2.97eq). The reaction was stirred at 0°C for 10min and then moved to room temperature and stirred for 2h. After purification, 1.50g of intermediate 29-2 was obtained;
3、将中间体29-2(100mg，0.29mmol，1.00eq)溶解在3m的LDMF中，依次加入实施例1的SDHA-B(168mg，0.56mmol，1.95eq)和碳酸钾(79mg，0.57mmol，2.00eq)，反应在室温下搅拌2h，纯化得到102mg化合物29B收率51％，化合物29B为无色油状液体。3. Dissolve intermediate 29-2 (100 mg, 0.29 mmol, 1.00 eq) in 3 m of LDMF, and add SDHA-B (168 mg, 0.56 mmol, 1.95 eq) and potassium carbonate (79 mg, 0.57 mmol) of Example 1 in sequence. , 2.00eq), the reaction was stirred at room temperature for 2 h, and 102 mg of compound 29B was purified with a yield of 51%. Compound 29B was a colorless oily liquid.
4、将中间体29-2(100mg，0.29mmol，1.00eq)溶解在3mL的DMF中，依次加入实施例1的SDHA-A(168mg，0.56mmol，1.95eq)和碳酸钾(79mg，0.57mmol，2.00eq)，反应在室温下搅拌2h，纯化得到104mg化合物29A，收率52％，化合物29A为白色固体。4. Dissolve intermediate 29-2 (100 mg, 0.29 mmol, 1.00 eq) in 3 mL of DMF, and add SDHA-A (168 mg, 0.56 mmol, 1.95 eq) and potassium carbonate (79 mg, 0.57 mmol) of Example 1 in sequence. , 2.00eq), the reaction was stirred at room temperature for 2 h, and 104 mg of compound 29A was obtained after purification, with a yield of 52%. Compound 29A was a white solid.
化合物29的核磁结果如下：The NMR results of compound 29 are as follows:
化合物29A： 1HNMR(600MHz,CDCl 3)δ5.18(s,2H),4.46(d,J＝10.7Hz,2H),2.86(d,J＝13.2Hz,2H),2.73(d,J＝13.3Hz,2H),2.51–2.41(m,2H),2.29(td,J＝14.1,3.9Hz,2H),1.97–1.90(m,2H),1.83–1.76(m,2H),1.69–1.58(m,7H),1.50(dt,J＝13.3,4.0Hz,2H),1.45–1.33(m,10H),1.31–1.22(m,5H),1.21–1.14(m,2H),1.01–0.92(m,2H),0.89(d,J＝6.3Hz,6H),0.85(d,J＝7.2Hz,6H). Compound 29A: 1 HNMR (600MHz, CDCl 3 ) δ5.18 (s, 2H), 4.46 (d, J = 10.7Hz, 2H), 2.86 (d, J = 13.2Hz, 2H), 2.73 (d, J = 13.3Hz,2H),2.51–2.41(m,2H),2.29(td,J＝14.1,3.9Hz,2H),1.97–1.90(m,2H),1.83–1.76(m,2H),1.69–1.58 (m,7H),1.50(dt,J＝13.3,4.0Hz,2H),1.45–1.33(m,10H),1.31–1.22(m,5H),1.21–1.14(m,2H),1.01–0.92 (m,2H),0.89(d,J＝6.3Hz,6H),0.85(d,J＝7.2Hz,6H).
化合物29B： 1HNMR(600MHz,CDCl 3)δ5.60(s,2H),5.22(d,J＝5.6Hz,2H),3.03–3.01(m,2H),2.85(d,J＝14.3Hz,2H),2.74d,J＝12.3Hz,2H),2.36(td,J＝14.1,4.0Hz,2H),1.84–1.72(m,2H),1.70–1.58(m,13H),1.50–1.33(m,12H),1.25–1.23(m,3H),0.98–0.94(m,14H). Compound 29B: 1 HNMR (600MHz, CDCl 3 ) δ5.60 (s, 2H), 5.22 (d, J = 5.6Hz, 2H), 3.03–3.01 (m, 2H), 2.85 (d, J = 14.3Hz, 2H),2.74d,J＝12.3Hz,2H),2.36(td,J＝14.1,4.0Hz,2H),1.84–1.72(m,2H),1.70–1.58(m,13H),1.50–1.33( m,12H),1.25–1.23(m,3H),0.98–0.94(m,14H).
实施例30：化合物30的制备Example 30: Preparation of Compound 30
Figure PCTCN2022131906-appb-000046
Figure PCTCN2022131906-appb-000046
1、将原料30(50.00g，128.10mmol，1.00eq)和硫代乙酸(12.71g，166.51mmol，1.30eq)溶解在650mL的DCM中，降温至0℃，缓慢滴加三氟化硼乙醚(29.11g，204.9mmol，1.60eq)，滴加完毕后移至室温搅拌过夜，纯化得到28.22g中间体30-1；1. Dissolve raw material 30 (50.00g, 128.10mmol, 1.00eq) and thioacetic acid (12.71g, 166.51mmol, 1.30eq) in 650mL of DCM, cool to 0°C, and slowly add boron trifluoride ether ( 29.11g, 204.9mmol, 1.60eq), after the dropwise addition, move to room temperature and stir overnight, and purify to obtain 28.22g of intermediate 30-1;
2、将中间体30-1(18.00g，44.29mmol，1.00eq)加入到1.5L甲醇中，降温至-25℃，缓慢滴加97mL的0.5M甲醇钠的甲醇溶液，滴完后继续在-25℃下搅拌30min，反应用阳离子交换树脂调节pH值至中性，纯化得到16.00g中间体30-2；2. Add intermediate 30-1 (18.00g, 44.29mmol, 1.00eq) to 1.5L methanol, cool to -25°C, slowly add 97mL of 0.5M sodium methoxide methanol solution dropwise, and continue to - Stir for 30 minutes at 25°C, adjust the pH value to neutral using cation exchange resin, and purify to obtain 16.00g of intermediate 30-2;
3、将DHA(18.73g，65..87mmol，1.50eq)溶解在400mL乙醚中，降温至0℃，滴加三氟化硼乙醚(12.46g，87.82mmol，2.00eq)，随后将中间体30-2(16.00g，43.91mmol，1.00eq)用40mL乙醚溶解并滴加至反应中，滴加完毕后反应移至室温搅拌过夜，纯化得到20.15g中间体30-3；3. Dissolve DHA (18.73g, 65..87mmol, 1.50eq) in 400mL ether, cool to 0°C, add boron trifluoride ether (12.46g, 87.82mmol, 2.00eq) dropwise, and then add intermediate 30 -2 (16.00g, 43.91mmol, 1.00eq) was dissolved in 40mL of diethyl ether and added dropwise to the reaction. After the addition was completed, the reaction was moved to room temperature and stirred overnight. After purification, 20.15g of intermediate 30-3 was obtained;
4、将中间体30-3(20.00g，31.71mmol，1.00eq)溶解在320mL甲醇中，降温至0℃，加入甲醇钠(1.03g，19.03mmol，0.60eq)，反应在0℃下搅拌10min后移至室温搅拌2h，反应液用阳离子交换树脂调节pH值至中性，纯化得到13.22g中间体30-4；4. Dissolve intermediate 30-3 (20.00g, 31.71mmol, 1.00eq) in 320mL methanol, cool to 0°C, add sodium methoxide (1.03g, 19.03mmol, 0.60eq), and stir the reaction at 0°C for 10 min. Then it was moved to room temperature and stirred for 2 hours. The pH value of the reaction solution was adjusted to neutral with cation exchange resin, and 13.22g of intermediate 30-4 was obtained after purification;
5、将中间体30-4(3.00g，6.49mmol，1.00eq)溶解在30mL吡啶中，降温至0℃，加入对甲苯环酰氯(1.36g，7.13mmol，1.10eq)和DMAP(79mg，0.65mmol，0.10eq)，反应在0℃下搅拌10min后移至室温搅拌3h；TLC(5％MeOH/DCM)显示反应完全，纯化得到2.30g中间体30-5；5. Dissolve intermediate 30-4 (3.00g, 6.49mmol, 1.00eq) in 30mL pyridine, cool to 0°C, add p-toluoyl chloride (1.36g, 7.13mmol, 1.10eq) and DMAP (79mg, 0.65 mmol, 0.10 eq), the reaction was stirred at 0°C for 10 min and then moved to room temperature and stirred for 3 h; TLC (5% MeOH/DCM) showed that the reaction was complete, and 2.30 g of intermediate 30-5 was obtained after purification;
6、将中间体30-5(1.00g，1.62mmol，1.00eq)和实施例1的SDHA-A(731mg，2.43mmol，1.50eq)溶解在32mL的DMF中，加入碳酸钾(448mg，3.24mmol，2.00eq)，反应在室温下搅拌过夜，纯化得到160mg化合物30，收率13％，化合物30为淡红色固体。6. Dissolve intermediate 30-5 (1.00g, 1.62mmol, 1.00eq) and SDHA-A of Example 1 (731mg, 2.43mmol, 1.50eq) in 32mL of DMF, and add potassium carbonate (448mg, 3.24mmol , 2.00eq), the reaction was stirred at room temperature overnight, and 160 mg of compound 30 was purified, with a yield of 13%. Compound 30 was a light red solid.
化合物30的核磁结果如下：The NMR results of compound 30 are as follows:
1HNMR(500MHz,CDCl 3)δ5.69(d,J＝5.2Hz,1H),5.61(s,1H),5.37(s,1H),4.51(d,J＝10.7Hz,1H),4.35(d,J＝9.5Hz,1H),4.15(d,J＝4.4Hz,1H),4.02(td,J＝9.2,4.7Hz,1H),3.83(t,J＝8.7Hz,1H),3.59(dd,J＝17.1,8.8Hz,2H),3.20(d,J＝13.0Hz,1H),3.04(dd,J＝6.6,2.8Hz,3H),2.97(s,1H),2.60(d,J＝10.8H z,1H),2.36(t,J＝14.0Hz,2H),2.08–1.99(m,2H),1.96–1.84(m,2H),1.79–1.57(m,6H),1.55–1.31(m,12H),1.26(tt,J＝11.8,6.1Hz,3H),1.09–1.01(m,1H),1.00–0.90(m,12H). 1 HNMR (500MHz, CDCl 3 ) δ5.69(d,J＝5.2Hz,1H),5.61(s,1H),5.37(s,1H),4.51(d,J＝10.7Hz,1H),4.35( d,J＝9.5Hz,1H),4.15(d,J＝4.4Hz,1H),4.02(td,J＝9.2,4.7Hz,1H),3.83(t,J＝8.7Hz,1H),3.59( dd,J＝17.1,8.8Hz,2H),3.20(d,J＝13.0Hz,1H),3.04(dd,J＝6.6,2.8Hz,3H),2.97(s,1H),2.60(d,J ＝10.8H z,1H),2.36(t,J＝14.0Hz,2H),2.08–1.99(m,2H),1.96–1.84(m,2H),1.79–1.57(m,6H),1.55–1.31 (m,12H),1.26(tt,J＝11.8,6.1Hz,3H),1.09–1.01(m,1H),1.00–0.90(m,12H).
实施例31：化合物31的制备Example 31: Preparation of Compound 31
Figure PCTCN2022131906-appb-000047
Figure PCTCN2022131906-appb-000047
将30-4(1.70g，3.68mmol，1.00eq)和DHA(1.25g，4.41mmol，1.20eq)溶解在70mL乙醚中，降温至0℃并搅拌10min，滴加三氟化硼乙醚(538mg，4.04mmol，1.10eq)，反应在0℃下搅拌30min后移至室温搅拌过夜；TLC(5％MeOH/DCM)显示原料消失，将反应液倒入200mL饱和碳酸氢钠溶液中，搅拌，用70mLEA萃取3次，合并有机层，50mL饱和食盐水洗涤1次，无水硫酸钠干燥，过滤，滤液浓缩至干，1～3％MeOH/DCM柱层析得到白色固体31A(530mg)和31B(230mg)，收率20％。Dissolve 30-4 (1.70g, 3.68mmol, 1.00eq) and DHA (1.25g, 4.41mmol, 1.20eq) in 70mL ether, cool to 0°C and stir for 10 minutes, add boron trifluoride ether (538mg, 4.04mmol, 1.10eq), the reaction was stirred at 0°C for 30min and then moved to room temperature and stirred overnight; TLC (5% MeOH/DCM) showed that the raw materials disappeared. Pour the reaction solution into 200mL saturated sodium bicarbonate solution, stir, and use 70mLEA Extract three times, combine the organic layers, wash once with 50 mL saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness. 1-3% MeOH/DCM column chromatography obtains white solids 31A (530 mg) and 31B (230 mg). ), yield 20%.
化合物31的核磁结果如下：The NMR results of compound 31 are as follows:
化合物31A： 1HNMR(500MHz,DMSO)δ5.57(d,J＝5.2Hz,1H),5.53(s,1H),5.35(s,1H),5.11(s,1H),5.05(d,J＝4.7Hz,1H),4.94(d,J＝5.3Hz,1H),4.72(d,J＝3.2Hz,1H),4.25(d,J＝9.4Hz,1H),3.80(dd,J＝11.1,4.6Hz,1H),3.57(d,J＝9.5Hz,1H),3.29(d,J＝4.3Hz,1H),3.26–3.20(m,1H),3.17(dd,J＝15.5,6.7Hz,2H),2.79(dd,J＝12.0,5.0Hz,1H),2.45–2.36(m,1H),2.18(td,J＝14.0,3.2Hz,2H),2.04–1.93(m,2H),1.79(t,J＝11.2Hz,3H),1.70–1.52(m,5H),1.49–1.26(m,12H),1.15(ddd,J＝24.9,11.6,6.7Hz,2H),0.94–0.83(m,14H). Compound 31A: 1 HNMR (500MHz, DMSO) δ5.57 (d, J = 5.2 Hz, 1H), 5.53 (s, 1H), 5.35 (s, 1H), 5.11 (s, 1H), 5.05 (d, J ＝4.7Hz,1H),4.94(d,J＝5.3Hz,1H),4.72(d,J＝3.2Hz,1H),4.25(d,J＝9.4Hz,1H),3.80(dd,J＝11.1 ,4.6Hz,1H),3.57(d,J＝9.5Hz,1H),3.29(d,J＝4.3Hz,1H),3.26–3.20(m,1H),3.17(dd,J＝15.5,6.7Hz ,2H),2.79(dd,J＝12.0,5.0Hz,1H),2.45–2.36(m,1H),2.18(td,J＝14.0,3.2Hz,2H),2.04–1.93(m,2H), 1.79(t,J＝11.2Hz,3H),1.70–1.52(m,5H),1.49–1.26(m,12H),1.15(ddd,J＝24.9,11.6,6.7Hz,2H),0.94–0.83( m,14H).
化合物31B： 1HNMR(500MHz,DMSO)δ5.78(s,1H),5.56(d,J＝5.2Hz,1H), 5.54(s,1H),5.22(d,J＝3.4Hz,1H),5.14(d,J＝6.6Hz,1H),4.99(d,J＝7.4Hz,1H),4.36(d,J＝9.8Hz,1H),4.18(t,J＝6.0Hz,1H),3.64(dd,J＝10.0,6.8Hz,1H),3.54(t,J＝8.8Hz,1H),3.49–3.43(m,1H),3.29–3.22(m,1H),3.18(ddd,J＝11.8,7.3,2.2Hz,2H),2.81(d,J＝7.1Hz,1H),2.37(dd,J＝7.1,4.0Hz,1H),2.26–2.12(m,2H),2.05–1.87(m,3H),1.86–1.75(m,2H),1.71–1.58(m,4H),1.53(d,J＝10.3Hz,1H),1.46(dd,J＝11.3,5.9Hz,1H),1.41–1.30(m,5H),1.27(d,J＝1.9Hz,6H),1.16(ddd,J＝31.9,11.4,6.5Hz,2H),0.96-0.79(m,14H). Compound 31B: 1 HNMR (500MHz, DMSO) δ5.78 (s, 1H), 5.56 (d, J = 5.2Hz, 1H), 5.54 (s, 1H), 5.22 (d, J = 3.4Hz, 1H), 5.14(d,J＝6.6Hz,1H),4.99(d,J＝7.4Hz,1H),4.36(d,J＝9.8Hz,1H),4.18(t,J＝6.0Hz,1H),3.64( dd,J＝10.0,6.8Hz,1H),3.54(t,J＝8.8Hz,1H),3.49–3.43(m,1H),3.29–3.22(m,1H),3.18(ddd,J＝11.8, 7.3,2.2Hz,2H),2.81(d,J＝7.1Hz,1H),2.37(dd,J＝7.1,4.0Hz,1H),2.26–2.12(m,2H),2.05–1.87(m,3H ),1.86–1.75(m,2H),1.71–1.58(m,4H),1.53(d,J＝10.3Hz,1H),1.46(dd,J＝11.3,5.9Hz,1H),1.41–1.30( m,5H),1.27(d,J＝1.9Hz,6H),1.16(ddd,J＝31.9,11.4,6.5Hz,2H),0.96-0.79(m,14H).
实施例32：化合物32的制备Example 32: Preparation of Compound 32
Figure PCTCN2022131906-appb-000048
Figure PCTCN2022131906-appb-000048
如实施例31，原料采用对苯二硫酚(500mg，3.52mmol，1.00eq)，得到423mg化合物32A、454mg化合物32B和453mg化合物32C，合并收率56％，化合物32A、化合物32B和化合物32C均为白色固体。As in Example 31, hydroquinone (500 mg, 3.52 mmol, 1.00 eq) was used as the raw material to obtain 423 mg of compound 32A, 454 mg of compound 32B and 453 mg of compound 32C. The combined yield was 56%. Compound 32A, compound 32B and compound 32C were all It is a white solid.
化合物32的核磁结果如下：The NMR results of compound 32 are as follows:
化合物32A： 1HNMR(600MHz,CDCl 3)δ7.30(s,4H),5.25(s,2H),4.40(d,J＝10.7Hz,2H),2.66–2.53(m,2H),2.38(td,J＝14.1,3.9Hz,2H),2.09–2.00(m,2H),1.94–1.84(m,2H),1.70–1.59(m,4H),1.58–1.48(m,4H),1.47(s,6H),1.37–1.28(m,2H),1.28–1.21(m,4H),1.03–0.96(m,2H),0.95(d,J＝6.3Hz,6H),0.80(d,J＝7.2Hz,6H). Compound 32A: 1 HNMR (600MHz, CDCl 3 ) δ7.30 (s, 4H), 5.25 (s, 2H), 4.40 (d, J = 10.7Hz, 2H), 2.66–2.53 (m, 2H), 2.38 ( td,J＝14.1,3.9Hz,2H),2.09–2.00(m,2H),1.94–1.84(m,2H),1.70–1.59(m,4H),1.58–1.48(m,4H),1.47( s,6H),1.37–1.28(m,2H),1.28–1.21(m,4H),1.03–0.96(m,2H),0.95(d,J＝6.3Hz,6H),0.80(d,J＝ 7.2Hz,6H).
化合物32B： 1HNMR(600MHz,CDCl 3)δ7.27(d,J＝9.0Hz,4H),5.66(s,2H),5.18(d,J＝5.4Hz,2H),2.98(dd,J＝12.2,5.1Hz,2H),2.40–2.36(m,2H),2.12–2.01(m,2H),1.90–1.87(m,2H),1.85–1.74(m,2H),1.71–1.64(m,4H),1.62–1.47(m,4H),1.46(s,6H),1.44–1.35(m,3H),1.25(td,J＝11.6,6.6Hz, 3H),0.95(d,J＝6.4Hz,6H),0.82(d,J＝7.3Hz,6H). Compound 32B: 1 HNMR (600MHz, CDCl 3 ) δ7.27 (d, J = 9.0 Hz, 4H), 5.66 (s, 2H), 5.18 (d, J = 5.4 Hz, 2H), 2.98 (dd, J = 12.2,5.1Hz,2H),2.40–2.36(m,2H),2.12–2.01(m,2H),1.90–1.87(m,2H),1.85–1.74(m,2H),1.71–1.64(m, 4H),1.62–1.47(m,4H),1.46(s,6H),1.44–1.35(m,3H),1.25(td,J＝11.6,6.6Hz, 3H),0.95(d,J＝6.4Hz ,6H),0.82(d,J＝7.3Hz,6H).
化合物32C： 1HNMR(600MHz,CDCl 3)δ7.32-7.26(m,4H),5.61(s,1H),5.26(s,1H),5.19(d,J＝5.4Hz,1H),4.40(d,J＝10.7Hz,1H),2.97(d,J＝5.1Hz,1H),2.66–2.53(m,1H),2.39-2.30(m,2H),2.12–2.01(m,2H),1.94–1.88(m,2H),1.85–1.78(m,1H),1.70–1.59(m,4H),1.58–1.47(s,9H),1.37–1.21(m,7H),1.03–0.96(m,1H),0.95-0.80(m,12H). Compound 32C: 1 HNMR (600MHz, CDCl 3 ) δ7.32-7.26 (m, 4H), 5.61 (s, 1H), 5.26 (s, 1H), 5.19 (d, J = 5.4Hz, 1H), 4.40 ( d,J＝10.7Hz,1H),2.97(d,J＝5.1Hz,1H),2.66–2.53(m,1H),2.39-2.30(m,2H),2.12–2.01(m,2H),1.94 –1.88(m,2H),1.85–1.78(m,1H),1.70–1.59(m,4H),1.58–1.47(s,9H),1.37–1.21(m,7H),1.03–0.96(m, 1H),0.95-0.80(m,12H).
实施例33：化合物33的制备Example 33: Preparation of Compound 33
Figure PCTCN2022131906-appb-000049
Figure PCTCN2022131906-appb-000049
如实施例31，原料采用邻苯二硫酚(600mg，4.22mmol，1.00eq)，得到415mg化合物33A、472mg化合物33B和363mg化合物33C收率44％，化合物33A、化合物33B和化合物33C均为白色固体。As in Example 31, pyrodithiol (600 mg, 4.22 mmol, 1.00 eq) was used as the raw material to obtain 415 mg of compound 33A, 472 mg of compound 33B and 363 mg of compound 33C, with a yield of 44%. Compound 33A, compound 33B and compound 33C were all white. solid.
化合物33的核磁结果如下：The NMR results of compound 33 are as follows:
化合物33A： 1HNMR(600MHz,CDCl 3)δ7.31(s,1H),7.26-7.22(m,3H),5.30(s,2H),4.42(d,J＝10.7Hz,2H),2.61(s,2H),2.38(d,J＝3.6Hz,2H),2.03(d,J＝14.8Hz,2H),1.87(m,2H),1.65(m,4H),1.59–0.99(m,18H),0.95(d,J＝6.3Hz,6H),0.82(d,J＝7.1Hz,6H). Compound 33A: 1 HNMR (600MHz, CDCl 3 ) δ7.31 (s, 1H), 7.26-7.22 (m, 3H), 5.30 (s, 2H), 4.42 (d, J = 10.7Hz, 2H), 2.61 ( s,2H),2.38(d,J＝3.6Hz,2H),2.03(d,J＝14.8Hz,2H),1.87(m,2H),1.65(m,4H),1.59–0.99(m,18H ),0.95(d,J＝6.3Hz,6H),0.82(d,J＝7.1Hz,6H).
化合物33B： 1HNMR(600MHz,CDCl 3)δ7.34(s,1H),7.24-7.21(m,3H),5.66(s,2H),5.21(d,J＝5.3Hz,2H),2.99(dd,J＝12.0,5.2Hz,2H),2.38(td,J＝14.0,3.7Hz,2H),2.06(d,J＝15.0Hz,2H),1.94–1.76(m,4H),1.72–1.63(m,4H),1.58–1.36(m,12H),1.25(td,J＝11.6,6.7Hz,4H),0.95(d,J＝6.4Hz,6H),0.85(d,J＝7.3Hz,6H). Compound 33B: 1 HNMR (600MHz, CDCl 3 ) δ7.34 (s, 1H), 7.24-7.21 (m, 3H), 5.66 (s, 2H), 5.21 (d, J = 5.3Hz, 2H), 2.99 ( dd,J＝12.0,5.2Hz,2H),2.38(td,J＝14.0,3.7Hz,2H),2.06(d,J＝15.0Hz,2H),1.94–1.76(m,4H),1.72–1.63 (m,4H),1.58–1.36(m,12H),1.25(td,J＝11.6,6.7Hz,4H),0.95(d,J＝6.4Hz,6H),0.85(d,J＝7.3Hz, 6H).
化合物33C： 1HNMR(600MHz,CDCl 3)δ7.32(s,1H),7.26-7.22(m,3H),5.66 (s,1H),5.30(s,1H),5.21(d,J＝5.3Hz,1H),4.42(d,J＝10.7Hz,1H),2.99(dd,J＝12.0,5.2Hz,1H),2.61(s,1H),2.40-2.36(m,2H),2.06–2.01(m,2H),1.94-1.86(m,4H),1.71-1.64(m,2H),1.59–0.99(m,18H),0.95-0.82(m,12H). Compound 33C: 1 HNMR (600MHz, CDCl 3 ) δ7.32 (s, 1H), 7.26-7.22 (m, 3H), 5.66 (s, 1H), 5.30 (s, 1H), 5.21 (d, J = 5.3 Hz,1H),4.42(d,J＝10.7Hz,1H),2.99(dd,J＝12.0,5.2Hz,1H),2.61(s,1H),2.40-2.36(m,2H),2.06–2.01 (m,2H),1.94-1.86(m,4H),1.71-1.64(m,2H),1.59–0.99(m,18H),0.95-0.82(m,12H).
实施例34：化合物34的制备Example 34: Preparation of Compound 34
Figure PCTCN2022131906-appb-000050
Figure PCTCN2022131906-appb-000050
1、将原料34(10.00g，80.51mmol，1.00eq)和三乙胺(12.22g，120.77mmol，1.50eq)加入到250mL的DCM中，加入乙酸酐(9.86g，96.62mmol，1.20eq)，反应在室温下搅拌过夜；TCL(3％EA/PE)显示原料消失，纯化得到11.50g中间体34-1；1. Add raw material 34 (10.00g, 80.51mmol, 1.00eq) and triethylamine (12.22g, 120.77mmol, 1.50eq) to 250mL of DCM, add acetic anhydride (9.86g, 96.62mmol, 1.20eq), The reaction was stirred at room temperature overnight; TCL (3% EA/PE) showed that the raw materials disappeared, and 11.50g of intermediate 34-1 was obtained after purification;
2、将中间体34-1(11.00g，66.17mmol，1.00eq)和NBS(12.96g，72.79mmol，1.10eq)加入110mLCCl 4中，加入AIBN(1.09g，6.62mmol，0.10eq)，置换氩气，反应升温至回流并在回流下搅拌3h，纯化得到12.50g中间体34-2； 2. Add intermediate 34-1 (11.00g, 66.17mmol, 1.00eq) and NBS (12.96g, 72.79mmol, 1.10eq) into 110mL CCl 4 , add AIBN (1.09g, 6.62mmol, 0.10eq), and replace argon. Gas, the reaction was heated to reflux and stirred under reflux for 3 h, and 12.50 g of intermediate 34-2 was obtained after purification;
3、将中间体34-2(2.00g，8.16mmol，1.00eq)和硫代乙酸钾(1.12g，9.79mmol，1.20eq)加入到25mL的DMF中，反应在60℃下下搅拌1h；TCL(3％EA/PE)显示原料消失，纯化得到1.00g中间体34-3；3. Add intermediate 34-2 (2.00g, 8.16mmol, 1.00eq) and potassium thioacetate (1.12g, 9.79mmol, 1.20eq) into 25mL of DMF, and stir the reaction at 60°C for 1h; TCL (3% EA/PE) showed that the raw materials disappeared, and 1.00g of intermediate 34-3 was obtained after purification;
4、将中间体34-3(1.00g，4.16mmol，1.00eq)溶解在20mL的95％乙醇中，降温至0℃，向反应中滴加2N氢氧化钠水溶液(6.2mL，12.48mmol，3.00eq)，0℃搅拌10min后移至室温搅拌1h；TCL(5％EA/PE)显示原料消失，纯化得到0.50g中间体34-4；4. Dissolve intermediate 34-3 (1.00g, 4.16mmol, 1.00eq) in 20mL of 95% ethanol, cool to 0°C, and add 2N aqueous sodium hydroxide solution (6.2mL, 12.48mmol, 3.00) dropwise to the reaction. eq), stir at 0°C for 10 min and then move to room temperature and stir for 1 h; TCL (5% EA/PE) showed that the raw material disappeared, and 0.50g of intermediate 34-4 was obtained after purification;
5、将中间体34-4(400mg，2.70mmol，1.00eq)和DHA(1.69g，5.93mmol，2.20eq)加入25mL乙醚中，降温至0℃，滴加三氟化硼乙醚(1.15g，8.09mmol，3.00eq)，0℃下搅拌10min后移至室温搅拌2h；TCL(15％EA/PE)显示原料消失，纯化得到1.1g化合物34，收率60％，化合物34为白色固体。5. Add intermediate 34-4 (400mg, 2.70mmol, 1.00eq) and DHA (1.69g, 5.93mmol, 2.20eq) into 25mL of diethyl ether, cool to 0°C, and add boron trifluoride diethyl ether (1.15g, 8.09mmol, 3.00eq), stirred at 0°C for 10min, then moved to room temperature and stirred for 2h; TCL (15% EA/PE) showed that the raw material disappeared, and 1.1g of compound 34 was obtained after purification, with a yield of 60%. Compound 34 was a white solid.
化合物34的核磁结果如下：The NMR results of compound 34 are as follows:
1HNMR(600MHz,CDCl 3)δ7.47(d,J＝8.2Hz,2H),7.27(d,J＝8.3Hz,2H),5.73(s,1H),5.65(s,1H),5.53(d,J＝5.3Hz,1H),5.19(d,J＝5.4Hz,1H),3.84(d,J＝5.2Hz,2H),3.05(dd,J＝72.7,7.1Hz,2H),2.38(ddd,J＝14.2,9.1,4.0Hz,2H),2.06(d,J＝14.4Hz,2H),1.94–1.86(m,2H),1.85–1.64(m,6H),1.56–1.21(m,16H),1.05(d,J＝7.3Hz,3H),0.98(d,J＝6.3Hz,3H),0.95(d,J＝6.4Hz,3H),0.84(d,J＝7.3Hz,3H). 1 HNMR (600MHz, CDCl 3 ) δ7.47(d,J＝8.2Hz,2H),7.27(d,J＝8.3Hz,2H),5.73(s,1H),5.65(s,1H),5.53( d,J＝5.3Hz,1H),5.19(d,J＝5.4Hz,1H),3.84(d,J＝5.2Hz,2H),3.05(dd,J＝72.7,7.1Hz,2H),2.38( ddd,J＝14.2,9.1,4.0Hz,2H),2.06(d,J＝14.4Hz,2H),1.94–1.86(m,2H),1.85–1.64(m,6H),1.56–1.21(m, 16H),1.05(d,J＝7.3Hz,3H),0.98(d,J＝6.3Hz,3H),0.95(d,J＝6.4Hz,3H),0.84(d,J＝7.3Hz,3H) .
实施例35：化合物35的制备Example 35: Preparation of Compound 35
Figure PCTCN2022131906-appb-000051
Figure PCTCN2022131906-appb-000051
将原料35(100mg，0.28mmol，1.00eq)和实施例1的SDHA-A(168mg， 0.56mmol，2.00eq)加入6mL的DMF中，加入碳酸钾(116mg，0.84mmol，3.00eq)反应，纯化得到140mg化合物35A，收率71％，35A为白色固体。Add raw material 35 (100 mg, 0.28 mmol, 1.00 eq) and SDHA-A of Example 1 (168 mg, 0.56 mmol, 2.00 eq) into 6 mL of DMF, add potassium carbonate (116 mg, 0.84 mmol, 3.00 eq) for reaction, and purify 140 mg of compound 35A was obtained with a yield of 71%. 35A was a white solid.
将原料35(300mg，0.84mmol，1.00eq)和实施例1的SDHA-B(503mg，1.68mmol，2.00eq)加入15mL的DMF中，加入碳酸钾(348mg，5.21mmol，3.00eq)反应，纯化得到310mg化合物35B，收率52％，化合物35B为白色固体。Add raw material 35 (300 mg, 0.84 mmol, 1.00 eq) and SDHA-B (503 mg, 1.68 mmol, 2.00 eq) of Example 1 to 15 mL of DMF, add potassium carbonate (348 mg, 5.21 mmol, 3.00 eq) for reaction, and purify 310 mg of compound 35B was obtained with a yield of 52%. Compound 35B was a white solid.
化合物35的核磁结果如下：The NMR results of compound 35 are as follows:
化合物35A： 1HNMR(600MHz,CDCl 3)δ7.30(s,4H),5.25(s,2H),4.40(d,J＝10.7Hz,2H),3.99(d,J＝13.1Hz,2H),3.85(d,J＝13.1Hz,2H),2.66–2.53(m,2H),2.38(td,J＝14.1,3.9Hz,2H),2.09–2.00(m,2H),1.94–1.84(m,2H),1.70–1.59(m,4H),1.58–1.48(m,4H),1.47(s,6H),1.37–1.28(m,2H),1.28–1.21(m,4H),1.03–0.96(m,2H),0.95(d,J＝6.3Hz,6H),0.80(d,J＝7.2Hz,6H). Compound 35A: 1 HNMR (600MHz, CDCl 3 ) δ7.30 (s, 4H), 5.25 (s, 2H), 4.40 (d, J = 10.7Hz, 2H), 3.99 (d, J = 13.1Hz, 2H) ,3.85(d,J＝13.1Hz,2H),2.66–2.53(m,2H),2.38(td,J＝14.1,3.9Hz,2H),2.09–2.00(m,2H),1.94–1.84(m ,2H),1.70–1.59(m,4H),1.58–1.48(m,4H),1.47(s,6H),1.37–1.28(m,2H),1.28–1.21(m,4H),1.03–0.96 (m,2H),0.95(d,J＝6.3Hz,6H),0.80(d,J＝7.2Hz,6H).
13CNMR(151MHz,CDCl 3)δ137.12,129.21,104.34,92.32,80.49,79.41,51.83,46.13,37.31,36.30,34.02,32.35,31.89,26.04,24.76,21.24,20.24,14.80. 13 CNMR (151MHz, CDCl 3 ) δ137.12,129.21,104.34,92.32,80.49,79.41,51.83,46.13,37.31,36.30,34.02,32.35,31.89,26.04,24.76,21.24,20.24,1 4.80.
化合物35B： 1HNMR(600MHz,CDCl 3)δ7.27(d,J＝9.0Hz,4H),5.66(s,2H),5.18(d,J＝5.4Hz,2H),3.85(s,4H),2.98(dd,J＝12.2,5.1Hz,2H),2.38(td,J＝14.1,3.9Hz,2H),2.12–2.01(m,2H),1.88(ddd,J＝13.4,6.5,3.3Hz,2H),1.85–1.74(m,2H),1.71–1.64(m,4H),1.62–1.47(m,4H),1.46(s,6H),1.44–1.35(m,3H),1.25(td,J＝11.6,6.6Hz,3H),0.95(d,J＝6.4Hz,6H),0.82(d,J＝7.3Hz,6H). Compound 35B: 1 HNMR (600MHz, CDCl 3 ) δ7.27 (d, J = 9.0 Hz, 4H), 5.66 (s, 2H), 5.18 (d, J = 5.4 Hz, 2H), 3.85 (s, 4H) ,2.98(dd,J＝12.2,5.1Hz,2H),2.38(td,J＝14.1,3.9Hz,2H),2.12–2.01(m,2H),1.88(ddd,J＝13.4,6.5,3.3Hz ,2H),1.85–1.74(m,2H),1.71–1.64(m,4H),1.62–1.47(m,4H),1.46(s,6H),1.44–1.35(m,3H),1.25(td ,J＝11.6,6.6Hz,3H),0.95(d,J＝6.4Hz,6H),0.82(d,J＝7.3Hz,6H).
实施例36：化合物36的制备Example 36: Preparation of Compound 36
Figure PCTCN2022131906-appb-000052
Figure PCTCN2022131906-appb-000052
1、将原料36(2.00g，14.48mmol，1.00eq)、三苯基膦(7.59g，28.95mmol，2.00eq)和咪唑(1.97g，28.95mmol，2.00eq)溶解在150mL的DCM中，降温至0℃搅拌10min，分批缓慢加入碘(7.35g，28.95mmol，2.00eq)，加完后移至室温搅拌1h；TCL(3％EA/PE)显示原料消失，纯化得到3.70g中间体36-1；1. Dissolve raw material 36 (2.00g, 14.48mmol, 1.00eq), triphenylphosphine (7.59g, 28.95mmol, 2.00eq) and imidazole (1.97g, 28.95mmol, 2.00eq) in 150mL of DCM, and cool down. Stir for 10 minutes at 0°C, slowly add iodine (7.35g, 28.95mmol, 2.00eq) in batches, move to room temperature and stir for 1 hour after addition; TCL (3% EA/PE) shows that the raw material disappears, and 3.70g of intermediate 36 is obtained after purification -1;
2、将中间体36-1(300mg，0.84mmol，1.00eq)和实施例1的SDHA-A(503mg，1.68mmol，2.00eq)溶解在17mL的DMF中，加入碳酸钾(348mg，2.51mmol，3.00eq)，反应在室温下搅拌2h；TCL(10％EA/PE)显示原料消失，纯化得到300mg化合物36A，收率51％，化合物36A为白色固体；2. Dissolve intermediate 36-1 (300 mg, 0.84 mmol, 1.00 eq) and SDHA-A of Example 1 (503 mg, 1.68 mmol, 2.00 eq) in 17 mL of DMF, and add potassium carbonate (348 mg, 2.51 mmol, 3.00eq), the reaction was stirred at room temperature for 2 h; TCL (10% EA/PE) showed that the raw material disappeared, and 300 mg of compound 36A was obtained after purification, with a yield of 51%, and compound 36A was a white solid;
3、将中间体36-1(300mg，0.84mmol，1.00eq)和实施例2的SDHA-B(503mg，1.68mmol，2.00eq)溶解在17mL的DMF中，加入碳酸钾(348mg，2.51mmol，3.00eq)，反应在室温下搅拌2h；TCL(10％EA/PE)显示原料消失，纯化得到240mg化合物36B收率40％，化合物36B为白色固体。3. Dissolve intermediate 36-1 (300 mg, 0.84 mmol, 1.00 eq) and SDHA-B of Example 2 (503 mg, 1.68 mmol, 2.00 eq) in 17 mL of DMF, and add potassium carbonate (348 mg, 2.51 mmol, 3.00eq), the reaction was stirred at room temperature for 2 h; TCL (10% EA/PE) showed that the raw materials disappeared, and 240 mg of compound 36B was purified with a yield of 40%. Compound 36B was a white solid.
化合物36的核磁结果如下：The NMR results of compound 36 are as follows:
化合物36A： 1HNMR(600MHz,CDCl 3)δ7.31(s,1H),7.26-7.22(m,3H),5.30(s,2H),4.42(d,J＝10.7Hz,2H),3.98(d,J＝12.8Hz,2H),3.86(d,J＝12.8Hz,2H),2.61(s,2H),2.38(d,J＝3.6Hz,2H),2.03(d,J＝14.8Hz,2H),1.87(m,2H),1.65(m,4H),1.59–0.99(m,18H),0.95(d,J＝6.3Hz,6H),0.82(d,J＝7.1Hz,6H). Compound 36A: 1 HNMR (600MHz, CDCl 3 ) δ7.31 (s, 1H), 7.26-7.22 (m, 3H), 5.30 (s, 2H), 4.42 (d, J = 10.7Hz, 2H), 3.98 ( d,J＝12.8Hz,2H),3.86(d,J＝12.8Hz,2H),2.61(s,2H),2.38(d,J＝3.6Hz,2H),2.03(d,J＝14.8Hz, 2H),1.87(m,2H),1.65(m,4H),1.59–0.99(m,18H),0.95(d,J＝6.3Hz,6H),0.82(d,J＝7.1Hz,6H).
化合物36B： 1HNMR(600MHz,CDCl 3)δ7.34(s,1H),7.24-7.21(m,3H),5.66 (s,2H),5.21(d,J＝5.3Hz,2H),3.86(dd,J＝27.3,13.0Hz,4H),2.99(dd,J＝12.0,5.2Hz,2H),2.38(td,J＝14.0,3.7Hz,2H),2.06(d,J＝15.0Hz,2H),1.94–1.76(m,4H),1.72–1.63(m,4H),1.58–1.36(m,12H),1.25(td,J＝11.6,6.7Hz,4H),0.95(d,J＝6.4Hz,6H),0.85(d,J＝7.3Hz,6H). Compound 36B: 1 HNMR (600MHz, CDCl 3 ) δ7.34 (s, 1H), 7.24-7.21 (m, 3H), 5.66 (s, 2H), 5.21 (d, J = 5.3Hz, 2H), 3.86 ( dd,J＝27.3,13.0Hz,4H),2.99(dd,J＝12.0,5.2Hz,2H),2.38(td,J＝14.0,3.7Hz,2H),2.06(d,J＝15.0Hz,2H ),1.94–1.76(m,4H),1.72–1.63(m,4H),1.58–1.36(m,12H),1.25(td,J＝11.6,6.7Hz,4H),0.95(d,J＝6.4 Hz, 6H), 0.85 (d, J = 7.3Hz, 6H).
实施例37：化合物37的制备Example 37: Preparation of Compound 37
Figure PCTCN2022131906-appb-000053
Figure PCTCN2022131906-appb-000053
1、将四氢锂铝(2.31g，60.76mmol，3.00eq)溶解在100mL的THF中，降温至0℃搅拌10min，将原料37(3.00g，20.25mmol，1.00eq)溶解在20mL的THF中并缓慢滴加至反应中，反应在0℃下搅拌30min后移至室温搅拌过夜；TLC(30％EA/PE)显示原料消失，纯化得到2.50g中间体37-1；1. Dissolve lithium aluminum tetrahydrogen (2.31g, 60.76mmol, 3.00eq) in 100mL of THF, cool to 0°C and stir for 10 minutes. Dissolve raw material 37 (3.00g, 20.25mmol, 1.00eq) in 20mL of THF. And slowly added dropwise to the reaction, the reaction was stirred at 0°C for 30 minutes and then moved to room temperature and stirred overnight; TLC (30% EA/PE) showed that the raw materials disappeared, and 2.50g of intermediate 37-1 was obtained after purification;
2、如实施例36，采用中间体37-1(1.50g，10.86mmol，1.00eq)，得到140mg化合物37A和190mg化合物37B，收率24％，化合物37A和化合物37B均为白色固体。2. As in Example 36, intermediate 37-1 (1.50g, 10.86mmol, 1.00eq) was used to obtain 140 mg of compound 37A and 190 mg of compound 37B, with a yield of 24%. Compound 37A and compound 37B were both white solids.
化合物37的核磁结果如下：The NMR results of compound 37 are as follows:
化合物37A： 1HNMR(600MHz,CDCl 3)δ7.33(dd,J＝5.3,3.6Hz,2H),7.18(dd,J＝5.5,3.4Hz,2H),5.25(d,J＝8.5Hz,2H),4.43(d,J＝10.7Hz,2H),4.10(m,4H),2.68–2.52(m,2H),2.38(td,J＝14.0,3.7Hz,2H),2.02(s,2H),1.92–1.83(m,2H),1.69–1.60(m,4H),1.57–1.38(m,10H),1.35–1.19(m,8H),1.04–0 .96(m,2H),0.95(d,J＝6.3Hz,6H),0.81(d,J＝7.2Hz,6H). Compound 37A: 1 HNMR (600MHz, CDCl 3 ) δ7.33 (dd, J＝5.3, 3.6Hz, 2H), 7.18 (dd, J＝5.5, 3.4Hz, 2H), 5.25 (d, J＝8.5Hz, 2H),4.43(d,J＝10.7Hz,2H),4.10(m,4H),2.68–2.52(m,2H),2.38(td,J＝14.0,3.7Hz,2H),2.02(s,2H ),1.92–1.83(m,2H),1.69–1.60(m,4H),1.57–1.38(m,10H),1.35–1.19(m,8H),1.04–0.96(m,2H),0.95 (d,J＝6.3Hz,6H),0.81(d,J＝7.2Hz,6H).
化合物37B： 1HNMR(600MHz,CDCl 3)δ7.31(dd,J＝5.4,3.5Hz,2H),7.21–7.16(m,2H),5.66(s,2H),5.24(d,J＝5.3Hz,2H),4.15–4.07(m,2H),3.98(d,J＝13.1Hz,2H),2.99(dd,J＝12.2,5.1Hz,2H),2.38(td,J＝14.1,3.9Hz,2H),2.09–2.03(m,2H),1.93–1.85(m,2H),1.80(qd,J＝13.9,3.8Hz,2H),1.70–1.61(m,4H),1.58–1.44(m,10H),1.41–1.33(m,2H),1.22(m,4H),0.95(d,J＝6.4Hz,6H),0.81(d,J＝7.3Hz,6H). Compound 37B: 1 HNMR (600MHz, CDCl 3 ) δ7.31 (dd, J＝5.4, 3.5Hz, 2H), 7.21–7.16 (m, 2H), 5.66 (s, 2H), 5.24 (d, J＝5.3 Hz,2H),4.15–4.07(m,2H),3.98(d,J＝13.1Hz,2H),2.99(dd,J＝12.2,5.1Hz,2H),2.38(td,J＝14.1,3.9Hz ,2H),2.09–2.03(m,2H),1.93–1.85(m,2H),1.80(qd,J＝13.9,3.8Hz,2H),1.70–1.61(m,4H),1.58–1.44(m ,10H),1.41–1.33(m,2H),1.22(m,4H),0.95(d,J＝6.4Hz,6H),0.81(d,J＝7.3Hz,6H).
实施例38：化合物38的制备Example 38: Preparation of Compound 38
Figure PCTCN2022131906-appb-000054
Figure PCTCN2022131906-appb-000054
如实施例19，原料采用原料38，得到0.70g化合物38，收率36％，化合物38为白色泡沫状化合物。As in Example 19, raw material 38 was used as the raw material, and 0.70 g of compound 38 was obtained with a yield of 36%. Compound 38 was a white foam compound.
化合物38的核磁结果如下：The NMR results of compound 38 are as follows:
1HNMR(500MHz,CDCl 3)δ5.52(s,2H),5.40(d,J＝4.8Hz,2H),3.94(q,J＝13.2Hz,4H),3.04(d,J＝5.6Hz,2H),2.36(t,J＝13.3Hz,2H),2.04(d,J＝14.3Hz,2H),1.86(s,2H),1.69(dd,J＝33.2,13.3Hz,6H),1.54–1.31(m,12H),1.29–1.18(m,2H),0.98–0.82(m,14H). 1 HNMR (500MHz, CDCl 3 ) δ5.52 (s, 2H), 5.40 (d, J = 4.8Hz, 2H), 3.94 (q, J = 13.2Hz, 4H), 3.04 (d, J = 5.6Hz, 2H),2.36(t,J＝13.3Hz,2H),2.04(d,J＝14.3Hz,2H),1.86(s,2H),1.69(dd,J＝33.2,13.3Hz,6H),1.54– 1.31(m,12H),1.29–1.18(m,2H),0.98–0.82(m,14H).
13CNMR(126MHz,CDCl 3)δ104.25,87.96,87.12,81.00,52.62,44.98,37.18,36.32,34.37,32.15，26.03,24.51,23.58,20.29,14.58. 13 CNMR (126MHz, CDCl 3 ) δ104.25,87.96,87.12,81.00,52.62,44.98,37.18,36.32,34.37,32.15,26.03,24.51,23.58,20.29,14.58.
实施例39：化合物39的制备Example 39: Preparation of Compound 39
Figure PCTCN2022131906-appb-000055
Figure PCTCN2022131906-appb-000055
1、氩气保护下将LiAlH 4(351mg，9.25mmol，2.50eq)分散在22mL的THF中，降温至0℃，将原料39(1.00g，3.70mmol，1.00eq)溶解在15mL的THF中滴加至反应中，滴完后反应回温至8℃搅拌12h，纯化得到0.70g中间体39-1； 1. Disperse LiAlH 4 (351 mg, 9.25 mmol, 2.50 eq) in 22 mL of THF under argon protection, cool to 0°C, and dissolve raw material 39 (1.00 g, 3.70 mmol, 1.00 eq) in 15 mL of THF. Add to the reaction. After the dripping is completed, the reaction is warmed to 8°C and stirred for 12 hours. After purification, 0.70g of intermediate 39-1 is obtained;
2、如实施例19，采用中间体39-1(0.70g，3.27mmol，1.00eq)，得到0.40g化合物39，收率35％，化合物39为白色泡沫状固体。2. As in Example 19, using intermediate 39-1 (0.70g, 3.27mmol, 1.00eq), 0.40g of compound 39 was obtained with a yield of 35%. Compound 39 was a white foamy solid.
化合物39的核磁结果如下：The NMR results of compound 39 are as follows:
1HNMR(500MHz,CDCl 3)δ7.52(d,J＝7.7Hz,4H),7.42(d,J＝7.8Hz,4H),5.69(s,2H),5.25(d,J＝4.3Hz,2H),3.92(s,4H),3.00(s,2H),2.39(t,J＝12.8Hz,2H),2.07(d,J＝15.2Hz,2H),1.83-1.71(m,4H),1.68(t,J＝13.4Hz,4H),1.56–1.44(m,8H),1.40(s,2H),1.26(d,J＝5.3Hz,4H),0.96(m,8H),0.86(d,J＝7.1Hz,6H). 1 HNMR (500MHz, CDCl 3 ) δ7.52 (d, J = 7.7Hz, 4H), 7.42 (d, J = 7.8Hz, 4H), 5.69 (s, 2H), 5.25 (d, J = 4.3Hz, 2H),3.92(s,4H),3.00(s,2H),2.39(t,J＝12.8Hz,2H),2.07(d,J＝15.2Hz,2H),1.83-1.71(m,4H), 1.68(t,J＝13.4Hz,4H),1.56–1.44(m,8H),1.40(s,2H),1.26(d,J＝5.3Hz,4H),0.96(m,8H),0.86(d ,J＝7.1Hz,6H).
实施例40：化合物40的制备Example 40: Preparation of Compound 40
Figure PCTCN2022131906-appb-000056
Figure PCTCN2022131906-appb-000056
1、将原料40(1.50g，6.94mmol，1.00eq)溶在30mL的MeOH中，加入SOCl 2(4.13g，34.69mmol，5.00eq)，反应加热至80℃并搅拌12h，纯化得到1.69g中间体40-1； 1. Dissolve raw material 40 (1.50g, 6.94mmol, 1.00eq) in 30mL of MeOH, add SOCl 2 (4.13g, 34.69mmol, 5.00eq), heat the reaction to 80°C and stir for 12h, purify to obtain 1.69g of intermediate Body 40-1;
2、如实施例39，采用中间体40-1(2.20g，9.01mmoL，1.00eq)，得到0.30g化合物40A和0.70g化合物40B，化合物40A和化合物40B均为白色泡沫状。2. As in Example 39, intermediate 40-1 (2.20g, 9.01mmoL, 1.00eq) was used to obtain 0.30g of compound 40A and 0.70g of compound 40B. Both compound 40A and compound 40B were in the form of white foam.
化合物40的核磁结果如下：The NMR results of compound 40 are as follows:
化合物40A： 1HNMR(500MHz,CDCl 3)δ8.34–8.21(m,2H),7.55(d,J＝3.0Hz,2H),7.39(s,2H),5.32(s,2H),4.47(d,J＝11.8Hz,2H),4.47(d,J＝11.8Hz,4H),4.32(d,J＝12.8Hz,2H),2.70(s,2H),2.41(t,J＝13.8Hz,2H),2.06(d,J＝14.4 Hz,2H),1.89(s,2H),1.72–1.46(m,12H),1.26-1.21(m,6H),1.01-0.95(m,7H),0.93–0.65(m,7H). Compound 40A: 1 HNMR (500MHz, CDCl 3 ) δ8.34–8.21 (m, 2H), 7.55 (d, J = 3.0Hz, 2H), 7.39 (s, 2H), 5.32 (s, 2H), 4.47 ( d,J＝11.8Hz,2H),4.47(d,J＝11.8Hz,4H),4.32(d,J＝12.8Hz,2H),2.70(s,2H),2.41(t,J＝13.8Hz, 2H),2.06(d,J＝14.4 Hz,2H),1.89(s,2H),1.72–1.46(m,12H),1.26-1.21(m,6H),1.01-0.95(m,7H),0.93 –0.65(m,7H).
化合物40B： 1HNMR(500MHz,CDCl 3)δ8.17(s,2H),7.56(s,2H),7.41(s,2H),,5.71(s,2H),5.34(s,2H),4.39(d,J＝13.0Hz,2H),4.24(d,J＝12.9Hz,2H),3.01(s,2H),2.39(t,J＝13.6Hz,2H),2.09(d,J＝14.1Hz,2H),1.88(s,2H),1.84–1.71(m,2H),1.69–1.42(m,14H),1.37(s,2H),1.25(d,J＝6.1Hz,2H),0.91(m,8H),0.77(d,J＝6.8Hz,6H). Compound 40B: 1 HNMR (500MHz, CDCl 3 ) δ8.17(s,2H),7.56(s,2H),7.41(s,2H),,5.71(s,2H),5.34(s,2H),4.39 (d,J＝13.0Hz,2H),4.24(d,J＝12.9Hz,2H),3.01(s,2H),2.39(t,J＝13.6Hz,2H),2.09(d,J＝14.1Hz ,2H),1.88(s,2H),1.84–1.71(m,2H),1.69–1.42(m,14H),1.37(s,2H),1.25(d,J＝6.1Hz,2H),0.91( m,8H),0.77(d,J＝6.8Hz,6H).
13CNMR(126MHz,CDCl 3)δ133.42,133.42,131.99,127.04,125.88,124.95,104.29,88.27,85.97,81.25,52.69,45.10,37.17,36.42,34.37,34.04,32.04,26.23,24.65,24.43,20.35,14.63. 13 CNMR (126MHz, CDCl 3 ) δ133.42,133.42,131.99,127.04,125.88,124.95,104.29,88.27,85.97,81.25,52.69,45.10,37.17,36.42,34.37,34.04,32. 04,26.23,24.65,24.43,20.35, 14.63.
实施例41：化合物41的制备Example 41: Preparation of Compound 41
Figure PCTCN2022131906-appb-000057
Figure PCTCN2022131906-appb-000057
1、将原料41(1.00g，4.74mmol，1.00eq)溶于乙酸酐(8.9mL，94.73mmol，20.00eq)中，置换氩气，升温至100℃反应16h，纯化得到0.90g中间体41-1；1. Dissolve raw material 41 (1.00g, 4.74mmol, 1.00eq) in acetic anhydride (8.9mL, 94.73mmol, 20.00eq), replace the argon gas, raise the temperature to 100°C, react for 16h, and purify to obtain 0.90g of intermediate 41- 1;
2、将中间体41-1(0.50g，2.09mmol，1.00eq)溶于4mL的THF中，置换氩气，降温至0℃，然后滴加DIBAH(8.57mL，8.57mmol，4.10eq)，反应在0℃下30min后升温至室温搅拌18h，纯化得到100mg中间体41-2；2. Dissolve intermediate 41-1 (0.50g, 2.09mmol, 1.00eq) in 4mL of THF, replace the argon gas, cool to 0°C, then add DIBAH (8.57mL, 8.57mmol, 4.10eq) dropwise, and react. After 30 min at 0°C, the temperature was raised to room temperature and stirred for 18 h. After purification, 100 mg of intermediate 41-2 was obtained;
3、将中间体41-2(100mg，0.55mmol，1.00eq)溶于3mL的DCM中，降温至0℃，加入三乙胺(0.22mL，1.64mmol，3.00eq)，滴加MsCl(0.11mL，1.36mmol，2.50eq)，反应在0℃下搅拌30min后回到室温搅拌1h，纯化得到150mg中间体41-3；3. Dissolve intermediate 41-2 (100 mg, 0.55 mmol, 1.00 eq) in 3 mL of DCM, cool to 0°C, add triethylamine (0.22 mL, 1.64 mmol, 3.00 eq), and add MsCl (0.11 mL) dropwise. , 1.36mmol, 2.50eq), the reaction was stirred at 0°C for 30min and then returned to room temperature and stirred for 1h. After purification, 150mg of intermediate 41-3 was obtained;
4、氩气保护下将中间体41-3(180mg，0.53mmol，1.00eq)和实施例1的SDHA-A(318mg，1.06mmol，2.00eq)溶于4mL的DMF中，加入K 2CO 3(183mg， 1.33mmol，2.50eq)；反应在室温下搅拌3h，纯化得到180mg化合物41A，，收率45％，化合物41A为淡黄色固体； 4. Dissolve intermediate 41-3 (180 mg, 0.53 mmol, 1.00 eq) and SDHA-A of Example 1 (318 mg, 1.06 mmol, 2.00 eq) in 4 mL of DMF under argon protection, and add K 2 CO 3 (183mg, 1.33mmol, 2.50eq); the reaction was stirred at room temperature for 3h, and purified to obtain 180mg of compound 41A, with a yield of 45%. Compound 41A was a light yellow solid;
5、氩气保护下将中间体41-3(230mg，0.68mmol，1.00eq)和实施例1的SDHA-B(407mg，1.69mmol，2.50eq)溶于4mL的DMF中，加入K 2CO 3(234mg，1.69mmol，2.50eq)；反应在室温下搅拌3h，纯化得到243mg化合物41B，收率48％，化合物41B为淡黄色固体。 5. Under argon protection, dissolve intermediate 41-3 (230 mg, 0.68 mmol, 1.00 eq) and SDHA-B of Example 1 (407 mg, 1.69 mmol, 2.50 eq) in 4 mL of DMF, and add K 2 CO 3 (234 mg, 1.69 mmol, 2.50 eq); the reaction was stirred at room temperature for 3 h, and 243 mg of compound 41B was purified, with a yield of 48%. Compound 41B was a light yellow solid.
化合物41的核磁结果如下：The NMR results of compound 41 are as follows:
化合物41A： 1HNMR(600MHz,CDCl 3)δ7.69(d,J＝7.8Hz,1H),7.64(d,J＝7.4Hz,1H),7.32(dd,J＝19.4,12.0Hz,1H),5.27(d,J＝8.4Hz,2H),4.73(d,J＝10.8Hz,1H),4.57(d,J＝10.5Hz,1H),4.48(d,J＝11.0Hz,1H),4.39–4.29(m,2H),4.16(d,J＝13.2Hz,1H),3.16-3.08(m,1H),2.71(s,1H),2.56(d,J＝45.1Hz,2H),2.37(d,J＝13.4Hz,3H),2.20–2.07(m,1H),2.01(d,J＝12.0Hz,3H),1.88(s,3H),1.67(s,2H),1.57-1.44(m,9H),1.25(s,2H),0.99-0.83(m,15H). Compound 41A: 1 HNMR (600MHz, CDCl 3 ) δ7.69 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 7.4 Hz, 1H), 7.32 (dd, J = 19.4, 12.0 Hz, 1H) ,5.27(d,J＝8.4Hz,2H),4.73(d,J＝10.8Hz,1H),4.57(d,J＝10.5Hz,1H),4.48(d,J＝11.0Hz,1H),4.39 –4.29(m,2H),4.16(d,J＝13.2Hz,1H),3.16-3.08(m,1H),2.71(s,1H),2.56(d,J＝45.1Hz,2H),2.37( d,J＝13.4Hz,3H),2.20–2.07(m,1H),2.01(d,J＝12.0Hz,3H),1.88(s,3H),1.67(s,2H),1.57-1.44(m ,9H),1.25(s,2H),0.99-0.83(m,15H).
化合物41B： 1HNMR(500MHz,CDCl 3)δ7.72(d,J＝7.8Hz,1H),7.55(d,J＝7.4Hz,1H),7.30(dd,J＝17.3,9.5Hz,1H),5.58(d,J＝7.5Hz,2H),5.30(s,2H),4.36(t,J＝15.8Hz,1H),4.22(d,J＝13.2Hz,1H),4.12(s,2H),3.73(dd,J＝13.9,7.1Hz,1H),3.01(s,2H),2.37(t,J＝14.0Hz,2H),2.04(d,J＝7.1Hz,2H),1.89-1.80(m,2H),1.76(s,2H),1.65(d,J＝17.9Hz,5H),1.49-1.44(m,8H),1.37(s,2H),1.30–1.18(m,4H),0.95(s,6H),0.88(d,J＝5.6Hz,6H). Compound 41B: 1 HNMR (500MHz, CDCl 3 ) δ7.72 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 7.4 Hz, 1H), 7.30 (dd, J = 17.3, 9.5 Hz, 1H) ,5.58(d,J＝7.5Hz,2H),5.30(s,2H),4.36(t,J＝15.8Hz,1H),4.22(d,J＝13.2Hz,1H),4.12(s,2H) ,3.73(dd,J＝13.9,7.1Hz,1H),3.01(s,2H),2.37(t,J＝14.0Hz,2H),2.04(d,J＝7.1Hz,2H),1.89-1.80( m,2H),1.76(s,2H),1.65(d,J＝17.9Hz,5H),1.49-1.44(m,8H),1.37(s,2H),1.30–1.18(m,4H),0.95 (s,6H),0.88(d,J=5.6Hz,6H).
13CNMR(126MHz,CDCl 3)δ150.70,140.10,134.84,132.06,127.60,123.96,104.26,104.21,88.11,88.02,86.84,86.17,81.07,52.63,44.99,37.21,37.17,36.35,34.36,34.05,32.13,32.03,28.90,26.09,24.60,24.42,20.32,14.61,14.54. 13 CNMR (126MHz, CDCl 3 ) δ150.70,140.10,134.84,132.06,127.60,123.96,104.26,104.21,88.11,88.02,86.84,86.17,81.07,52.63,44.99,37.21,37 .17,36.35,34.36,34.05,32.13, 32.03,28.90,26.09,24.60,24.42,20.32,14.61,14.54.
实施例42：化合物42的制备Example 42: Preparation of Compound 42
Figure PCTCN2022131906-appb-000058
Figure PCTCN2022131906-appb-000058
如实施例39，原料采用原料42(1.00g，5.10mmol，1.00eq)，得到414mg化合物42A和422mg化合物42B，合并收率67％，化合物42A和化合物42B均为白色固体。As in Example 39, raw material 42 (1.00g, 5.10mmol, 1.00eq) was used to obtain 414 mg of compound 42A and 422 mg of compound 42B. The combined yield was 67%. Both compound 42A and compound 42B were white solids.
化合物42的核磁结果如下：The NMR results of compound 42 are as follows:
化合物42A: 1HNMR(500MHz,CDCl 3)δ6.91(s,1H),6.80(s,2H),5.30(s,2H),4.45(d,J＝10.7Hz,2H),3.95(d,J＝12.8Hz,2H),3.85(d,J＝12.8Hz,2H),3.80(s,3H),2.65–2.56(m,2H),2.38-2.27(m,2H),2.03-1.96(m,3H),1.92–1.84(m,3H),1.71–1.40(m,12H),1.28-1.13(m,6H),1.05–0.79(m,14H). Compound 42A: 1 HNMR (500MHz, CDCl 3 ) δ6.91 (s, 1H), 6.80 (s, 2H), 5.30 (s, 2H), 4.45 (d, J = 10.7Hz, 2H), 3.95 (d, J＝12.8Hz,2H),3.85(d,J＝12.8Hz,2H),3.80(s,3H),2.65–2.56(m,2H),2.38-2.27(m,2H),2.03-1.96(m ,3H),1.92–1.84(m,3H),1.71–1.40(m,12H),1.28-1.13(m,6H),1.05–0.79(m,14H).
13CNMR(126MHz,CDCl 3)δ159.85,139.81,122.54,113.33,104.31,92.34,80.50,79.58,55.30,51.86,46.17,37.26,36.32,35.43,34.06,32.82,31.96,26.04,24.73,21.24,20.27,14.86,14.13. 13 CNMR (126MHz, CDCl 3 ) δ159.85,139.81,122.54,113.33,104.31,92.34,80.50,79.58,55.30,51.86,46.17,37.26,36.32,35.43,34.06,32.82,31.96 ,26.04,24.73,21.24,20.27, 14.86,14.13.
化合物42B: 1HNMR(500MHz,CDCl 3)δ6.94(s,1H),6.82(s,2H),5.66(s,2H),5.26(d,J＝5.1Hz,2H),3.93(d,J＝12.6Hz,2H),3.83(d,J＝12.4Hz,2H),3.80(s,3H),2.02–2.97(m,2H),2.41–2.35(m,2H),2.08–1.99(m,3H),1.90–1.85(m,3H),1.70–1.40(m,12H),1.26-1.15(m,6H),0.95–0.93(m,14H). Compound 42B: 1 HNMR (500MHz, CDCl 3 ) δ6.94 (s, 1H), 6.82 (s, 2H), 5.66 (s, 2H), 5.26 (d, J = 5.1Hz, 2H), 3.93 (d, J＝12.6Hz,2H),3.83(d,J＝12.4Hz,2H),3.80(s,3H),2.02–2.97(m,2H),2.41–2.35(m,2H),2.08–1.99(m ,3H),1.90–1.85(m,3H),1.70–1.40(m,12H),1.26-1.15(m,6H),0.95–0.93(m,14H).
实施例43：化合物43的制备Example 43: Preparation of Compound 43
Figure PCTCN2022131906-appb-000059
Figure PCTCN2022131906-appb-000059
1、将原料43(500mg，3.56mmol，1.00eq)和NBS(1.39g，7.82mmol，2.20eq)加入到20mLCCl 4中，加入AIBN(58mg，0.36mmol，0.10eq)，置换氩气，反应升温至回流并搅拌16h，纯化得到864mg中间体43-1； 1. Add raw materials 43 (500mg, 3.56mmol, 1.00eq) and NBS (1.39g, 7.82mmol, 2.20eq) into 20mL CCl 4 , add AIBN (58mg, 0.36mmol, 0.10eq), replace the argon gas, and heat up the reaction. After refluxing and stirring for 16 h, 864 mg of intermediate 43-1 was obtained after purification;
2、将中间体43-1(300mg，1.01mmol，1.00eq)和实施例1的SDHA-A(604mg，2.02mmol，2.00eq)溶解在10mL的DMF中，加入碳酸钾(417mg，3.03mmol，3.00eq)，反应在室温下搅拌2h，纯化得到460mg化合物43A，收率62％，化合物43A为白色固体；2. Dissolve intermediate 43-1 (300 mg, 1.01 mmol, 1.00 eq) and SDHA-A of Example 1 (604 mg, 2.02 mmol, 2.00 eq) in 10 mL of DMF, and add potassium carbonate (417 mg, 3.03 mmol, 3.00eq), the reaction was stirred at room temperature for 2 h, and 460 mg of compound 43A was obtained after purification, with a yield of 62%. Compound 43A was a white solid;
3、将中间体43-1(300mg，1.01mmol，1.00eq)和实施例1的SDHA-B(604mg，2.02mmol，2.00eq)溶解在10mL的DMF中，加入碳酸钾(417mg，3.03mmol，3.00eq)，反应在室温下搅拌2h，纯化得到510mg化合物43B，收率69％，化合物43B为白色固体。3. Dissolve intermediate 43-1 (300 mg, 1.01 mmol, 1.00 eq) and SDHA-B of Example 1 (604 mg, 2.02 mmol, 2.00 eq) in 10 mL of DMF, and add potassium carbonate (417 mg, 3.03 mmol, 3.00eq), the reaction was stirred at room temperature for 2 h, and 510 mg of compound 43B was obtained after purification, with a yield of 69%. Compound 43B was a white solid.
化合物43的核磁结果如下：The NMR results of compound 43 are as follows:
化合物43A： 1HNMR(600MHz,CDCl 3)δ7.34(s,2H),7.32(s,1H),5.30(s,2H),4.42(d,J＝10.7Hz,2H),4.40(s,4H),2.61(s,2H),2.38(d,J＝3.6Hz,2H),2.03(d,J＝14.8Hz,2H),1.87(m,2H),1.65(m,4H),1.59–0.99(m,18H),0.95(d,J＝6.3Hz,6H),0.82(d,J＝7.1Hz,6H). Compound 43A: 1 HNMR (600MHz, CDCl 3 ) δ7.34 (s, 2H), 7.32 (s, 1H), 5.30 (s, 2H), 4.42 (d, J = 10.7Hz, 2H), 4.40 (s, 4H),2.61(s,2H),2.38(d,J＝3.6Hz,2H),2.03(d,J＝14.8Hz,2H),1.87(m,2H),1.65(m,4H),1.59– 0.99(m,18H),0.95(d,J＝6.3Hz,6H),0.82(d,J＝7.1Hz,6H).
化合物43B： 1HNMR(600MHz,CDCl 3)δ7.34(s,2H),7.31(s,1H),5.66(s, 2H),5.21(d,J＝5.3Hz,2H),4.42(s,4H),,2.99(dd,J＝12.0,5.2Hz,2H),2.38(td,J＝14.0,3.7Hz,2H),2.06(d,J＝15.0Hz,2H),1.94–1.76(m,4H),1.72–1.63(m,4H),1.58–1.36(m,12H),1.25(td,J＝11.6,6.7Hz,4H),0.95(d,J＝6.4Hz,6H),0.85(d,J＝7.3Hz,6H). Compound 43B: 1 HNMR (600MHz, CDCl 3 ) δ7.34 (s, 2H), 7.31 (s, 1H), 5.66 (s, 2H), 5.21 (d, J = 5.3Hz, 2H), 4.42 (s, 4H),,2.99(dd,J＝12.0,5.2Hz,2H),2.38(td,J＝14.0,3.7Hz,2H),2.06(d,J＝15.0Hz,2H),1.94–1.76(m, 4H),1.72–1.63(m,4H),1.58–1.36(m,12H),1.25(td,J＝11.6,6.7Hz,4H),0.95(d,J＝6.4Hz,6H),0.85(d ,J＝7.3Hz,6H).
实施例44：化合物44的制备Example 44: Preparation of Compound 44
Figure PCTCN2022131906-appb-000060
Figure PCTCN2022131906-appb-000060
1、将原料44(2.00g，9.92mmol，1.00eq)加入到10mL的SOCl 2中，滴加几滴DMF，升温至100℃并搅拌过夜；浓缩除去溶剂，加入20mL的DCM，降温至0℃，滴加10mL甲醇，反应在0℃下搅拌2h后移至室温搅拌过夜，纯化得到2.00g中间体44-1； 1. Add raw material 44 (2.00g, 9.92mmol, 1.00eq) into 10mL of SOCl 2 , add a few drops of DMF, heat to 100°C and stir overnight; concentrate to remove the solvent, add 20mL of DCM, and cool to 0°C. , 10 mL of methanol was added dropwise, the reaction was stirred at 0°C for 2 h, then moved to room temperature and stirred overnight, and 2.00 g of intermediate 44-1 was obtained after purification;
2、将中间体44-1(1.50g，6.53mmol，1.00eq)加入到100mL无水乙醇中，分批加入NaBH 4(1.24g，32.66mmol，6.00eq)，反应在室温下搅拌过夜，纯化得到985mg中间体44-2； 2. Add intermediate 44-1 (1.50g, 6.53mmol, 1.00eq) to 100mL absolute ethanol, add NaBH 4 (1.24g, 32.66mmol, 6.00eq) in batches, stir the reaction at room temperature overnight, and purify. Obtain 985 mg of intermediate 44-2;
3、将中间体44-2(0.98g，5.65mmol，1.00eq)和三乙胺(2.86g，28.23mmol，5.00eq)加入到20mL的DCM中，反应降温至0℃，滴加甲磺酰氯(1.94g，16.94mmol，3.00eq)，反应在0℃下搅拌3h，纯化得到1.80g中间体44-3；3. Add intermediate 44-2 (0.98g, 5.65mmol, 1.00eq) and triethylamine (2.86g, 28.23mmol, 5.00eq) into 20 mL of DCM, cool the reaction to 0°C, and add methanesulfonyl chloride dropwise. (1.94g, 16.94mmol, 3.00eq), the reaction was stirred at 0°C for 3h, and 1.80g of intermediate 44-3 was obtained after purification;
4、将中间体44-3(1.80g，5.46mmol，1.00eq)和硫代乙酸钾(1.87mg，16.38mmol，3.00eq)加入到30mL的DMF中，反应升温至60℃并搅拌过夜，纯化得到630mg中间体44-4；4. Add intermediate 44-3 (1.80g, 5.46mmol, 1.00eq) and potassium thioacetate (1.87mg, 16.38mmol, 3.00eq) into 30mL of DMF. The reaction is heated to 60°C and stirred overnight to purify. 630 mg of intermediate 44-4 was obtained;
5、将中间体44-4(630mg，2.17mmol，1.00eq)加入20mL的EtOH中，降温至0℃，滴加3.3mL的2M氢氧化钠水溶液，反应在0℃下搅拌2h，纯化得到440mg中间体44-5；5. Add intermediate 44-4 (630 mg, 2.17 mmol, 1.00 eq) to 20 mL of EtOH, cool to 0°C, add dropwise 3.3 mL of 2M sodium hydroxide aqueous solution, stir the reaction at 0°C for 2 hours, and purify to obtain 440 mg. Intermediate 44-5;
6、将中间体44-5(440mg，2.14mmol，1.00eq)和DHA(1.22mg，4.28mmol，2.00eq)加入到30mL乙醚中，反应降温至0℃，滴加三氟化硼乙醚(608mg，4.28mmol，2.00eq)，反应在0℃下搅拌10min后逐渐升至室温搅拌过夜，纯化得到510mg化合物44A和590mg化合物44B，合并收率70％，化合物44A和化合物44B均为白色固体。6. Add intermediate 44-5 (440 mg, 2.14 mmol, 1.00 eq) and DHA (1.22 mg, 4.28 mmol, 2.00 eq) into 30 mL of diethyl ether, cool the reaction to 0°C, and add boron trifluoride diethyl ether (608 mg) dropwise. , 4.28 mmol, 2.00 eq), the reaction was stirred at 0°C for 10 min and then gradually raised to room temperature and stirred overnight. After purification, 510 mg of compound 44A and 590 mg of compound 44B were obtained. The combined yield was 70%. Compound 44A and compound 44B were both white solids.
化合物44的核磁结果如下：The NMR results of compound 44 are as follows:
化合物44A： 1HNMR(500MHz,CDCl 3)δ7.23(s,2H),5.29(s,2H),4.52(d,J＝10.7Hz,2H),4.05(d,J＝13.4Hz,2H),3.93(d,J＝13.3Hz,2H),3.05(d,J＝5.2Hz,2H),2.34(t,J＝14.0Hz,2H),2.07(d,J＝14.6Hz,2H),1.93–1.65(m,10H),1.61–1.31(m,11H),1.08–0.85(m,14H). Compound 44A: 1 HNMR (500MHz, CDCl 3 ) δ7.23 (s, 2H), 5.29 (s, 2H), 4.52 (d, J = 10.7Hz, 2H), 4.05 (d, J = 13.4Hz, 2H) ,3.93(d,J＝13.3Hz,2H),3.05(d,J＝5.2Hz,2H),2.34(t,J＝14.0Hz,2H),2.07(d,J＝14.6Hz,2H),1.93 –1.65(m,10H),1.61–1.31(m,11H),1.08–0.85(m,14H).
化合物44B： 1HNMR(500MHz,CDCl 3)δ7.23(s,2H),5.65(s,2H),5.37(d,J＝4.8Hz,2H),4.03(d,J＝13.4Hz,2H),3.97(d,J＝13.3Hz,2H),3.00(d,J＝5.2Hz,2H),2.35(t,J＝14.0Hz,2H),2.05(d,J＝14.6Hz,2H),1.93–1.63(m,10H),1.60–1.35(m,11H),1.25(dd,J＝17.8,11.2Hz,2H),0.98–0.84(m,12H). Compound 44B: 1 HNMR (500MHz, CDCl 3 ) δ7.23 (s, 2H), 5.65 (s, 2H), 5.37 (d, J = 4.8Hz, 2H), 4.03 (d, J = 13.4Hz, 2H) ,3.97(d,J＝13.3Hz,2H),3.00(d,J＝5.2Hz,2H),2.35(t,J＝14.0Hz,2H),2.05(d,J＝14.6Hz,2H),1.93 –1.63(m,10H),1.60–1.35(m,11H),1.25(dd,J＝17.8,11.2Hz,2H),0.98–0.84(m,12H).
实施例45：化合物45的制备Example 45: Preparation of Compound 45
Figure PCTCN2022131906-appb-000061
Figure PCTCN2022131906-appb-000061
1、将原料45(1.00g，7.19mmol，1.00eq.)溶解于36mL的DCM中，降温至0℃，加入三乙胺(4.36g，43.12mmol，6.00eq)，随后缓慢滴加MsCl(3.29g，28.75mmol，4.00eq)，加完后移至室温搅拌2h，纯化得到1.31g中间体45-1；1. Dissolve raw material 45 (1.00g, 7.19mmol, 1.00eq.) in 36mL of DCM, cool to 0°C, add triethylamine (4.36g, 43.12mmol, 6.00eq.), and then slowly add MsCl (3.29 g, 28.75mmol, 4.00eq), after addition, move to room temperature and stir for 2h, purify to obtain 1.31g of intermediate 45-1;
2、将中间体45-1(200.0mg，0.677mmol，1.00eq)、实施例1的SDHA-A(447.58mg，1.49mmol，2.20eq)和K 2CO 3(561.57mg，4.06mmol，6.00eq)溶解于14mLDMF中，置换Ar，反应在室温下搅拌16h，纯化得342mg化合物45A，收率72％，化合物45A为白色泡沫状固体； 2. Combine intermediate 45-1 (200.0mg, 0.677mmol, 1.00eq), SDHA-A of Example 1 (447.58mg, 1.49mmol, 2.20eq) and K 2 CO 3 (561.57mg, 4.06mmol, 6.00eq) ) was dissolved in 14 mL DMF, Ar was replaced, the reaction was stirred at room temperature for 16 hours, and 342 mg of compound 45A was purified, with a yield of 72%. Compound 45A was a white foamy solid;
3、将中间体45-1(200.0mg，0.677mmol，1.00eq)、实施例1的SDHA-B(447.58mg，1.49mmol，2.20eq)和K 2CO 3(561.57mg，4.06mmol，6.0eq)溶解于14mLDMF中，置换Ar，反应在室温下搅拌16h，纯化得到365mg化合物45B，收率77％，化合物45B为白色泡沫状固。 3. Combine intermediate 45-1 (200.0mg, 0.677mmol, 1.00eq), SDHA-B of Example 1 (447.58mg, 1.49mmol, 2.20eq) and K 2 CO 3 (561.57mg, 4.06mmol, 6.0eq) ) was dissolved in 14 mL of DMF, Ar was replaced, and the reaction was stirred at room temperature for 16 h. After purification, 365 mg of compound 45B was obtained with a yield of 77%. Compound 45B was a white foamy solid.
化合物45的核磁结果如下：The NMR results of compound 45 are as follows:
化合物45A： 1HNMR(500MHz,CDCl 3)δ7.58(t,J＝7.6Hz,1H),7.23(d,J＝7.6Hz,2H),5.29(s,2H),4.52(d,J＝10.7Hz,2H),4.05(d,J＝13.4Hz,2H),3.91(d,J＝13.3Hz,2H),3.05(d,J＝5.2Hz,2H),2.33(t,J＝14.0Hz,2H),2.07(d,J＝14.6Hz,2H),1.93–1.62(m,10H),1.61–1.31(m,12H),1.08–0.83(m,14H). Compound 45A: 1 HNMR (500MHz, CDCl 3 ) δ7.58 (t, J＝7.6Hz, 1H), 7.23 (d, J＝7.6Hz, 2H), 5.29 (s, 2H), 4.52 (d, J＝ 10.7Hz,2H),4.05(d,J＝13.4Hz,2H),3.91(d,J＝13.3Hz,2H),3.05(d,J＝5.2Hz,2H),2.33(t,J＝14.0Hz ,2H),2.07(d,J=14.6Hz,2H),1.93–1.62(m,10H),1.61–1.31(m,12H),1.08–0.83(m,14H).
化合物45B： 1HNMR(500MHz,CDCl 3)δ7.57(t,J＝7.6Hz,1H),7.22(d,J＝7.6Hz,2H),5.65(s,2H),5.37(d,J＝4.8Hz,2H),4.03(d,J＝13.4Hz,2H),3.96 (d,J＝13.3Hz,2H),3.01(d,J＝5.2Hz,2H),2.37(t,J＝14.0Hz,2H),2.05(d,J＝14.6Hz,2H),1.93–1.62(m,10H),1.60–1.35(m,12H),1.25(dd,J＝17.8,11.2Hz,2H),0.98–0.83(m,12H). Compound 45B: 1 HNMR (500MHz, CDCl 3 ) δ7.57 (t, J＝7.6Hz, 1H), 7.22 (d, J＝7.6Hz, 2H), 5.65 (s, 2H), 5.37 (d, J＝ 4.8Hz,2H),4.03(d,J＝13.4Hz,2H),3.96 (d,J＝13.3Hz,2H),3.01(d,J＝5.2Hz,2H),2.37(t,J＝14.0Hz ,2H),2.05(d,J＝14.6Hz,2H),1.93–1.62(m,10H),1.60–1.35(m,12H),1.25(dd,J＝17.8,11.2Hz,2H),0.98– 0.83(m,12H).
13CNMR(126MHz,CDCl 3)δ158.15,136.99,121.42,104.20,88.14,85.94,81.20,52.71,45.14,38.09,37.18,36.41,34.44,32.06,26.15,24.63,24.44,20.34,14.63. 13 CNMR (126MHz, CDCl 3 ) δ158.15,136.99,121.42,104.20,88.14,85.94,81.20,52.71,45.14,38.09,37.18,36.41,34.44,32.06,26.15,24.63,24.44, 20.34,14.63.
实施例46：化合物46的制备Example 46: Preparation of Compound 46
Figure PCTCN2022131906-appb-000062
Figure PCTCN2022131906-appb-000062
1、将原料46(800mg，3.28mmol，1.00eq)溶解于33mL无水甲醇中，降温至0℃，搅拌下缓慢滴加浓硫酸(3.27g，32.76mmol，10.00eq)，加完后加热至回流并搅拌16h，纯化得到801mg中间体46-1；1. Dissolve raw material 46 (800mg, 3.28mmol, 1.00eq) in 33mL of anhydrous methanol, cool to 0°C, slowly add concentrated sulfuric acid (3.27g, 32.76mmol, 10.00eq) dropwise while stirring, and heat to Reflux and stir for 16 h, and purify to obtain 801 mg of intermediate 46-1;
2、将中间体46-1(800mg，2.94mmol，1.00eq)溶解在30mL无水乙醇中，降温至0℃，搅拌下分批加入NaBH 4(1.33g，35.26mmol，12.00eq)，随后反应加热至回流下搅拌3h，纯化得到602mg中间体46-2； 2. Dissolve intermediate 46-1 (800 mg, 2.94 mmol, 1.00 eq) in 30 mL of absolute ethanol, cool to 0°C, add NaBH 4 (1.33 g, 35.26 mmol, 12.00 eq) in batches while stirring, and then react. Heated to reflux and stirred for 3 hours, purified to obtain 602 mg of intermediate 46-2;
3、将中间体46-2(600mg，2.77mmol，1.00eq)溶解在27mL的DCM中， 降温至0℃，加入三乙胺(1.68g，16.65mmol，6.00eq)，随后缓慢滴加MsCl(1.27g，11.10mmol，4.00eq)，加完后移至室温搅拌2h，纯化得412mg中间体46-3；3. Dissolve intermediate 46-2 (600mg, 2.77mmol, 1.00eq) in 27mL of DCM, cool to 0°C, add triethylamine (1.68g, 16.65mmol, 6.00eq), and then slowly add MsCl ( 1.27g, 11.10mmol, 4.00eq), after the addition, move to room temperature and stir for 2h, and purify to obtain 412mg of intermediate 46-3;
4、将中间体46-3(120mg，0.32mmol，1.00eq)和实施例1的SDHA-A(242mg，0.81mmol，2.50eq)溶在6.5mL的DMF中，加入K 2CO 3(267mg，1.93mmol，6.00eq)，反应在室温下搅拌16h，纯化得到151mg化合物46A，，收率60％，化合物46A为白色泡沫状固体； 4. Dissolve intermediate 46-3 (120 mg, 0.32 mmol, 1.00 eq) and SDHA-A of Example 1 (242 mg, 0.81 mmol, 2.50 eq) in 6.5 mL of DMF, and add K 2 CO 3 (267 mg, 1.93mmol, 6.00eq), the reaction was stirred at room temperature for 16h, and 151mg of compound 46A was purified, with a yield of 60%. Compound 46A was a white foamy solid;
5、将中间体46-3(200mg，0.54mmol，1.00eq)、和实施例1的SDHA-B(403mg，1.34mmol，2.50eq)溶在10.7mL的DMF中，加入K 2CO 3(445mg，3.22mmol，6.00eq)，反应在室温下搅拌16h，纯化得到311mg化合物46B，收率74％，化合物46B为白色泡沫状固体。 5. Dissolve intermediate 46-3 (200 mg, 0.54 mmol, 1.00 eq) and SDHA-B of Example 1 (403 mg, 1.34 mmol, 2.50 eq) in 10.7 mL of DMF, and add K 2 CO 3 (445 mg , 3.22 mmol, 6.00 eq), the reaction was stirred at room temperature for 16 h, and 311 mg of compound 46B was purified, with a yield of 74%. Compound 46B was a white foamy solid.
化合物46的核磁结果如下：The NMR results of compound 46 are as follows:
化合物46A： 1HNMR(500MHz,CDCl 3)δ8.61(s,2H),8.36(s,2H),7.39(s,2H),5.34(s,2H),4.47(d,J＝10.4Hz,2H),4.09(d,J＝13.2Hz,2H),3.89(d,J＝13.1Hz,2H),2.62(s,2H),2.39(t,J＝13.6Hz,2H),2.04(d,J＝13.1Hz,2H),1.88(s,2H),1.78(s,2H),1.73–1.18(m,18H),1.06–0.77(m,14H). Compound 46A: 1 HNMR (500MHz, CDCl 3 ) δ8.61 (s, 2H), 8.36 (s, 2H), 7.39 (s, 2H), 5.34 (s, 2H), 4.47 (d, J = 10.4Hz, 2H),4.09(d,J＝13.2Hz,2H),3.89(d,J＝13.1Hz,2H),2.62(s,2H),2.39(t,J＝13.6Hz,2H),2.04(d, J＝13.1Hz,2H),1.88(s,2H),1.78(s,2H),1.73–1.18(m,18H),1.06–0.77(m,14H).
13CNMR(126MHz,CDCl 3)δ156.24,149.34,148.93,124.26,121.76,104.40,100.00,92.33,80.49,79.47,51.76,46.07,37.32,36.27,33.97,32.00,31.72,26.00,24.77,21.26,20.24,14.76. 13 CNMR (126MHz, CDCl 3 ) δ156.24,149.34,148.93,124.26,121.76,104.40,100.00,92.33,80.49,79.47,51.76,46.07,37.32,36.27,33.97,32.00,31. 72,26.00,24.77,21.26,20.24, 14.76.
化合物46B： 1HNMR(500MHz,CDCl 3)δ8.61(d,J＝3.5Hz,2H),8.38(s,2H),7.34(s,2H),5.64(s,2H),5.22(s,2H),3.93(q,J＝13.5Hz,4H),3.01(s,2H),2.37(t,J＝13.7Hz,2H),2.06(d,J＝12.5Hz,2H),1.96–1.63(m,10H),1.60–1.34(m,10H),1.25(d,J＝6.4Hz,2H),1.04–0.80(m,14H). Compound 46B: 1 HNMR (500MHz, CDCl 3 ) δ8.61 (d, J = 3.5Hz, 2H), 8.38 (s, 2H), 7.34 (s, 2H), 5.64 (s, 2H), 5.22 (s, 2H),3.93(q,J＝13.5Hz,4H),3.01(s,2H),2.37(t,J＝13.7Hz,2H),2.06(d,J＝12.5Hz,2H),1.96–1.63( m,10H),1.60–1.34(m,10H),1.25(d,J=6.4Hz,2H),1.04–0.80(m,14H).
13CNMR(126MHz,CDCl 3)δ149.32(s),148.42(s),124.21(s),121.67(s),104.29(s),88.15(s),85.68(s),81.12(s),52.66(s),45.01(s),37.20(s),36 .36(s),35.21(s),34.38(s),31.95(s),26.13(s),24.61(s),24.44(s),20.33(s),14.58(s). 13 CNMR(126MHz, CDCl 3 )δ149.32(s),148.42(s),124.21(s),121.67(s),104.29(s),88.15(s),85.68(s),81.12(s), 52.66(s),45.01(s),37.20(s),36.36(s),35.21(s),34.38(s),31.95(s),26.13(s),24.61(s),24.44(s) ),20.33(s),14.58(s).
实施例47：化合物47的制备Example 47: Preparation of Compound 47
Figure PCTCN2022131906-appb-000063
Figure PCTCN2022131906-appb-000063
如实施例46，原料采用原料47(1.00g，5.98mmol，1.00eq)，得到210mg化合物47A和280mg化合物47B，化合物47A和化合物47B均为白色固体；As in Example 46, raw material 47 (1.00g, 5.98mmol, 1.00eq) was used to obtain 210 mg of compound 47A and 280 mg of compound 47B. Both compound 47A and compound 47B were white solids;
化合物47的核磁结构如下：The nuclear magnetic structure of compound 47 is as follows:
化合物47A： 1HNMR(500MHz,CDCl 3)δ8.46(d,J＝3.8Hz,1H),7.35(s,1H),7.18(s,1H),5.29(d,J＝15.7Hz,2H),4.59(d,J＝10.7Hz,1H),4.39(d,J＝10.7Hz,1H),4.11(d,J＝13.0Hz,1H),3.97(dd,J＝21.0,13.3Hz,2H),3.78(d,J＝13.4Hz,1H),2.57(s,2H),2.36(t,J＝12.6Hz,2H),2.02(d,J＝14.9Hz,2H),1.88(s,3H),1.67(d,J＝13.3Hz,4H),1.53(s,1H),1.48(d,J＝14.6Hz,2H),1.43(s,6H),1.33(d,J＝10.7Hz,3H),1.28–1.18(m,3H),0.99(d,J＝12.4Hz,2H),0.94(d,J＝5.4Hz,6H),0.81(d,J＝6.2Hz,6H). Compound 47A: 1 HNMR (500MHz, CDCl 3 ) δ8.46 (d, J = 3.8 Hz, 1H), 7.35 (s, 1H), 7.18 (s, 1H), 5.29 (d, J = 15.7 Hz, 2H) ,4.59(d,J＝10.7Hz,1H),4.39(d,J＝10.7Hz,1H),4.11(d,J＝13.0Hz,1H),3.97(dd,J＝21.0,13.3Hz,2H) ,3.78(d,J＝13.4Hz,1H),2.57(s,2H),2.36(t,J＝12.6Hz,2H),2.02(d,J＝14.9Hz,2H),1.88(s,3H) ,1.67(d,J＝13.3Hz,4H),1.53(s,1H),1.48(d,J＝14.6Hz,2H),1.43(s,6H),1.33(d,J＝10.7Hz,3H) ,1.28–1.18(m,3H),0.99(d,J＝12.4Hz,2H),0.94(d,J＝5.4Hz,6H),0.81(d,J＝6.2Hz,6H).
13CNMR(126MHz,CDCl 3)δ158.42,149.76,148.06,123.70,122.40,104.31,104.23,88.16,88.12,86.16,85.75,81.20,81.12,53.21,52.68,45.10,44.98,38.40,37.20,37.14,36.35,34.99,34.41,34.36,32.08,31.95,26.14,24.62,24.41,20.33,14.66,14.58. 13 CNMR (126MHz, CDCl 3 ) δ158.42,149.76,148.06,123.70,122.40,104.31,104.23,88.16,88.12,86.16,85.75,81.20,81.12,53.21,52.68,45.10,44. 98,38.40,37.20,37.14,36.35, 34.99,34.41,34.36,32.08,31.95,26.14,24.62,24.41,20.33,14.66,14.58.
化合物47B： 1HNMR(500MHz,CDCl 3)δ8.48(s,1H),7.34(s,1H),7.16(s,1H),5.62(d,J＝11.4Hz,2H),5.35(s,1H),5.17(d,J＝4.3Hz,1H),4.00(s,2H),3.81(dd,J＝29.8,13.6Hz,2H),3.00(s,2H),2.36(t,J＝13.8Hz,2H),2.05(d,J＝12.5Hz,2H),1.87(s,3H),1.82–1.74(m,2H),1.68(d,J＝16.1Hz,4H),1.48(d,J＝12.2Hz,4H),1.44(s,5H),1.39(s,2H),1.24(s,2H),0.99–0.90(m,8H),0.89–0.82(m,6H). Compound 47B: 1 HNMR (500MHz, CDCl 3 ) δ8.48 (s, 1H), 7.34 (s, 1H), 7.16 (s, 1H), 5.62 (d, J = 11.4Hz, 2H), 5.35 (s, 1H),5.17(d,J＝4.3Hz,1H),4.00(s,2H),3.81(dd,J＝29.8,13.6Hz,2H),3.00(s,2H),2.36(t,J＝13.8 Hz,2H),2.05(d,J＝12.5Hz,2H),1.87(s,3H),1.82–1.74(m,2H),1.68(d,J＝16.1Hz,4H),1.48(d,J =12.2Hz,4H),1.44(s,5H),1.39(s,2H),1.24(s,2H),0.99–0.90(m,8H),0.89–0.82(m,6H).
13CNMR(126MHz,CDCl 3)δ158.42,149.76,148.06,123.70,122.40,104.31,104.23,88.16,88.12,86.16,85.75,81.20,81.12,53.21,52.68,45.10,44.98,38.40,37.20,37.14,36.35,34.99,34.41,34.36,32.08,31.95,26.14,24.62,24.41,20.33,14.66,14.58. 13 CNMR (126MHz, CDCl 3 ) δ158.42,149.76,148.06,123.70,122.40,104.31,104.23,88.16,88.12,86.16,85.75,81.20,81.12,53.21,52.68,45.10,44. 98,38.40,37.20,37.14,36.35, 34.99,34.41,34.36,32.08,31.95,26.14,24.62,24.41,20.33,14.66,14.58.
实施例48：化合物48的制备Example 48: Preparation of Compound 48
Figure PCTCN2022131906-appb-000064
Figure PCTCN2022131906-appb-000064
1、将原料48(0.46g，2.06mmol，1.00eq)化合物溶21mL乙醇中，降温至0℃，加入硼氢化钠(935mg，24.73mmol，12.00eq)，反应在0℃下搅拌30min后逐渐升温至回流并搅拌4h，反应降温至室温后滴加5mL丙酮淬灭，纯化得到100mg中间体48-1；1. Dissolve raw material 48 (0.46g, 2.06mmol, 1.00eq) in 21mL of ethanol, cool to 0°C, add sodium borohydride (935mg, 24.73mmol, 12.00eq), stir the reaction at 0°C for 30 minutes and then gradually heat up. After refluxing and stirring for 4 hours, the reaction was cooled to room temperature, then 5 mL of acetone was added dropwise to quench, and 100 mg of intermediate 48-1 was obtained after purification;
2、将中间体48-1(100mg，0.72mmol，1.00eq)溶于4mL的DCM中，降温至0℃，加入三乙胺(0.6mL，4.31mmol，6.00eq)，再滴加MsCl(0.22mL，2.87mmol，4.00eq)，反应逐渐升温至室温搅拌0.5h，纯化得到210mg中间体48-2；2. Dissolve intermediate 48-1 (100 mg, 0.72 mmol, 1.00 eq) in 4 mL of DCM, cool to 0°C, add triethylamine (0.6 mL, 4.31 mmol, 6.00 eq), and then add MsCl (0.22) dropwise mL, 2.87mmol, 4.00eq), the reaction was gradually heated to room temperature and stirred for 0.5h, and 210mg of intermediate 48-2 was obtained after purification;
3、将中间体48-2(50mg，0.17mmol，1.00eq)和实施例1的SDHA-A(112mg，0.37mmol，2.20eq)加入2mL的DMF中，加入碳酸钾(59mg，0.42mmol，2.50eq)，反应在室温下搅拌1.5h，纯化得56mg化合物48A，化合物48A为白色固体，收率48％；3. Add intermediate 48-2 (50 mg, 0.17 mmol, 1.00 eq) and SDHA-A of Example 1 (112 mg, 0.37 mmol, 2.20 eq) into 2 mL of DMF, and add potassium carbonate (59 mg, 0.42 mmol, 2.50 eq), the reaction was stirred at room temperature for 1.5h, and 56 mg of compound 48A was obtained after purification. Compound 48A was a white solid, and the yield was 48%;
4、将中间体48-2(50mg，0.17mmol，1.00eq)和实施例1的SDHA-B(112mg，0.37mmol，2.20eq)加入2mL发热DMF中，加入碳酸钾(59mg，0.42mmol， 2.50eq)，反应在室温下搅拌1.5h，纯化得66mg化合物48B，化合物48B为白色固体，收率55％。4. Add intermediate 48-2 (50 mg, 0.17 mmol, 1.00 eq) and SDHA-B of Example 1 (112 mg, 0.37 mmol, 2.20 eq) into 2 mL of heating DMF, and add potassium carbonate (59 mg, 0.42 mmol, 2.50 eq), the reaction was stirred at room temperature for 1.5 h, and 66 mg of compound 48B was obtained after purification. Compound 48B was a white solid with a yield of 55%.
化合物48的核磁结果如下：The NMR results of compound 48 are as follows:
化合物48A： 1HNMR(500MHz,CDCl 3)δ8.43(s,2H),7.71(s,1H),5.33(s,2H),4.42(d,J＝10.7Hz,2H),4.14–4.06(m,4H),3.01(d,J＝5.2Hz,2H),2.35–2.31(m,2H),2.11-2.02(m,2H),1.91–1.65(m,10H),1.62–1.31(m,12H),1.09–0.83(m,14H). Compound 48A: 1 HNMR (500MHz, CDCl 3 ) δ8.43 (s, 2H), 7.71 (s, 1H), 5.33 (s, 2H), 4.42 (d, J = 10.7Hz, 2H), 4.14–4.06 ( m,4H),3.01(d,J＝5.2Hz,2H),2.35–2.31(m,2H),2.11-2.02(m,2H),1.91–1.65(m,10H),1.62–1.31(m, 12H),1.09–0.83(m,14H).
化合物48B： 1HNMR(500MHz,CDCl 3)δ8.43(s,2H),7.71(s,1H),5.61(s,2H),5.23(d,J＝5.4Hz,2H),4.05(d,J＝13.4Hz,2H),3.98(d,J＝13.3Hz,2H),3.01–2.96(m,2H),2.37-3.31(m,2H),2.05(d,J＝14.6Hz,2H),1.93–1.62(m,10H),1.60–1.35(m,12H),1.25–1.13(m,2H),0.98–0.83(m,12H). Compound 48B: 1 HNMR (500MHz, CDCl 3 ) δ8.43 (s, 2H), 7.71 (s, 1H), 5.61 (s, 2H), 5.23 (d, J = 5.4Hz, 2H), 4.05 (d, J＝13.4Hz,2H),3.98(d,J＝13.3Hz,2H),3.01–2.96(m,2H),2.37-3.31(m,2H),2.05(d,J＝14.6Hz,2H), 1.93–1.62(m,10H),1.60–1.35(m,12H),1.25–1.13(m,2H),0.98–0.83(m,12H).
实施例49：化合物49的制备Example 49: Preparation of Compound 49
Figure PCTCN2022131906-appb-000065
Figure PCTCN2022131906-appb-000065
如实施例40，原料采用原料49(500mg，2.90mmol，1.00eq)，得到186mg化合物49A和223mg化合物49B，化合物49A和化合物49B均为泡沫状白色固体。As in Example 40, raw material 49 (500 mg, 2.90 mmol, 1.00 eq) was used to obtain 186 mg of compound 49A and 223 mg of compound 49B. Both compound 49A and compound 49B were foamy white solids.
化合物49的核磁结果如下：The NMR results of compound 49 are as follows:
化合物49A： 1HNMR(500MHz,CDCl 3)δ7.17(s,2H),5.23(d,J＝7.5Hz,2H),4.37(d,J＝10.8Hz,2H),4.07(d,J＝13.8Hz,2H),4.00(d,J＝13.8Hz,2H),2.64–2.55(m,2H),2.37(td,J＝14.0,3.9Hz,2H),2.06–1.98(m,2H),1.91–1.84(m,2H),1.72–1.59(m,4H),1.56–1.41(m,10H),1.36–1.15(m,6H),1.05–0.92(m,8H),0.80(d,J＝7.2Hz,6H). Compound 49A: 1 HNMR (500MHz, CDCl 3 ) δ7.17 (s, 2H), 5.23 (d, J = 7.5Hz, 2H), 4.37 (d, J = 10.8Hz, 2H), 4.07 (d, J = 13.8Hz,2H),4.00(d,J＝13.8Hz,2H),2.64–2.55(m,2H),2.37(td,J＝14.0,3.9Hz,2H),2.06–1.98(m,2H), 1.91–1.84(m,2H),1.72–1.59(m,4H),1.56–1.41(m,10H),1.36–1.15(m,6H),1.05–0.92(m,8H),0.80(d,J =7.2Hz,6H).
13CNMR(126MHz,CDCl 3)δ137.01,124.20,104.32,92.27,80.49,79.61,51.84,46.14,37.34,36.32,34.03,31.89,26.27,26.07,24.76,21.21,20.25,14.84. 13 CNMR (126MHz, CDCl 3 ) δ137.01,124.20,104.32,92.27,80.49,79.61,51.84,46.14,37.34,36.32,34.03,31.89,26.27,26.07,24.76,21.21,20.25,1 4.84.
化合物49B： 1HNMR(500MHz,CDCl 3)δ7.17(s,2H),5.63(s,2H),5.15(d,J＝5.3Hz,2H),3.96(s,4H),3.01–2.93(m,2H),2.37(td,J＝14.1,3.8Hz,2H),2.09–2.01(m,2H),1.87(s,2H),1.77(d,J＝3.8Hz,2H),1.72–1.64(m,4H),1.62–1.34(m,10H),1.26(dd,J＝11.5,6.4Hz,4H),1.02–0.88(m,8H),0.78(d,J＝7.3Hz,6H). Compound 49B: 1 HNMR (500MHz, CDCl 3 ) δ7.17 (s, 2H), 5.63 (s, 2H), 5.15 (d, J = 5.3Hz, 2H), 3.96 (s, 4H), 3.01–2.93 ( m,2H),2.37(td,J＝14.1,3.8Hz,2H),2.09–2.01(m,2H),1.87(s,2H),1.77(d,J＝3.8Hz,2H),1.72–1.64 (m,4H),1.62–1.34(m,10H),1.26(dd,J＝11.5,6.4Hz,4H),1.02–0.88(m,8H),0.78(d,J＝7.3Hz,6H).
13CNMR(126MHz,CDCl 3)δ136.09,124.79,104.23,88.27,85.13,81.16,52.69,45.07,37.23,36.39,34.42,31.94,29.43,26.17,24.62,24.42,20.36,14.58. 13 CNMR (126MHz, CDCl 3 ) δ136.09,124.79,104.23,88.27,85.13,81.16,52.69,45.07,37.23,36.39,34.42,31.94,29.43,26.17,24.62,24.42,20.36,1 4.58.
实施例50：化合物50的制备Example 50: Preparation of Compound 50
Figure PCTCN2022131906-appb-000066
Figure PCTCN2022131906-appb-000066
1、将原料50(200mg，1.56mmol，1.00eq)溶于10mL无水二氯甲烷中，加入三乙胺(0.8mL，6.24mmol，4.00eq)，降温至-20℃下并搅拌10min，缓慢滴加甲基磺酰氯(0.3mL，3.9mmol，2.50eq)，反应在-20℃下搅拌30min，纯化得到380mg中间体50-1；1. Dissolve raw material 50 (200mg, 1.56mmol, 1.00eq) in 10mL anhydrous dichloromethane, add triethylamine (0.8mL, 6.24mmol, 4.00eq), cool to -20°C and stir for 10min, slowly Methanesulfonyl chloride (0.3 mL, 3.9 mmol, 2.50 eq) was added dropwise, the reaction was stirred at -20°C for 30 min, and 380 mg of intermediate 50-1 was obtained after purification;
2、将实施例1的SDHA-A(350mg，1.16mmol，2.20eq)溶于5mL无水DMF中，加入无水碳酸钾(321mg，1.58mmol，3.00eq)，搅拌30min；将中间体50-1(150mg，0.53mmol，1.00eq)用3mLDMF溶解后滴加到体系内，反应在室温下搅拌2h，纯化得到73mg化合物50A，化合物50A为白色固体，收率20％；2. Dissolve SDHA-A (350 mg, 1.16 mmol, 2.20 eq) of Example 1 in 5 mL anhydrous DMF, add anhydrous potassium carbonate (321 mg, 1.58 mmol, 3.00 eq), and stir for 30 min; add intermediate 50- 1 (150 mg, 0.53 mmol, 1.00 eq) was dissolved with 3 mL of DMF and then added dropwise into the system. The reaction was stirred at room temperature for 2 h. After purification, 73 mg of compound 50A was obtained. Compound 50A was a white solid with a yield of 20%;
3、将实施例1的SDHA-B(350mg，1.16mmol，2.20eq)溶于5mL无水DMF中，加入无水碳酸钾(321mg，1.58mmol，3.00eq)，搅拌30min；将中间体50-1(150mg，0.53mmol，1.00eq)用3mLDMF溶解后滴加到体系内，反应在室温下搅拌2h，纯化得到83mg化合物50B，化合物50B为白色固体，收率28％。3. Dissolve SDHA-B (350 mg, 1.16 mmol, 2.20 eq) of Example 1 in 5 mL anhydrous DMF, add anhydrous potassium carbonate (321 mg, 1.58 mmol, 3.00 eq), and stir for 30 min; add intermediate 50- 1 (150 mg, 0.53 mmol, 1.00 eq) was dissolved in 3 mL of DMF and added dropwise to the system. The reaction was stirred at room temperature for 2 h. After purification, 83 mg of compound 50B was obtained. Compound 50B was a white solid with a yield of 28%.
化合物50的核磁结果如下：The NMR results of compound 50 are as follows:
化合物50A： 1HNMR(500MHz,CDCl 3)δ6.11(s,2H),5.29(s,2H),4.56(d,J＝10.7Hz,2H),4.02(d,J＝14.6Hz,2H),3.82(d,J＝14.5Hz,2H),2.60(s,2H),2.37(t,J＝13.7Hz,2H),2.02(d,J＝14.0Hz,2H),1.87(s,2H),1.68(t,J＝13.2Hz,4H),1.59–1.55(m,4H),1.51-1.43(m,6H),1.34-1.24(m,6H),1.06–0.79(m, 14H). Compound 50A: 1 HNMR (500MHz, CDCl 3 ) δ6.11 (s, 2H), 5.29 (s, 2H), 4.56 (d, J = 10.7Hz, 2H), 4.02 (d, J = 14.6Hz, 2H) ,3.82(d,J＝14.5Hz,2H),2.60(s,2H),2.37(t,J＝13.7Hz,2H),2.02(d,J＝14.0Hz,2H),1.87(s,2H) ,1.68(t,J＝13.2Hz,4H),1.59–1.55(m,4H),1.51-1.43(m,6H),1.34-1.24(m,6H),1.06–0.79(m, 14H).
13CNMR(126MHz,CDCl3)δ151.51,108.31,104.34,100.09,92.42,80.52,79.75,51.85,46.17,37.31,36.31,34.05,32.04,26.03,25.20,24.75,21.26,20.26,14.81. 13 CNMR (126MHz, CDCl3) δ151.51,108.31,104.34,100.09,92.42,80.52,79.75,51.85,46.17,37.31,36.31,34.05,32.04,26.03,25.20,24.75,21.26,2 0.26,14.81.
化合物50B： 1HNMR(500MHz,CDCl 3)δ6.13(s,2H),5.62(s,2H),5.30(d,J＝4.7Hz,2H),3.90(d,J＝14.7Hz,2H),3.78(d,J＝14.6Hz,2H),3.02(s,2H),2.37(t,J＝14.1Hz,2H),2.05(d,J＝14.6Hz,2H),1.87(s,2H),1.84–1.63(m,8H),1.65–1.31(m,10H),1.26(s,4H),0.96–0.85(m,12H). Compound 50B: 1 HNMR (500MHz, CDCl 3 ) δ6.13 (s, 2H), 5.62 (s, 2H), 5.30 (d, J = 4.7Hz, 2H), 3.90 (d, J = 14.7Hz, 2H) ,3.78(d,J＝14.6Hz,2H),3.02(s,2H),2.37(t,J＝14.1Hz,2H),2.05(d,J＝14.6Hz,2H),1.87(s,2H) ,1.84–1.63(m,8H),1.65–1.31(m,10H),1.26(s,4H),0.96–0.85(m,12H).
13CNMR(126MHz,CDCl 3)δ151.01,108.65,104.24,100.00,88.21,85.65,81.18,52.70,45.09,37.20,36.39,34.41,32.02,28.30,26.16,24.62,24.39,20.34,14.62. 13 CNMR (126MHz, CDCl 3 ) δ151.01,108.65,104.24,100.00,88.21,85.65,81.18,52.70,45.09,37.20,36.39,34.41,32.02,28.30,26.16,24.62,24.39, 20.34,14.62.
实施例51：化合物51的制备Example 51: Preparation of Compound 51
Figure PCTCN2022131906-appb-000067
Figure PCTCN2022131906-appb-000067
如实施例40，原料采用原料41(1.00g，5.95mmol，1.00eq)，312mg化合物51A和286mg化合物51B，化合物51A和化合物51B均为白色泡沫状，。As in Example 40, raw material 41 (1.00g, 5.95mmol, 1.00eq), 312mg compound 51A and 286mg compound 51B were used. Both compound 51A and compound 51B were in the form of white foam.
化合物51的核磁结果如下：The NMR results of compound 51 are as follows:
化合物51A： 1HNMR(600MHz,CDCl 3)δ8.35(s,2H),5.25(s,2H),4.66(d,J＝10.7Hz,2H),4.26(s,4H),2.56(s,2H),2.37-2.32(m,2H),1.99(d,J＝14.3Hz,2H),1.87-1.82(s,2H),1.75(s,2H),1.67(t,J＝15.1Hz,4H),1.55(d,J＝13.2Hz,2H),1.48-1.38(m,4H),1.36-1.30(m,4H),1.23(dd,J＝11.1,6.6Hz,4H),0.97(dd,J＝33.6,9.4Hz,2H),0.87(d,J＝7.1Hz,6H),0.80(d,J＝7.0Hz,6H). Compound 51A: 1 HNMR (600MHz, CDCl 3 ) δ8.35 (s, 2H), 5.25 (s, 2H), 4.66 (d, J = 10.7Hz, 2H), 4.26 (s, 4H), 2.56 (s, 2H),2.37-2.32(m,2H),1.99(d,J＝14.3Hz,2H),1.87-1.82(s,2H),1.75(s,2H),1.67(t,J＝15.1Hz,4H ),1.55(d,J＝13.2Hz,2H),1.48-1.38(m,4H),1.36-1.30(m,4H),1.23(dd,J＝11.1,6.6Hz,4H),0.97(dd, J＝33.6,9.4Hz,2H),0.87(d,J＝7.1Hz,6H),0.80(d,J＝7.0Hz,6H).
13CNMR(151MHz,CDCl 3)δ153.30,142.00,104.27,92.20,80.50,80.43,51.79,46.12,37.34,36.27,34.04,32.37,32.31,26.01,24.76,21.24,20.24,14.82. 13 CNMR (151MHz, CDCl 3 ) δ153.30,142.00,104.27,92.20,80.50,80.43,51.79,46.12,37.34,36.27,34.04,32.37,32.31,26.01,24.76,21.24,20.24,1 4.82.
化合物51B： 1HNMR(600MHz,CDCl 3)δ8.37(s,2H),5.56(s,2H),5.46(d,J＝ 4.8Hz,2H),4.21(d,J＝13.7Hz,2H),4.14(d,J＝13.6Hz,2H),3.01(d,J＝5.3Hz,2H),2.35(t,J＝13.8Hz,2H),2.02(d,J＝14.7Hz,2H),1.87–1.75(m,4H),1.71–1.62(m,4H),1.49(t,J＝16.7Hz,4H),1.43–1.35(m,8H),1.25–1.20(m,2H),0.95–0.82(m,14H). Compound 51B: 1 HNMR (600MHz, CDCl 3 ) δ8.37 (s, 2H), 5.56 (s, 2H), 5.46 (d, J = 4.8Hz, 2H), 4.21 (d, J = 13.7Hz, 2H) ,4.14(d,J＝13.6Hz,2H),3.01(d,J＝5.3Hz,2H),2.35(t,J＝13.8Hz,2H),2.02(d,J＝14.7Hz,2H),1.87 –1.75(m,4H),1.71–1.62(m,4H),1.49(t,J＝16.7Hz,4H),1.43–1.35(m,8H),1.25–1.20(m,2H),0.95–0.82 (m,14H).
13CNMR(151MHz,CDCl 3)δ152.70,142.20,104.22,88.11,86.39,81.04,52.62,45.03,37.19,36.35,35.41,34.39,32.06,26.09,24.61,24.44,20.33,14.63. 13 CNMR (151MHz, CDCl 3 ) δ152.70,142.20,104.22,88.11,86.39,81.04,52.62,45.03,37.19,36.35,35.41,34.39,32.06,26.09,24.61,24.44,20.33,1 4.63.
实施例52：化合物52的制备Example 52: Preparation of Compound 52
Figure PCTCN2022131906-appb-000068
Figure PCTCN2022131906-appb-000068
1、将原料52(2.00g，11.90mmol，1.00eq)溶于110mL的MeOH中，缓慢加入SOCl 2(7.10g，59.49mmol，5.00eq)，加完后升温至回流并搅拌6h，纯化得到1.74g中间体52-1； 1. Dissolve raw material 52 (2.00g, 11.90mmol, 1.00eq) in 110mL of MeOH, slowly add SOCl 2 (7.10g, 59.49mmol, 5.00eq), after adding, raise the temperature to reflux and stir for 6h, purify to obtain 1.74 g intermediate 52-1;
2、将中间体52-1(1.70g，8.67mmol，1.00eq)溶于87mL的MeOH/DCM＝4:1的混合溶剂中，降温至0℃并搅拌10min，缓慢分批加入NaBH 4(2.62g，89.33mmol，8.00eq)，加完后反应继续在0℃下搅拌4h，纯化得到790mg中间体52-2； 2. Dissolve intermediate 52-1 (1.70g, 8.67mmol, 1.00eq) in 87mL of MeOH/DCM=4:1 mixed solvent, cool to 0°C and stir for 10min, slowly add NaBH 4 (2.62 g, 89.33mmol, 8.00eq), after the addition, the reaction was continued to stir at 0°C for 4h, and 790mg of intermediate 52-2 was obtained after purification;
3、将中间体52-2(650mg，4.64mmol，1.00eq)溶于46mL无水二氯甲烷， 并降温至0℃，加入三乙胺(3.2mL，23.19mmol，3.00eq)，搅拌10min后滴加甲基磺酰氯(1.59g，13.91mmol，2.50eq)；加完后移至室温搅拌2h，纯化得到840mg中间体52-3；3. Dissolve intermediate 52-2 (650 mg, 4.64 mmol, 1.00 eq) in 46 mL anhydrous dichloromethane, cool to 0°C, add triethylamine (3.2 mL, 23.19 mmol, 3.00 eq), and stir for 10 min. Methanesulfonyl chloride (1.59g, 13.91mmol, 2.50eq) was added dropwise; after the addition was completed, it was moved to room temperature and stirred for 2h, and 840mg of intermediate 52-3 was obtained after purification;
4、将中间体52-3(840mg，2.83mmol，1.00eq)溶解在95mL的DMF中，加入硫代乙酸钾(835mg，8.50mmol，3.00eq)；反应升温至60℃并搅拌4h，反应自然降温至室温，纯化得到510mg中间体52-4；4. Dissolve intermediate 52-3 (840 mg, 2.83 mmol, 1.00 eq) in 95 mL of DMF, and add potassium thioacetate (835 mg, 8.50 mmol, 3.00 eq); the reaction is heated to 60°C and stirred for 4 hours. The reaction occurs naturally. Cool to room temperature and purify to obtain 510 mg of intermediate 52-4;
5、将中间体52-4(570mg，2.22mmol，1.00eq)溶于25mL乙醇中，降温至0℃，滴加2.78mL的2M氢氧化钠溶液；反应在0℃搅拌反应1h，纯化得到320mg中间体52-5；5. Dissolve intermediate 52-4 (570 mg, 2.22 mmol, 1.00 eq) in 25 mL of ethanol, cool to 0°C, add 2.78 mL of 2M sodium hydroxide solution dropwise; stir the reaction at 0°C for 1 hour, and purify to obtain 320 mg. Intermediate 52-5;
6、将双氢青蒿素(1.09g，3.83mmol，2.20eq)加入到35mL无水乙醚中，充分搅拌混匀，降温至0℃并搅拌10min，将中间体52-5(300mg，1.74mmol，1.00eq)溶于10mL乙醚滴加到反应中，再缓慢滴加三氟化硼乙醚(742mg，5.22mmol，3.00eq)，反应在0℃下搅拌1h后移至室温反应4h，纯化得到500mg化合物52，化合物52为浅黄色油状物，收率41％。6. Add dihydroartemisinin (1.09g, 3.83mmol, 2.20eq) into 35mL of anhydrous ether, stir and mix thoroughly, cool to 0°C and stir for 10min, add intermediate 52-5 (300mg, 1.74mmol , 1.00eq) was dissolved in 10mL ether and added dropwise to the reaction, and then boron trifluoride ether (742mg, 5.22mmol, 3.00eq) was slowly added dropwise. The reaction was stirred at 0°C for 1h and then moved to room temperature for 4h. Purification gave 500mg Compound 52, compound 52 was a light yellow oil, and the yield was 41%.
化合物52的核磁结果如下：The NMR results of compound 52 are as follows:
1HNMR(500MHz,CDCl 3)δ8.56(s,2H),5.55(s,2H),5.35(d,J＝4.3Hz,2H),4.05(d,J＝13.8Hz,2H),3.96(d,J＝13.8Hz,2H),3.01(d,J＝4.3Hz,2H),2.44–2.28(m,2H),2.06(t,J＝20.4Hz,2H),1.76(m,8H),1.56–1.16(m,14H),1.00–0.77(m,14H). 1 HNMR (500MHz, CDCl 3 ) δ8.56 (s, 2H), 5.55 (s, 2H), 5.35 (d, J = 4.3Hz, 2H), 4.05 (d, J = 13.8Hz, 2H), 3.96 ( d,J＝13.8Hz,2H),3.01(d,J＝4.3Hz,2H),2.44–2.28(m,2H),2.06(t,J＝20.4Hz,2H),1.76(m,8H), 1.56–1.16(m,14H),1.00–0.77(m,14H).
13CNMR(126MHz,CDCl 3)δ152.23,143.79,104.27,88.02,86.15,81.06,52.62,45.01,37.19,36.31,35.27,34.38,32.02,26.06,24.61,24.40,20.30,14.60. 13 CNMR (126MHz, CDCl 3 ) δ152.23,143.79,104.27,88.02,86.15,81.06,52.62,45.01,37.19,36.31,35.27,34.38,32.02,26.06,24.61,24.40,20.30,1 4.60.
实施例53：化合物53的制备Example 53: Preparation of Compound 53
Figure PCTCN2022131906-appb-000069
Figure PCTCN2022131906-appb-000069
如实施例40，原料采用原料53(1.00g，5.88mmol，1.00eq)，得到269mg化合物53A和236mg化合物53B，化合物53A和化合物53B均为白色泡沫状。As in Example 40, raw material 53 (1.00g, 5.88mmol, 1.00eq) was used as the raw material, and 269 mg of compound 53A and 236 mg of compound 53B were obtained. Both compound 53A and compound 53B were in the form of white foam.
化合物53的核磁结果如下：The NMR results of compound 53 are as follows:
化合物53A： 1HNMR(500MHz,CDCl 3)δ7.36(s,1H),5.66(s,1H),5.60(s,1H),5.32(d,J＝5.3Hz,1H),5.22(d,J＝5.3Hz,1H),4.05–3.84(m,4H),3.64(s,3H),2.99(td,J＝12.4,6.5Hz,2H),2.39-2.33(m,2H),2.05-1.97(m,4H),1.89(dd,J＝23.9,11.1Hz,4H),1.76-1.68(m,4H),1.57–1.35(m,12H),1.32–1.20(m,2H),0.98–0.81(m,12H). Compound 53A: 1 HNMR (500MHz, CDCl 3 ) δ7.36 (s, 1H), 5.66 (s, 1H), 5.60 (s, 1H), 5.32 (d, J = 5.3Hz, 1H), 5.22 (d, J＝5.3Hz,1H),4.05–3.84(m,4H),3.64(s,3H),2.99(td,J＝12.4,6.5Hz,2H),2.39-2.33(m,2H),2.05-1.97 (m,4H),1.89(dd,J＝23.9,11.1Hz,4H),1.76-1.68(m,4H),1.57–1.35(m,12H),1.32–1.20(m,2H),0.98–0.81 (m,12H).
化合物53B： 1HNMR(500MHz,CDCl 3)δ7.40(s,1H),5.39(s,1H),5.35(s,1H),4.80(d,J＝10.7Hz,1H),4.56(d,J＝10.5Hz,1H),3.14-3.80(m,4H),3.67(s,3H),2.58(s,2H),2.37(t,J＝13.3Hz,2H),2.06–1.90(m,8H),1.73–1.60(m,4H),1.56(d,J＝13.5Hz,2H),1.52–1.39(m,8H),1.28-1.20(m,2H),1.10– 0.79(m,14H). Compound 53B: 1 HNMR (500MHz, CDCl 3 ) δ7.40 (s, 1H), 5.39 (s, 1H), 5.35 (s, 1H), 4.80 (d, J = 10.7Hz, 1H), 4.56 (d, J＝10.5Hz,1H),3.14-3.80(m,4H),3.67(s,3H),2.58(s,2H),2.37(t,J＝13.3Hz,2H),2.06–1.90(m,8H ),1.73–1.60(m,4H),1.56(d,J＝13.5Hz,2H),1.52–1.39(m,8H),1.28-1.20(m,2H),1.10–0.79(m,14H).
实施例54：化合物54的制备Example 54: Preparation of Compound 54
Figure PCTCN2022131906-appb-000070
Figure PCTCN2022131906-appb-000070
将实施例5制得的化合物5A(200mg，0.31mmol，1.00eq)溶解在5mL乙腈中，将NaOCl(25mg，0.34mmol，1.10eq)溶解在1mL水中缓慢滴加至反应中，反应在室温下搅拌20min后用10mL饱和亚硫酸氢钠溶液淬灭，纯化得到93mg化合物54A，化合物54A为白色固体，收率44％；Compound 5A (200 mg, 0.31 mmol, 1.00 eq) prepared in Example 5 was dissolved in 5 mL acetonitrile, and NaOCl (25 mg, 0.34 mmol, 1.10 eq) was dissolved in 1 mL water and slowly added dropwise to the reaction. The reaction was at room temperature. After stirring for 20 minutes, it was quenched with 10 mL of saturated sodium bisulfite solution and purified to obtain 93 mg of compound 54A as a white solid with a yield of 44%;
将实施例5制得的化合物5B(200mg，0.31mmol，1.00eq)溶解在5mL乙腈中；将NaOCl(25mg，0.34mmol，1.10eq)溶解在1mL水中缓慢滴加至反应中，反应在室温下搅拌20min后用10mL饱和亚硫酸氢钠溶液淬灭，纯化得到84mg化合物54B，化合物54B为白色固体，收率40％。Compound 5B (200 mg, 0.31 mmol, 1.00 eq) prepared in Example 5 was dissolved in 5 mL acetonitrile; NaOCl (25 mg, 0.34 mmol, 1.10 eq) was dissolved in 1 mL water and slowly added dropwise to the reaction. The reaction was at room temperature. After stirring for 20 minutes, the mixture was quenched with 10 mL of saturated sodium bisulfite solution and purified to obtain 84 mg of compound 54B as a white solid with a yield of 40%.
化合物54的核磁结果如下：The NMR results of compound 54 are as follows:
化合物54A： 1HNMR(400MHz,CDCl 3)δ5.28(s,2H),4.44(d,J＝10.6Hz,2H),3.11–3.05(m,4H),2.80–2.76(m,2H),2.36-2.30(m,2H),2.01(d,J＝14.4Hz,2H),1.91–1.83(m,2H),1.83–1.75(m,4H),1.75–1.68(m,4H),1.60-1.56(m,2H),1.51–1.32(m,12H),1.26–1.20(m,2H),1.08–0.98(m,2H),0.95-0.92(m,12H). Compound 54A: 1 HNMR (400MHz, CDCl 3 ) δ5.28 (s, 2H), 4.44 (d, J = 10.6Hz, 2H), 3.11–3.05 (m, 4H), 2.80–2.76 (m, 2H), 2.36-2.30(m,2H),2.01(d,J＝14.4Hz,2H),1.91–1.83(m,2H),1.83–1.75(m,4H),1.75–1.68(m,4H),1.60- 1.56(m,2H),1.51–1.32(m,12H),1.26–1.20(m,2H),1.08–0.98(m,2H),0.95-0.92(m,12H).
化合物54B： 1HNMR(400MHz,CDCl 3)δ5.84(s,2H),5.13(d,J＝5.8Hz,2H),3.19–3.11(m,2H),3.09–2.97(m,4H),2.37–2.30(m,2H),2.04–2.00(m,2H),1.94–1.79(m,4H),1.77–1.60(m,8H),1.55–1.47(m,4H),1.45–1.34(m,10H),1.25(m,2H),0.99–0.90(m,12H). Compound 54B: 1 HNMR (400MHz, CDCl 3 ) δ5.84 (s, 2H), 5.13 (d, J = 5.8Hz, 2H), 3.19–3.11 (m, 2H), 3.09–2.97 (m, 4H), 2.37–2.30(m,2H),2.04–2.00(m,2H),1.94–1.79(m,4H),1.77–1.60(m,8H),1.55–1.47(m,4H),1.45–1.34(m ,10H),1.25(m,2H),0.99–0.90(m,12H).
实施例55：化合物55的制备Example 55: Preparation of Compound 55
Figure PCTCN2022131906-appb-000071
Figure PCTCN2022131906-appb-000071
将实施例5制得的化合物5A(200mg，0.31mmol，1.00eq)和NaCO 3(129mg，1.53mmol，5.00eq)加入到20mL乙腈中，降温至-40℃；将TFAA(193mg，0.92mmol，3.00eq)滴加到UHP(87mg，0.92mmol，3.00eq)的20mL乙腈中，室温下搅拌10min后缓慢滴加至反应中，反应在-40℃下搅拌20min，纯化得到145mg化合物55A,收率66％； Compound 5A (200 mg, 0.31 mmol, 1.00 eq) and NaCO 3 (129 mg, 1.53 mmol, 5.00 eq) prepared in Example 5 were added to 20 mL acetonitrile, and the temperature was cooled to -40°C; TFAA (193 mg, 0.92 mmol, 3.00eq) was added dropwise to 20mL acetonitrile of UHP (87mg, 0.92mmol, 3.00eq), stirred at room temperature for 10min and then slowly added dropwise to the reaction, the reaction was stirred at -40°C for 20min, and purified to obtain 145mg of compound 55A, yield 66%;
将实施例5制得的化合物5B(200mg，0.31mmol，1.00eq)和NaCO 3(129mg，1.53mmol，5.00eq)加入到20mL乙腈中，降温至-40℃；将TFAA(193mg，0.92mmol，3.00eq)滴加到UHP(87mg，0.92mmol，3.00eq)的20mL乙腈中，室温下搅拌10min后缓慢滴加至反应中，反应在-40℃下搅拌20min，纯化得到158mg化合物55B,收率72％。 Compound 5B (200 mg, 0.31 mmol, 1.00 eq) and NaCO 3 (129 mg, 1.53 mmol, 5.00 eq) prepared in Example 5 were added to 20 mL acetonitrile, and the temperature was cooled to -40°C; TFAA (193 mg, 0.92 mmol, 3.00eq) was added dropwise to 20mL acetonitrile of UHP (87mg, 0.92mmol, 3.00eq), stirred at room temperature for 10min and then slowly added dropwise to the reaction, the reaction was stirred at -40°C for 20min, and purified to obtain 158mg of compound 55B, yield 72%.
化合物55的核磁结果如下：The NMR results of compound 55 are as follows:
化合物55A： 1HNMR(400MHz,CDCl 3)δ5.37(s,2H),4.38(d,J＝10.8Hz,2H),3.20–3.16(m,2H),3.11–3.07(m,2H),2.87–2.83(m,2H),2.36(td,J＝14.0,3.8Hz,2H),2.02(d,J＝14.2Hz,2H),1.90–1.83(m,2H),1.82–1.75(m,4H),1.74–1.68(m,4H),1.59(dt,J＝13.5,4.0Hz,2H),1.52–1.30(m,12H),1.22(dt,J＝11.3,6.9Hz,2H),1.09–0.98(m,2H),0.96(d,J＝6.3Hz,6H),0.93(d,J＝7.1Hz,6H). Compound 55A: 1 HNMR (400MHz, CDCl 3 ) δ5.37 (s, 2H), 4.38 (d, J = 10.8Hz, 2H), 3.20–3.16 (m, 2H), 3.11–3.07 (m, 2H), 2.87–2.83(m,2H),2.36(td,J＝14.0,3.8Hz,2H),2.02(d,J＝14.2Hz,2H),1.90–1.83(m,2H),1.82–1.75(m, 4H),1.74–1.68(m,4H),1.59(dt,J＝13.5,4.0Hz,2H),1.52–1.30(m,12H),1.22(dt,J＝11.3,6.9Hz,2H),1.09 –0.98(m,2H),0.96(d,J＝6.3Hz,6H),0.93(d,J＝7.1Hz,6H).
化合物55B： 1HNMR(400MHz,CDCl 3)δ5.90(s,2H),5.08(d,J＝6.6Hz,2H),3.23–3.19(m,2H),3.18–3.10(m,4H),2.37(td,J＝14.1,3.6Hz,2H),2.04(dd,J＝14.6,2.9Hz,2H),1.92–1.79(m,4H),1.77–1.63(m,8H),1.55–1.48(m,4H),1.44–1.34(m,10H),1.27–1.24(m,2H),0.99–0.91(m,12H). Compound 55B: 1 HNMR (400MHz, CDCl 3 ) δ5.90 (s, 2H), 5.08 (d, J = 6.6Hz, 2H), 3.23–3.19 (m, 2H), 3.18–3.10 (m, 4H), 2.37(td,J＝14.1,3.6Hz,2H),2.04(dd,J＝14.6,2.9Hz,2H),1.92–1.79(m,4H),1.77–1.63(m,8H),1.55–1.48( m,4H),1.44–1.34(m,10H),1.27–1.24(m,2H),0.99–0.91(m,12H).
实验例Experimental example
化合物1-55的抗癌活性测试Testing of anticancer activity of compounds 1-55
实验原理：Experimental principle:
MTS法检测细胞活性原理：MTS为一种全新的MTT类似物，全称为3-(4，5-dimethylthiazol-2-yl)-5(3-carboxymethoxyphenyl)-2-(4-sulfopheny)-2H-tetrazolium，是一种黄颜色的染料。活细胞线粒体中琥珀酸脱氢酶能够代谢还原MTS，生成可溶性的甲臜(Formazan)化合物，甲臜的含量可以用酶标仪在490nm处进行测定。在通常情况下，甲臜生成量与活细胞数成正比，因此可根据光密度OD值推测出活细胞的数目。Principle of cell activity detection by MTS method: MTS is a new MTT analogue, whose full name is 3-(4,5-dimethylthiazol-2-yl)-5(3-carboxymethoxyphenyl)-2-(4-sulfopheny)-2H- Tetrazolium is a yellow dye. Succinate dehydrogenase in the mitochondria of living cells can metabolize and reduce MTS to generate soluble formazan compounds. The content of formazan can be measured at 490nm with a microplate reader. Under normal circumstances, the amount of formazan produced is directly proportional to the number of viable cells, so the number of viable cells can be estimated based on the optical density OD value.
实验方法：experimental method:
接种细胞：用含10％胎牛血清的培养液(DMEM或者RMPI1640)配成单个细胞悬液，Inoculated cells: Use culture medium (DMEM or RMPI1640) containing 10% fetal calf serum to make a single cell suspension.
以每孔3000～15000个细胞接种到96孔板，每孔体积100ul，贴壁细胞提前12～24小时接种培养。Inoculate 3,000 to 15,000 cells per well into a 96-well plate with a volume of 100ul per well. Adherent cells are inoculated and cultured 12 to 24 hours in advance.
加入待测化合物溶液：化合物用DMSO溶解，化合物以40uM浓度初筛，每孔终体积200ul，每种处理均设3个复孔。Add the solution of the compound to be tested: dissolve the compound in DMSO, and initially screen the compound at a concentration of 40uM. The final volume of each well is 200ul. Each treatment has 3 duplicate wells.
显色：37℃培养48小时后，贴壁细胞弃孔内培养液，每孔加MTS溶液20ul和培Color development: After culturing at 37°C for 48 hours, discard the culture medium in the well for adherent cells, add 20ul of MTS solution to each well and culture.
养液100ul；悬浮细胞弃100ul培养上清液，每孔加20ul的MTS溶液；设3个空白复孔(MTS溶液20ul和培养液100ul的混合液)，继续孵育2～4小时，使反应充分进行后测定光吸收值。100ul of culture medium; discard 100ul of culture supernatant for suspended cells, and add 20ul of MTS solution to each well; set up 3 blank duplicate wells (a mixture of 20ul of MTS solution and 100ul of culture medium), and continue to incubate for 2 to 4 hours to allow the reaction to be sufficient After proceeding, the light absorption value was measured.
比色：选择492nm波长，多功能酶标仪(MULTISKAN FC)读取各孔光吸收值，记录结果，最终取3次结果的平均值。Colorimetry: Select the wavelength of 492nm, read the light absorption value of each well with a multifunctional microplate reader (MULTISKAN FC), record the results, and finally take the average of the three results.
阳性对照化合物：每次实验均设顺铂(DDP)和紫杉醇(Taxol)两个阳性化 合物。Positive control compounds: Each experiment includes two positive compounds: cisplatin (DDP) and paclitaxel (Taxol).
化合物1-55的含硫类青蒿素二聚体对肿瘤细胞抑制率的测定结果如表1所示：The results of measuring the inhibitory rate of tumor cells by the sulfur-containing artemisinin dimer of compound 1-55 are shown in Table 1:
表1：含硫类青蒿素二聚体对肿瘤细胞抑制率的测定结果(n＝3)Table 1: Determination results of the inhibitory rate of tumor cells by sulfur-containing artemisinin dimers (n=3)
Figure PCTCN2022131906-appb-000072
Figure PCTCN2022131906-appb-000072
续表1：Continuation of Table 1:
Figure PCTCN2022131906-appb-000073
Figure PCTCN2022131906-appb-000073
续表2Continued table 2
Figure PCTCN2022131906-appb-000074
Figure PCTCN2022131906-appb-000074
续表3Continued table 3
Figure PCTCN2022131906-appb-000075
Figure PCTCN2022131906-appb-000075
参考文件：reference document:
[1]Woerdenbag,H.J.；Lüers,J.F.J.；van Uden,W.；Pras,N.；Malingré,T.Alfermann,A.W.,Plant Cell,Tissue and Organ Culture,1993,32,247-257.[1] Woerdenbag, H.J.; Lüers, J.F.J.; van Uden, W.; Pras, N.; Malingré, T. Alfermann, A.W., Plant Cell, Tissue and Organ Culture, 1993, 32, 247-257.
以上所述仅为本发明的较佳实施例，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。The above are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included in the protection of the present invention. within the range.

Claims (10)

  1. 一种含硫类青蒿素二聚体，其特征在于，其化学结构式如式Ⅰ表示的化合物或其药学上可接受的盐：A sulfur-containing artemisinin dimer, characterized in that its chemical structural formula is a compound represented by formula I or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022131906-appb-100001
    Figure PCTCN2022131906-appb-100001
    其中，W表示为：S、SO和SO 2中的任意一种； Among them, W represents: any one of S, SO and SO 2 ;
    Z表示为：S、SO、SO 2、O、NR 1和CR 1 2中的任意一种； Z represents: any one of S, SO, SO 2 , O, NR 1 and CR 1 2 ;
    Y表示为：单键、烷基、芳基、环基、醚和氨中的任意一种；Y represents: any one of single bond, alkyl group, aryl group, cyclic group, ether and ammonia;
    R 1表示为：氢、卤素、烷基、芳基、环基、醚和氨中的任意一种； R 1 represents: any one of hydrogen, halogen, alkyl, aryl, cyclic group, ether and ammonia;
    n和m各自独立的选自：0～15的整数。n and m are each independently selected from: an integer from 0 to 15.
  2. 根据权利要求1所述的含硫类青蒿素二聚体，其特征在于，所述含硫类青蒿素二聚体具有以下任一的结构：The sulfur-containing artemisinin dimer according to claim 1, characterized in that the sulfur-containing artemisinin dimer has any of the following structures:
    Figure PCTCN2022131906-appb-100002
    Figure PCTCN2022131906-appb-100002
    Figure PCTCN2022131906-appb-100003
    Figure PCTCN2022131906-appb-100003
    其中，Y表示为：单键、烷基、芳基、环基、醚和氨中的任意一种；Among them, Y represents: any one of single bond, alkyl group, aryl group, cyclic group, ether and ammonia;
    R 1表示为：氢、卤素、烷基、芳基、环基、醚和氨中的任意一种； R 1 represents: any one of hydrogen, halogen, alkyl, aryl, cyclic group, ether and ammonia;
    n、m各自独立的选自：0～15的整数。n and m are each independently selected from: an integer from 0 to 15.
  3. 根据权利要求1或2所述的含硫类青蒿素二聚体，其特征在于，Y表示为：单键、NR 2、O、S、SO、SO 2、SR 2 x、PR 2 x、C1～C5杂烷基、被1～5个R 2取代的C1～C5杂烷基、C1～C10烷基、被1～5个R 2取代的C1～C10烷基、芳基、被1～5个R 2取代的芳基、3～10元环基、被1～5个R 2取代的3～10元环基、3～10元杂环基、被1～5个R 2取代的3～10元杂环基、醚和被1～5个R 2取代的醚中的任意任意一种； The sulfur-containing artemisinin dimer according to claim 1 or 2, characterized in that Y represents: single bond, NR 2 , O, S, SO, SO 2 , SR 2 x , PR 2 x , C1～C5 heteroalkyl, C1～C5 heteroalkyl substituted by 1～5 R 2 , C1～C10 alkyl, C1～C10 alkyl substituted by 1～5 R 2 , aryl group, substituted by 1～ Aryl group substituted with 5 R 2 , 3-10 membered ring group, 3-10 membered ring group substituted with 1-5 R 2 , 3-10 membered heterocyclic group, 3 substituted with 1-5 R 2 Any one of ~10-membered heterocyclyl, ether, and ether substituted by 1 to 5 R 2 ;
    其中，所述R 2表示为：H、F、O、Cl、Br、I、CN、C1～C5烷基、芳基、环基、醚和氨中的任意一种； Wherein, the R 2 represents: any one of H, F, O, Cl, Br, I, CN, C1-C5 alkyl, aryl, cyclic group, ether and ammonia;
    所述x选自1～4的整数；The x is selected from an integer from 1 to 4;
    所述芳基选自苯基、吡啶基、吡嗪基、哒嗪基、噻吩基、噻唑基、萘基、吡咯基、呋喃基、吲哚基、喹啉基、嘌呤基和联芳基中的任意一种；The aryl group is selected from phenyl, pyridyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, naphthyl, pyrrolyl, furyl, indolyl, quinolyl, purinyl and biaryl. any kind of;
    所述3～10元杂环基中的1～6个环原子独立的选自O、S和N中的任意一种。The 1 to 6 ring atoms in the 3 to 10 membered heterocyclic group are independently selected from any one of O, S and N.
    所述环基包括饱和单环基、不饱和单环基、饱和多环基体系和不饱和多环基体系，所述多环基体系包括螺环、并环、桥环和联环；The ring group includes a saturated monocyclic group, an unsaturated monocyclic group, a saturated polycyclic group system and an unsaturated polycyclic group system, and the polycyclic group system includes a spiro ring, a paracyclic ring, a bridged ring and a linked ring;
    所述杂环基包括饱和单杂环基、不饱和单杂环基、饱和多杂环基体系和不饱和多杂环基体系，所述多杂环基体系包括螺环、并环、桥环和联环。The heterocyclyl group includes a saturated monoheterocyclyl group, an unsaturated monoheterocyclyl group, a saturated polyheterocyclyl system and an unsaturated polyheterocyclyl system, and the polyheterocyclyl system includes a spiro ring, a paracyclic ring, and a bridged ring. and linked rings.
  4. 根据权利要求1或2所述的含硫类青蒿素二聚体，其特征在于，R 1表示为：H、F、Cl、Br、I、CN、NR 2、S、SO、SO 2、SR 2 x、PR 2 x、C1～C5杂烷基、被1～5个R 2取代的C1～C5杂烷基、C1～C10烷基、被1～5个R 2取代的C1～C10烷基、芳基、被1～5个R 2取代的芳基、3～10元环基、被1～5个R 2取代的3～10元环基、3～10元杂环基、被1～5个R 2取代的3～10元杂环基、醚和被1～5个R 2取代的醚中的任意任意一种； The sulfur-containing artemisinin dimer according to claim 1 or 2, wherein R 1 represents: H, F, Cl, Br, I, CN, NR 2 , S, SO, SO 2 , SR 2 x , PR 2 x , C1 to C5 heteroalkyl, C1 to C5 heteroalkyl substituted by 1 to 5 R 2 , C1 to C10 alkyl, C1 to C10 alkyl substituted by 1 to 5 R 2 base, aryl group, aryl group substituted by 1 to 5 R 2 , 3 to 10 membered ring group, 3 to 10 membered ring group substituted by 1 to 5 R 2 , 3 to 10 membered heterocyclic group, 1 Any one of 3 to 10-membered heterocyclic groups substituted by ~5 R 2 , ethers, and ethers substituted by 1 to 5 R 2 ;
    其中所述R 2表示为：H、F、O、Cl、Br、I、CN、C1～C5烷基、芳基、环基、醚和氨中的任意一种； Wherein R 2 represents: any one of H, F, O, Cl, Br, I, CN, C1-C5 alkyl, aryl, cyclic group, ether and ammonia;
    所述x选自1～4的整数；The x is selected from an integer from 1 to 4;
    所述芳基选自苯基、吡啶基、吡嗪基、哒嗪基、噻吩基、噻唑基、萘基、吡咯基、呋喃基、吲哚基、喹啉基、嘌呤基和联芳基中的任意一种；The aryl group is selected from phenyl, pyridyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, naphthyl, pyrrolyl, furyl, indolyl, quinolyl, purinyl and biaryl. any kind of;
    所述3～10元杂环基中的1～6个环原子独立的选自O、S和N中的任意一种。The 1 to 6 ring atoms in the 3 to 10 membered heterocyclic group are independently selected from any one of O, S and N.
    所述环基包括饱和环基和不饱和环基，还包括单环和多环体系，多环体系包括螺环、并环、桥环和联环；The cyclic groups include saturated cyclic groups and unsaturated cyclic groups, and also include single and polycyclic ring systems. Polycyclic ring systems include spirocyclic rings, paracyclic rings, bridged rings and jointed rings;
    所述杂环基包括饱和单杂环基、不饱和单杂环基、饱和多杂环基体系和不饱和多杂环基体系，所述多杂环基体系包括螺环、并环、桥环和联环。The heterocyclyl group includes a saturated monoheterocyclyl group, an unsaturated monoheterocyclyl group, a saturated polyheterocyclyl system and an unsaturated polyheterocyclyl system, and the polyheterocyclyl system includes a spiro ring, a paracyclic ring, and a bridged ring. and linked rings.
  5. 根据权利要求3所述的含硫类青蒿素二聚体，其特征在于，所述含硫类青蒿素二聚体具有以下任一的结构：The sulfur-containing artemisinin dimer according to claim 3, characterized in that the sulfur-containing artemisinin dimer has any of the following structures:
    Figure PCTCN2022131906-appb-100004
    Figure PCTCN2022131906-appb-100004
    Figure PCTCN2022131906-appb-100005
    Figure PCTCN2022131906-appb-100005
    Figure PCTCN2022131906-appb-100006
    Figure PCTCN2022131906-appb-100006
    Figure PCTCN2022131906-appb-100007
    Figure PCTCN2022131906-appb-100007
  6. 一种权利要求1-5任一项所述的含硫类青蒿素二聚体的制备方法，其特征在于，反应式如下：A method for preparing the sulfur-containing artemisinin dimer according to any one of claims 1 to 5, characterized in that the reaction formula is as follows:
    Figure PCTCN2022131906-appb-100008
    Figure PCTCN2022131906-appb-100008
    其中，W表示为：S、SO和SO 2中的任意一种； Among them, W represents: any one of S, SO and SO 2 ;
    Z表示为：S、SO、SO 2、O、NR 1和CR 1 2中的任意一种； Z represents: any one of S, SO, SO 2 , O, NR 1 and CR 1 2 ;
    Y表示为：单键、烷基、芳基、环基、醚和氨中的任意一种；Y represents: any one of single bond, alkyl group, aryl group, cyclic group, ether and ammonia;
    R 1表示为：氢、卤素、烷基、芳基、环基、醚和氨中的任意一种； R 1 represents: any one of hydrogen, halogen, alkyl, aryl, cyclic group, ether and ammonia;
    n和m各自独立的选自：0～15的整数；n and m are each independently selected from: integers from 0 to 15;
    酸选自：盐酸、硫酸、硝酸、磷酸、甲酸、乙酸、三氟乙酸、三氟化硼乙醚络合物、四氯化钛、氯化锌、三氯化铝、三氟甲磺酸三甲基硅酯和对甲苯磺酸中的任意一种；The acid is selected from: hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, boron trifluoride etherate complex, titanium tetrachloride, zinc chloride, aluminum trichloride, trimethyltrifluoromethanesulfonate Any one of silyl ester and p-toluenesulfonic acid;
    上述反应式的具体反应如下：The specific reactions of the above reaction formula are as follows:
    如反应式一所示，将式Ⅱ的化合物与双氢青蒿素分散于溶剂中，-78℃～25℃下，滴加酸进行反应，即得到含硫类青蒿素二聚体。As shown in reaction formula 1, the compound of formula II and dihydroartemisinin are dispersed in a solvent, and acid is added dropwise to react at -78°C to 25°C to obtain sulfur-containing artemisinin dimer.
  7. 一种权利要求1-5任一项所述的含硫类青蒿素二聚体的制备方法， 其特征在于，反应式如下：A method for preparing the sulfur-containing artemisinin dimer according to any one of claims 1 to 5, characterized in that the reaction formula is as follows:
    Figure PCTCN2022131906-appb-100009
    Figure PCTCN2022131906-appb-100009
    其中，W表示为：S、SO和SO 2中的任意一种； Among them, W represents: any one of S, SO and SO 2 ;
    Z表示为：S、SO、SO 2、O、NR 1和CR 1 2中的任意一种； Z represents: any one of S, SO, SO 2 , O, NR 1 and CR 1 2 ;
    Y表示为：单键、烷基、芳基、环基、醚和氨中的任意一种；Y represents: any one of single bond, alkyl group, aryl group, cyclic group, ether and ammonia;
    R 1表示为：氢、卤素、烷基、芳基、环基、醚和氨中的任意一种； R 1 represents: any one of hydrogen, halogen, alkyl, aryl, cyclic group, ether and ammonia;
    X表示为：卤素和类卤素中的任意一种；所述卤素选自：F、Cl、Br和I中的任意一种；所述类卤素选自：甲磺酰氧基、三氟甲磺酰氧基、对甲苯磺酰氧基、对硝基苯磺酰氧基和酰氧基中的任意一种；X represents: any one of halogen and halogen-like; the halogen is selected from: any one of F, Cl, Br and I; the halogen-like is selected from: methanesulfonyloxy, trifluoromethanesulfonate Any one of acyloxy group, p-toluenesulfonyloxy group, p-nitrobenzenesulfonyloxy group and acyloxy group;
    n和m各自独立的选自：0～15的整数；n and m are each independently selected from: integers from 0 to 15;
    上述反应式的具体反应如下：The specific reactions of the above reaction formula are as follows:
    如反应式二所示，将双氢青蒿素硫代反应制备成式Ⅲ所示的硫代双氢青蒿素，将硫代双氢青蒿素与式Ⅳ所示的化合物反应，即得到含硫类青蒿素二聚体。As shown in reaction formula 2, dihydroartemisinin is thio-reacted to prepare thiodihydroartemisinin represented by formula III, and thiodihydroartemisinin is reacted with the compound represented by formula IV to obtain Sulfur-containing artemisinin dimers.
  8. 一种权利要求1-5任一项所述的含硫类青蒿素二聚体的制备方法，其特征在于，反应式如下：A method for preparing the sulfur-containing artemisinin dimer according to any one of claims 1 to 5, characterized in that the reaction formula is as follows:
    Figure PCTCN2022131906-appb-100010
    Figure PCTCN2022131906-appb-100010
    其中，W表示为：S、SO和SO 2中的任意一种； Among them, W represents: any one of S, SO and SO 2 ;
    Z表示为：S、SO、SO 2、O、NR 1和CR 1 2中的任意一种； Z represents: any one of S, SO, SO 2 , O, NR 1 and CR 1 2 ;
    Y表示为：单键、烷基、芳基、环基、醚和氨中的任意一种；Y represents: any one of single bond, alkyl group, aryl group, cyclic group, ether and ammonia;
    R 1表示为：氢、卤素、烷基、芳基、环基、醚和氨中的任意一种； R 1 represents: any one of hydrogen, halogen, alkyl, aryl, cyclic group, ether and ammonia;
    TMS表示为：三甲基硅基团；TMS represents: trimethylsilyl group;
    n、m各自独立的选自：0～15的整数；n and m are each independently selected from: integers from 0 to 15;
    酸选自：盐酸、硫酸、硝酸、磷酸、甲酸、乙酸、三氟乙酸、三氟化硼乙醚络合物、四氯化钛、氯化锌、三氯化铝、三氟甲磺酸三甲基硅酯和对甲苯磺酸中的任意一种；The acid is selected from: hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, boron trifluoride etherate complex, titanium tetrachloride, zinc chloride, aluminum trichloride, trimethyltrifluoromethanesulfonate Any one of silyl ester and p-toluenesulfonic acid;
    上述反应式的具体反应如下：The specific reactions of the above reaction formula are as follows:
    如反应式三所示，将式Ⅴ所示的化合物与双氢青蒿素溶解在溶剂中，-78℃～25℃下，滴加酸反应，得到含硫类青蒿素二聚体。As shown in reaction formula 3, the compound represented by formula V and dihydroartemisinin are dissolved in a solvent, and acid is added dropwise to react at -78°C to 25°C to obtain sulfur-containing artemisinin dimers.
  9. 一种权利要求1-5任一项所述的含硫类青蒿素二聚体的制备方法，其特征在于，在溶剂中，将含低氧化态硫的含硫类青蒿素二聚体用氧化剂氧化反应，即得含高氧化态硫的含硫类青蒿素二聚体；A method for preparing sulfur-containing artemisinin-like dimers according to any one of claims 1 to 5, characterized in that, in a solvent, the sulfur-containing artemisinin-like dimers containing low oxidation state sulfur are Oxidation reaction with an oxidizing agent yields sulfur-containing artemisinin dimers containing high oxidation state sulfur;
    所述氧化剂选自：臭氧、过氧化脲、双氧水、次氯酸、次氯酸盐、高氯酸、高氯酸盐、过硫酸氢盐、过硫酸盐、高锰酸盐、重铬酸盐、高碘酸、高碘酸盐和过氧有机酸中的任意一种；The oxidant is selected from: ozone, urea peroxide, hydrogen peroxide, hypochlorous acid, hypochlorite, perchloric acid, perchlorate, perhydrogen persulfate, persulfate, permanganate, and dichromate , any one of periodic acid, periodate and peroxy organic acid;
    所述低氧化态硫表示为：负二价硫；The low oxidation state sulfur is expressed as: negative divalent sulfur;
    所述高氧化态硫表示为：SO或SO 2。 The highly oxidized sulfur is expressed as: SO or SO 2 .
  10. 一种权利要求1-5任一项所述的含硫类青蒿素二聚体在制备抗肿瘤药物中的应用。An application of the sulfur-containing artemisinin dimer according to any one of claims 1 to 5 in the preparation of anti-tumor drugs.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101421276A (en) * 2006-04-11 2009-04-29 赛诺菲-安万特 Dimers of artemisinin derivatives, their preparation and their therapeutic use
WO2013130725A1 (en) * 2012-02-28 2013-09-06 The Johns Hopkins University Trioxane thioacetal monomers and dimers and methods of use thereof
CN107383048A (en) * 2017-08-11 2017-11-24 昆药集团股份有限公司 A kind of artemisinin derivatives, its synthesis and application

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102153564B (en) * 2011-01-31 2013-07-24 中国科学院上海药物研究所 Nitrogen-atom-containing arteannuin dimers, and preparation method and application thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101421276A (en) * 2006-04-11 2009-04-29 赛诺菲-安万特 Dimers of artemisinin derivatives, their preparation and their therapeutic use
WO2013130725A1 (en) * 2012-02-28 2013-09-06 The Johns Hopkins University Trioxane thioacetal monomers and dimers and methods of use thereof
CN107383048A (en) * 2017-08-11 2017-11-24 昆药集团股份有限公司 A kind of artemisinin derivatives, its synthesis and application

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
DATABASE Registry 8 June 2008 (2008-06-08), ANONYMOUS: "3,12-Epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepin, 10-[[[4-[[[(3R,5aS,6R,8aS,9R,10S,12S,12aR)-decahydro-3,6,9-trimethyl-3,12- epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepin-10- yl]thio]methyl]phenyl]methyl]thio]decahydro-3,6,9-trimethyl-, (3R,5aS,6R,8aS,9R,10S,12S,12aR)- (CA INDEX NAME)", XP093117502, retrieved from STNext Database accession no. 1026475-31-9 *
GAUR RASHMI, CHEEMA HARVEER SINGH, KUMAR YOGESH, SINGH SURIYA PRATAP, YADAV DHARMENDRA K., DAROKAR MAHENDRA PADURANG, KHAN FEROZ, : "In vitro antimalarial activity and molecular modeling studies of novel artemisinin derivatives", RSC ADVANCES, ROYAL SOCIETY OF CHEMISTRY, GB, vol. 5, no. 59, 1 January 2015 (2015-01-01), GB , pages 47959 - 47974, XP093117497, ISSN: 2046-2069, DOI: 10.1039/C5RA07697H *
JACOBINE ALEXANDER M., MAZZONE JENNIFER R., SLACK RACHEL D., TRIPATHI ABHAI K., SULLIVAN DAVID J., POSNER GARY H.: "Malaria-Infected Mice Live Until at Least Day 30 after a New Artemisinin-Derived Thioacetal Thiocarbonate Combined with Mefloquine Are Administered Together in a Single, Low, Oral Dose", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 55, no. 17, 13 September 2012 (2012-09-13), US , pages 7892 - 7899, XP093117500, ISSN: 0022-2623, DOI: 10.1021/jm3009986 *
OH SANGTAE, JEONG IN HOWA, LEE SEOKJOON: "Efficient Synthesis of e xo -Olefinated Deoxoartemisinin Derivatives by Ramberg−Bäcklund Rearrangement", THE JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, vol. 69, no. 3, 1 February 2004 (2004-02-01), pages 984 - 986, XP093117499, ISSN: 0022-3263, DOI: 10.1021/jo035505x *
SHEN SHENGQIANG, CHEN WEI, DONG LILI, YANG QING, LU HUIZHE, ZHANG JIANJUN: "Design and synthesis of naphthalimide group-bearing thioglycosides as novel β- N -acetylhexosaminidases inhibitors", JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, INFORMA HEALTHCARE, GB, vol. 33, no. 1, 1 January 2018 (2018-01-01), GB , pages 445 - 452, XP093117498, ISSN: 1475-6366, DOI: 10.1080/14756366.2017.1419217 *
VENUGOPALAN, B. ET AL.: "Antimalarial Activity of New Ethers and Thioethers of Dihydroartemisinin", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 30, no. 9, 31 December 1995 (1995-12-31), XP004040197, DOI: 10.1016/0223-5234(96)88287-0 *

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