CN111825699B - Sulfur-containing heterocyclic compounds and process for producing the same - Google Patents
Sulfur-containing heterocyclic compounds and process for producing the same Download PDFInfo
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Abstract
The invention relates to a sulfur-containing heterocyclic compound and a preparation method thereof. Specifically, the invention discloses a preparation method of a compound A, which comprises the following steps: in an organic solvent, under the action of formic acid, carrying out cyclization reaction on a compound shown as a formula A16; the compound A is a compound shown as a formula A17, a compound shown as a formula A17', or a mixture of the compounds shown as the formula A17 and the formula A17'; wherein R is 2 And R 3 Independently is C 1 ‑C 4 Alkyl group of (1). The preparation method avoids the step of regulating and controlling the newly formed chiral center of the thia ring by introducing the n-hexane side chain on the azacyclo, and the yield of the intermediate step is higher, and the protecting group is not easy to remove.
Description
Technical Field
The invention relates to a sulfur-containing heterocyclic compound and a preparation method thereof.
Background
Influenza, a potentially significant public health problem, can cause about 300-500 million serious cases each year, resulting in about 25-50 million deaths. The effects of influenza are more severe for children under 2 years old, elderly people over 65 years old, pregnant women, and other people with low immunity.
24.24.2018, the innovative anti-influenza drug xoffluza (baloxavir marboxil, formerly known as S-033188) from the salt famese pharmaceutical (Shionogi) was subject to accelerated approval and was marketed in japan. 24/10/2018, xofluza was approved by the FDA for marketing. The structures of Xofluza and its enantiomers are shown in the following figure:
the approval of Xofluza is expected to bring about major changes in the treatment of influenza patients. Xofluza is an innovative Cap-dependent endonuclease inhibitor and is a small number of new drugs which can inhibit the proliferation of influenza viruses in the world. The compound can inhibit the CAP structure at the 5' end of host mRNA obtained from host cells aiming at the key link of the replication of the influenza virus, thereby inhibiting the transcription of the self mRNA of the influenza virus. Since there is no protease with a similar mechanism in the host cell, this drug theoretically has no effect on the host cell.
In 2017, in 10 months, the phase 3 clinical result of the new medicine is published. Patients receiving Xofluza treatment resolved the fever trouble one day later (24.5 hours) compared to the control group patients. This data for the control group was 42 hours. In addition, the patients receiving the drug returned to pre-influenza health after 129.2 hours, which is 168.8 hours in the control group, with a difference of nearly 40 hours. Some experts point out that 1 tablet of the new drug can reach up to 10 tablets of the current standard therapy and can continue to take effect for 10 days. This allows individuals in any region of the world to use a simple, quick Fang Rushi to combat the severe epidemic of influenza.
The literature on the synthesis of xofflaza is relatively few at present, and the synthetic route reported in patent WO2017221869 is as follows:
scheme 1:
the method comprises the steps of synthesizing a target product through ten steps, firstly preparing fragments A8 and A15, connecting the two fragments, closing a ring to prepare a racemate C2, obtaining a target product C4 through prosthetic group resolution, then obtaining a compound C5 through prosthetic group removal, replacing a side chain of the compound C5, connecting the compound C5 with C12, regulating a newly formed thia ring chiral center through a nitrogen heterocyclic chiral center to obtain a compound C13, and removing the upper new side chain to obtain the target compound.
Patent WO2016175224 discloses another route for preparing xofflza, as shown in synthesis route 2, compared with synthesis route 1, the route is different only when a C2 fragment is constructed, the subsequent steps are basically the same, the C2 fragment is resolved by using a chiral prosthetic group, the prosthetic group is removed to obtain a compound C5, the compound C5 is bonded with a sulfur-containing fragment, and a new side chain is deprotected to obtain a target compound.
Scheme 2:
the compound C4 is obtained from the compound C2, the two synthetic routes adopt the step of chiral prosthetic group resolution, but the prosthetic group is expensive, and the literature does not disclose the optical purity of the compound C4 or C5. The inventors have found, when repeating the preparation process of patent WO2017221869, that the yield of one step of chiral prosthetic group resolution reported herein is 48%, but the actual yield of repetition is 28.8%, which is only about 60% reported in the literature, and the reproducibility of the yield is poor. During the synthesis of compound C5 from compound C4, part of the benzyl groups will be removed, resulting in a low yield in this step. And the nitrogen heterocycle is connected with the n-hexyl side chain to regulate the newly formed chiral center of the sulfur heterocycle, so that the dr value of the product C13 is only 1.5, which is far lower than that of 15.5 reported in the literature. Thus, the yield of the intermediate steps of the route is low. In addition, this route has a problem that the nitrogen heterocycle is easily debenzylated when the side chain protecting group is replaced.
Disclosure of Invention
The invention aims to solve the technical problems of single synthetic route, lower yield of intermediate steps, poor yield reproducibility, easy removal of protecting groups and the like of the existing Xofluza, and provides a sulfur-containing heterocyclic compound and a preparation method thereof. The preparation method avoids the step of regulating the newly formed chiral center of the thia ring by introducing the n-hexane side chain on the azacyclo, and has higher yield of the intermediate step and difficult removal of the protecting group.
The present invention solves the above-mentioned problems by the following technical solutions.
The invention provides a preparation method of a compound A, which comprises the following steps: in an organic solvent, under the action of formic acid, carrying out cyclization reaction on a compound shown as a formula A16; the compound A is a compound shown as a formula A17, a compound shown as a formula A17', or a mixture of the compounds shown as the formula A17 and the formula A17';
wherein R is 2 And R 3 Independently is C 1 -C 4 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, also e.g., methyl).
In the cyclization reaction of the present invention, the organic solvent may be an organic solvent conventional in the reaction of this type in the art, preferably a nitrile solvent (e.g., acetonitrile), an ether solvent (e.g., tetrahydrofuran (THF)) and an acid solvent (preferably C) 2 -C 4 Of straight-chain saturated monobasic fatty acids, such as acetic acid), more preferably nitrile solvents.
In the ring formation reaction of the present invention, the molar volume ratio of the compound represented by the formula A16 to the formic acid is preferably 0.2 to 2mol/L, more preferably 0.3 to 1.7mol/L (e.g., 0.52mol/L or 1.61 mol/L), and still more preferably 0.4 to 0.6mol/L (e.g., 0.52 mol/L).
In the cyclization reaction of the present invention, the volume ratio of the formic acid to the organic solvent is preferably 1:2-1, 15, more preferably 1:3-1 (e.g., 1.2;
in the ring formation reaction of the present invention, the molar concentration of the compound represented by the formula A16 in the organic solvent is preferably 0.1 to 0.5mol/L (e.g., 0.16mol/L or 0.3 mol/L), and more preferably 0.1 to 0.2mol/L (e.g., 0.16 mol/L).
In the cyclization reaction of the present invention, the reaction temperature is preferably 50 to 70 ℃ (for example, 60 ℃).
In the cyclization reaction of the present invention, the progress of the reaction can be monitored by a method conventional in the art (e.g., TLC, LCMS), and the reaction time is preferably 31 hours to 5 days, more preferably 31 to 42 hours.
In a preferred embodiment of the present invention, the cyclization reaction comprises the following steps: adding the compound shown as the formula A16 into a mixed solvent of formic acid and an organic solvent, and carrying out the cyclization reaction at the temperature of 50-70 ℃.
After the ring-forming reaction is finished, the method can further comprise the operation of post-treatment. The methods and conditions of the work-up may be those conventional in the art for such reactions, and the following are preferred in the present invention: quenching the reaction liquid of the cyclization reaction in a solvent, extracting to obtain an organic layer, concentrating, separating and purifying. The solvent for quenching may be a solvent conventional in the art for such reactions, preferably sodium bicarbonate solution. The extraction operations and conditions may be those commonly used in the art, and the organic solvent used in the extraction may be one commonly used in the art, preferably an ester solvent, such as ethyl acetate. The concentrating operations and conditions may be those conventional in the art for concentrating, and vacuum concentration is preferred. The separation and purification operations and conditions may be those conventional in the art, and column chromatography is preferred. The developing solvent for separation and purification can be a developing solvent conventional in the art, and preferably alcohol solvents and halogenated hydrocarbon solvents, such as methanol and dichloromethane.
In the preparation method of the compound a, the preparation method of the compound shown as the formula a16 may be the first method or the second method:
the first method comprises the following steps: in an organic solvent, carrying out amidation reaction on a compound shown as a formula A12 and a compound shown as a formula A15 under the action of a condensing agent;
the second method comprises the following steps: reacting a compound shown as a formula A12 with dimethyl sulfoxide in an organic solvent to prepare corresponding acyl chloride, and performing amidation reaction on the acyl chloride and a compound shown as a formula A15 in the presence of alkali to obtain the compound;
wherein R is 2 And R 3 All as described above.
In the first method, the organic solvent is preferably an ether solvent and/or an amide solvent, and more preferably an amide solvent. The ethereal solvent may be one conventional in the art, and Tetrahydrofuran (THF) is preferred. The amide-based solvent may be an amide-based solvent conventional in the art, and preferably N, N-Dimethylformamide (DMF).
In the first method, the condensing agent may be a condensing agent conventional in this type of reaction in the art, preferably a carbodiimide-type condensing agent and/or a urea cationic condensing agent, more preferably a carbodiimide-type condensing agent and a urea cationic condensing agent (e.g., EDCI and HOBt). The carbodiimide-type condensing agent may be a carbodiimide-type condensing agent that is conventional in the art, for example, one or more of Dicyclohexylcarbodiimide (DCC), N' -Diisopropylcarbodiimide (DIC), and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), with EDCI being preferred. The carbamide cationic condensing agent can be a carbamide cationic condensing agent conventional in the art, such as one or more of 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), O-benzotriazole-tetramethyluronium Hexafluorophosphate (HBTU), 1-hydroxy-7-azobenzotriazole (HOAT) and 1-hydroxybenzotriazole (HOBt), preferably HOBt.
In the first method, when the condensing agent is preferably a carbodiimide-type condensing agent and a urea cationic condensing agent, the molar ratio of the carbodiimide-type condensing agent to the urea cationic condensing agent may be a molar ratio as is conventional in the art, such as 1.1 to 1.5, preferably 1.
In the first method, the molar ratio of the condensing agent to the compound represented by formula a12 may be a molar ratio as is conventional in the art, such as 1.0.
In the first method, the molar concentration of the compound represented by the formula A12 in the organic solvent is preferably 0.1-0.3mol/L (e.g., 0.2 mol/L).
In the first method, the molar ratio of the compound shown in A15 to the compound shown in the formula A12 is preferably 1:1-3:1 (for example, 1.2.
In process one, the amidation reaction may also be carried out with the aid of a base, which may be a base conventional to the art such as one or more of Triethylamine (TEA), N-Diisopropylethylamine (DIPEA) and 4-Dimethylaminopyridine (DMAP), preferably DIPEA. The molar ratio of the base to the compound of formula a12 may be a molar ratio conventional in the art for such reactions, for example 1:1-4:1, preferably 1.2.
In the first method, the reaction temperature is preferably 20 to 30 ℃.
In method one, the progress of the reaction can be monitored by methods conventional in the art (e.g., TLC, LCMS), and the reaction time is preferably 4-40 hours.
In the second method, the conditions and methods of the amidation reaction are those conventional in the art.
After the amidation reaction described in the first and second methods, the method may further comprise a post-treatment operation. The methods and conditions of the work-up may be those conventional in the art for such reactions, and the following are preferred in the present invention: adding water into the reaction solution for quenching, extracting to obtain an organic layer, washing the organic layer, concentrating, separating and purifying to obtain the product. The extraction operations and conditions may be those conventional in the art, and the organic solvent used in the extraction may be those commonly used in the art, preferably an ester solvent, such as ethyl acetate. The washing operation and conditions may be those conventional in the art, and the solvent used in the washing may be a solvent commonly used in the art, preferably water. The concentrating operation and conditions may be those conventional in the art for concentrating, and vacuum concentration is preferred. The separation and purification operations and conditions may be those conventional in the art, and column chromatography is preferred. The developing solvent for separation and purification can be a developing solvent conventional in the art, and preferably alcohol solvents and halogenated hydrocarbon solvents, such as methanol and dichloromethane.
In the preparation method of the compound a, the preparation method of the compound shown as the formula a12 may further include the following steps: in a solvent, under the action of alkali, carrying out hydrolysis reaction on a compound shown as a formula A4 as shown in the specification;
wherein R is 1 Is C 1 -C 4 Alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, also e.g., methyl).
In the hydrolysis reaction, the alkali is preferably an alkali metal hydroxide. The metal hydroxide may be an alkali metal hydroxide conventional in the art, such as one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide, preferably sodium hydroxide.
In the hydrolysis reaction, the solvent is preferably water and an organic solvent, and the organic solvent is ethanol and/or tetrahydrofuran.
In the hydrolysis reaction, the molar concentration of the compound shown in the formula A4 in the solvent is preferably 0.1-0.3mol/L (e.g. 0.16 mol/L).
In the hydrolysis reaction, the molar ratio of the alkali to the compound shown in the formula A4 is preferably 1:1-3:1 (for example 2:1).
In the hydrolysis reaction, the temperature of the hydrolysis reaction is preferably 20-30 ℃.
In the hydrolysis reaction, the progress of the reaction can be monitored by methods conventional in the art (e.g., TLC, LCMS), and the reaction time is preferably 16 to 19 hours.
After the hydrolysis reaction is finished, the method can further comprise the operation of post-treatment. The methods and conditions of the work-up may be those conventional in the art for such reactions, and the following are preferred in the present invention: adjusting pH of the reaction solution to 2-4 (such as 3) with acid, filtering to obtain filter cake, washing the filter cake with alcohol solvent (such as ethanol), and oven drying. The acid may be an acid commonly used in the art for adjusting pH, preferably hydrochloric acid (e.g., 1N hydrochloric acid).
In the preparation method of the compound a, the preparation method of the compound shown in the formula A4 may further include the following steps: in an organic solvent, under the action of acid, carrying out substitution reaction on a compound shown as a formula A8 and a compound shown as a formula A3 as shown in the specification;
wherein R is 1 As previously described.
The conditions and methods of the substitution reaction described may be those conventional in the art for such reactions.
The invention also provides a compound shown as the formula I, which has the following structure:
wherein R is 4 is-OR 5 Or
R 5 、R 6 And R 7 Independently is H or C 1 -C 4 Alkyl (for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and also for example methyl).
In the present invention, C 1 -C 3 The alkylene group may be
And can be
In the present invention, C 1 -C 3 The alkylene group can be
And can be
In a preferred embodiment of the present invention, the compound of formula I can be of any of the following structures:
unless otherwise specified, the room temperature in the present invention means 20 to 30 ℃.
In the present invention, "° c" is given in degrees celsius unless otherwise specified.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available unless otherwise specified.
The positive progress effects of the invention are as follows: the preparation method avoids the step of regulating the newly formed chiral center of the thia ring by introducing the n-hexane side chain on the azacyclo, and has higher yield of the intermediate step and difficult removal of the protecting group.
Drawings
FIG. 1 is an HPLC chart of a mixture of compounds A17 and A17'.
The specific implementation formula is as follows
The invention is further illustrated by the following example Fang Rushi, but is not intended to be limited thereby in the scope of the examples described. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
EXAMPLE 1 preparation of Compound A7
Compound A6 (50.00g, 203mmol) was dissolved in 200mL of N, N-dimethylformamide, and sodium bicarbonate (22.17g, 264mmol) and dimethyl sulfate (30.78g, 244mmol) were added sequentially and reacted at room temperature for 14.5 hours, and LCMS monitored the completion of the reaction. 100mL of water was added to the reaction mixture to dilute the mixture, and the mixture was neutralized by slowly adding 6.17g of concentrated hydrochloric acid dropwise thereto, and after completion of the addition, the mixture was extracted with ethyl acetate (150 mL. Times.2). The organic phases were combined, washed successively with water (50 mL), brine (50 mL. Times.2) and the organic phase was concentrated to give the crude product. The crude product obtained was slurried with 150mL of n-heptane, filtered and dried to give Compound A7 (49.53g, 94%) as a yellow solid. LCMS (liquid Crystal display Module) [ M + H ]] + ：261.8。 1 H NMR(400MHz,Chloroform-d)δ7.73(d,J＝5.6Hz,1H),7.45(d,J＝1.9Hz,1H),7.43(d,J＝1.6Hz,1H),7.38–7.28(m,3H),6.46(d,J＝5.6Hz,1H),5.29(s,2H),3.85(s,3H).
Example 2: preparation of Compound A8
In a 250mL jacketed reaction flask, compound A7 (20.00g, 76.8mmol) and pyridinium p-toluenesulfonate (50.01g, 200mmol) were dissolved in 80g of N, N-dimethylacetamide, heated to 60 ℃ and after the temperature stabilized, a solution of t-butyl carbazate in N, N-dimethylacetamide (12.18 g of t-butyl carbazate in 40g of N, N-dimethylacetamide) was added dropwise over 6 hours, and after the reaction was continued for 14.5 hours, the reaction was controlled to completion by LCMS. The system was quenched by addition of 150mL of water, extracted with ethyl acetate (200 mL. Times.2), the combined organic phases were washed with 100mL of water and concentrated in vacuo to give the crude product. The crude product obtained was dissolved by adding 80mL of methanol, and 200mL of water was slowly added to the system to precipitate a large amount of solid, which was filtered and vacuum-dried to obtain Compound A8 (23.62g, 82%) as a pale yellow solid. LCMS (liquid Crystal display Module) [ M + H ]] + ：375.0。 1 H NMR(400MHz,Chloroform-d)δ9.06(s,1H),7.38(d,J＝1.9Hz,1H),7.36(d,J＝1.3Hz,1H),7.34–7.29(m,3H),7.29–7.24(m,2H),6.36(d,J＝7.8Hz,1H),5.19(s,2H),3.74(s,3H),1.43(s,9H).
Example 3: preparation of Compound A3
The preparation method and nuclear magnetic data of the compound A3 refer to TW201802097.
Example 4: preparation of Compound A4
Compound A8 (0.40g, 1.07mmol) and compound A3 (0.60g, 2.27mmol) were dissolved in 4mL glacial acetic acid, p-toluenesulfonic acid monohydrate (0.24g, 1.28mmol) was added and the reaction was complete after 18h on LCMS. The reaction solution was poured into 30mL of a saturated sodium bicarbonate solution, extracted with dichloromethane (30 mL. Times.2), and the organic phases were combined and concentrated in vacuo. The crude product obtained was separated by column chromatography (5% methanol/dichloromethane) to give compound A4 (0.55g, 98%) as a brown solid. LCMS (liquid Crystal display Module) [ M + H ]] + ：521.2。 1 H NMR(400MHz,DMSO-d 6 )δ8.20(d,J＝7.8Hz,1H),7.65(s,1H),7.39–7.28(m,4H),7.28–7.15(m,4H),7.14–6.97(m,3H),6.38(d,J＝7.7Hz,1H),5.58(s,1H),5.20(d,J＝14.4Hz,1H),4.97(d,J＝11.0Hz,1H),4.86(d,J＝11.1Hz,1H),3.97(d,J＝14.4Hz,1H),3.67(s,3H).
Example 5: preparation of Compound A12
Compound A4 (3.00g, 5.77mmol) was dissolved in 30mL ethanol, 5.8mL of 2N sodium hydroxide solution was added and the reaction was allowed to proceed for 16 h at room temperature and completed by LCMS. Adjusting pH to 3 with 1N hydrochloric acid, filtering the suspension, washing the filter cake with 10mL ethanol, oven drying to obtain compound A12 (2.55g, 87%),as a grey solid. LCMS [ M + H ]] + :507.8。 1 H NMR(400MHz,DMSO-d 6 )δ8.04(d,J＝7.8Hz,1H),7.55(s,1H),7.45–7.24(m,7H),7.24–7.16(m,1H),7.15–7.01(m,3H),6.27(d,J＝7.7Hz,1H),5.60(s,1H),5.40(d,J＝14.5Hz,1H),4.95(d,J＝10.9Hz,1H),4.91(d,J＝10.9Hz,1H),3.90(d,J＝14.5Hz,1H).
Example 6: preparation of Compound A12
The conditions and operation were the same as in example 5 except that the solvent used, the reaction time and the solvent used were different from those of example 5, wherein the solvent was tetrahydrofuran and the reaction time was 19 hours. The yield of compound a12 was 83%.
Example 7: preparation of Compound A12
The conditions and operation were the same as in example 5 except that the reaction time was different from example 5, wherein the reaction time was 18 hours. The yield of compound a12 was 100%.
Example 8: preparation of Compound A14
Dissolving a compound A13 (100.00g, 523mmol) in 500mLN, N-dimethylformamide, adding sodium tert-butoxide (74.90g, 779mmol) in batches under an ice bath condition, raising the temperature to 40 ℃ after the addition is finished, dropwise adding 2-bromo-1,1-dimethoxyethane (150.80g, 892mmol) into the reaction system, and controlling the reaction to be complete after 2 hours by LCMS. The system was cooled to 0 ℃, neutralized with 10g of glacial acetic acid, diluted with 300mL of saturated brine, extracted with ethyl acetate (1000 mL × 2), the combined organic phases were washed with 500mL of distilled water and concentrated in vacuo to give the crude product. The crude product was dissolved in 120mL of methanol, 300mL of water was slowly added dropwise until a large amount of solid precipitated, filtered, and dried to give Compound A14 (96.90g, 66%) as a yellow solid. LCMS [ M-OCH 3 ] + :247.7。 1 H NMR(400MHz,Chloroform-d)δ7.83(dd,J＝5.4,3.1Hz,2H),7.70(dd,J＝5.4,3.1Hz,2H),4.42(t,J＝5.2Hz,1H),3.88(t,J＝5.7Hz,2H),3.74(t,J＝5.8Hz,2H),3.51(d,J＝5.2Hz,2H),3.32(s,6H).
Example 9: preparation of Compound A15
Compound A14 (228.4g, 818mmol) was dissolved in a mixed solvent of 230mL of ethanol and 230mL of water, the temperature was raised to 60 ℃,85% hydrazine hydrate (103g, 1749mmol) was added dropwise, and completion of the reaction was monitored by TLC after 1 hour. The reaction was directly concentrated in vacuo, the resulting residue was adjusted to pH 10 with 17% potassium hydroxide solution, extracted with dichloromethane (120 mL. Times.4), and the combined organic phases were concentrated in vacuo to give Compound A15 (103.4 g, 85%) as a brown liquid. LCMS (liquid Crystal display Module) [ M + H ]] + :149.8。 1 H NMR(400MHz,Chloroform-d)δ4.38(t,J＝5.2Hz,1H),3.38(t,J＝5.2Hz,2H),3.37(d,J＝5.2Hz,2H),3.26(s,6H),2.73(t,J＝5.2Hz,2H),1.70(s,2H).
Example 10: preparation of Compound A16
Compound A12 (2.50g, 4.94mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.14g, 5.93mmol) and 1-hydroxybenzotriazole (0.80g, 5.93mmol) were dissolved in 25mL of N, N-dimethylformamide, and Compound A15 (0.88g, 5.93mmol) was added and reacted at room temperature for 4.5 hours with LCMS to control the reaction to completion. The system was quenched by addition of 50mL water, extracted with ethyl acetate (50 mL. Times.2), the organic phases combined and washed once with 50mL water and concentrated in vacuo to give the crude. The crude product obtained was separated by column chromatography (5% methanol/dichloromethane) to give compound a16 (2.77g, 88%) as a brown solid. LCMS (liquid Crystal display Module) [ M + H ]] + :638.5。 1 H NMR(400MHz,Chloroform-d)δ7.66(t,J＝5.6Hz,1H),7.51(d,J＝2.8Hz,1H),7.40–7.32(m,5H),7.18–7.07(m,2H),7.03(d,J＝7.8Hz,1H),6.97–6.86(m,2H),6.84–6.72(m,2H),6.01(d,J＝7.7Hz,1H),5.58(dd,J＝14.3,2.4Hz,1H),5.37(d,J＝11.1Hz,1H),5.27(d,J＝11.1Hz,1H),4.84–4.76(m,1H),4.42(t,J＝5.1Hz,1H),3.94(d,J＝14.2Hz,1H),3.66–3.47(m,4H),3.46(d,J＝5.1Hz,2H),3.33(s,3H),3.33(s,3H).
Example 11: preparation of Compound A16
The conditions and operation were the same as in example 10 except that the reaction time was different from example 10, wherein the reaction time was 6 hours. The yield of compound a16 was 30%.
Example 12: preparation of Compound A16
The same conditions and operation as in example 10 were carried out except that the solvent used, the reaction time and the solvent used were different from those of example 10, wherein the solvent was tetrahydrofuran and the reaction time was 16 hours. The yield of compound a16 was 30%.
Example 13: preparation of Compound A16
Compound A12 (2.50g, 4.94mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.14g, 5.93mmol) and 1-hydroxybenzotriazole (0.80g, 5.93mmol) were dissolved in 25mL of N, N-dimethylformamide under nitrogen protection, and N, N-diisopropylethylamine (0.76g, 5.93mmol) and compound A15 (0.88g, 5.93mmol) were added and reacted at room temperature for 40 hours with LCMS to complete the reaction. The system was quenched by addition of 50mL of water, extracted with ethyl acetate (50 mL. Times.2), the combined organic phases washed once with 50mL of water and concentrated in vacuo to give the crude product. The crude product obtained was separated by column chromatography (5% methanol/dichloromethane) to give compound A16 (1.54g, 49%).
Example 14: preparation of Compound A16
Under the protection of nitrogen, compound A12 (2.50g, 4.94mmol) is dissolved in 25mL DCM, thionyl chloride (0.59g, 1.1mmol) is added dropwise, heating and refluxing are carried out for 5 hours until the raw materials completely react, the mixture is cooled to room temperature, compound A15 (0.88g, 5.93mmol) and triethylamine (1.98g, 9.88mmol) are added for reaction at room temperature for 4 hours, and the reaction is controlled to be complete in LCMS. The system was quenched by addition of 50mL of water, extracted with ethyl acetate (50 mL. Times.2), the combined organic phases washed once with 50mL of water and concentrated in vacuo to give the crude product. The crude product obtained was separated by column chromatography (5% methanol/dichloromethane) to give compound A16 (1.77g, 54%).
Example 15: preparation of a mixture of Compounds A17 and A17
Compound A16 (1.23g, 1.93mmol) was dissolved in a mixed solvent of 12.3mL acetonitrile and 3.7mL formic acid, heated to 60 deg.C for 40 hours, and LCMS controlled to completion. The reaction solution was quenched by pouring into 30mL of saturated sodium bicarbonate solution, extracted with ethyl acetate (30 mL. Times.2), and the organic phases were combined and concentrated in vacuo. The resulting crude mixture of compounds A17 and A17 'was separated by column chromatography (5% methanol/dichloromethane) to give a mixture of compounds A17 and A17' (0.58g, 52%) as a brown solid. LCMS (liquid Crystal display Module) [ M + H ]] + :573.9。 1 H NMR(400MHz,Chloroform-d)δ7.62–7.58(m,2H),7.38–7.29(m,3H),7.12–7.03(m,3H),7.02–6.94(m,2H),6.68(ddd,J＝8.4,6.3,2.3Hz,1H),6.39(d,J＝7.7Hz,1H),5.79(d,J＝7.7Hz,1H),5.62(d,J＝140.8Hz,1H),5.45(d,J＝10.9Hz,1H),5.26–5.17(m,2H),4.66(dd,J＝13.6,2.5Hz,1H),4.45(dd,J＝13.6,2.5Hz,1H),4.03(d,J＝13.8Hz,1H),3.87(dd,J＝10.9,3.0Hz,1H),3.72(dd,J＝11.7,3.2Hz,1H),3.39–3.26(m,2H),2.88(ddd,J＝13.7,12.0,3.5Hz,1H).
The configuration of compounds a17 and a17' of this example was determined by comparison with nuclear magnetic data of the related compounds in TW201802097 a.
This example analyzes the reaction mixture by High Performance Liquid Chromatography (HPLC) under the following chromatographic conditions:
and (3) chromatographic column: daicel Chiralpak AD-H (4.6 mm. Times.250mm, 5 μm), HPLC-250-034; mobile phase A: n-hexane; mobile phase B: ethanol; mobile phase A: mobile phase B = 60; operating time: 20min; column temperature: 30 ℃; detection wavelength: 254nm; flow rate: 1.0mL/min.
FIG. 1 is an HPLC chart of a mixture of compounds A17 and A17'. Wherein peak 1 is compound A17 with a retention time of 10.125min, peak 2 is compound A17' with a retention time of 15.380min. The ratio of compounds A17 to A17' was determined by the peak areas of peak 1 and peak 2, which were 1:1.
Example 16: preparation of a mixture of Compounds A17 and A17
Compound A16 (1.23g, 1.93mmol) was dissolved in a mixed solvent of 12.3mL acetonitrile and 1.2mL formic acid, heated to 60 deg.C for 40 hours, and LCMS controlled to completion. The reaction solution was quenched by pouring into 30mL of saturated sodium bicarbonate solution, extracted with ethyl acetate (30 mL. Times.2), and the organic phases were combined and concentrated in vacuo. The resulting crude mixture of compounds A17 and A17 'was separated by column chromatography (5% methanol/dichloromethane) to give a mixture of compounds A17 and A17' (0.74g, 66%) as a brown solid.
Example 17: preparation of a mixture of Compounds A17 and A17
Compound A16 (1.23g, 1.93mmol) was dissolved in a mixed solvent of 6.2mL acetonitrile and 1.2mL formic acid, heated to 60 deg.C for 41 hours, and LCMS controlled to completion. The reaction solution was quenched by pouring it into 30mL of saturated sodium bicarbonate solution, extracted with ethyl acetate (30 mL. Times.2), and the organic phases were combined and concentrated in vacuo. The crude mixture of compounds A17 and A17 'was isolated by column chromatography (5% methanol in dichloromethane) to give a mixture of compounds A17 and A17' (0.41g, 37%) as a brown solid.
Example 18: preparation of a mixture of Compounds A17 and A17
Compound A16 (1.23g, 1.93mmol) was dissolved in a mixed solvent of 12.3mL acetonitrile and 3.7mL formic acid, heated to 60 deg.C for 31 hours, and LCMS controlled to completion. The reaction solution was quenched by pouring into 30mL of saturated sodium bicarbonate solution, extracted with ethyl acetate (30 mL. Times.2), and the organic phases were combined and concentrated in vacuo. The resulting crude mixture of compounds A17 and A17 'was separated by column chromatography (5% methanol/dichloromethane) to give a mixture of compounds A17 and A17' (0.79g, 71%) as a brown solid.
Example 19: preparation of a mixture of Compounds A17 and A17
Compound A16 (1.23g, 1.93mmol) was dissolved in a mixed solvent of 12.3mL tetrahydrofuran and 3.7mL formic acid, heated to 60 deg.C for 5 days, and LCMS controlled to completion. The reaction solution was quenched by pouring into 30mL of saturated sodium bicarbonate solution, extracted with ethyl acetate (30 mL. Times.2), and the organic phases were combined and concentrated in vacuo. The crude mixture of compounds A17 and A17 'was isolated by column chromatography (5% methanol in dichloromethane) to give a mixture of compounds A17 and A17' (0.13g, 12%) as a brown solid.
Example 20: preparation of a mixture of Compounds A17 and A17
Compound A16 (1.23g, 1.93mmol) was dissolved in a mixed solvent of 12.3mL of acetic acid and 3.7mL of formic acid, heated to 60 ℃ for 42 hours, and LCMS controlled to completion. The reaction solution was quenched by pouring into 30mL of saturated sodium bicarbonate solution, extracted with ethyl acetate (30 mL. Times.2), and the organic phases were combined and concentrated in vacuo. The resulting crude mixture of compounds A17 and A17 'was separated by column chromatography (5% methanol/dichloromethane) to give a mixture of compounds A17 and A17' (0.57g, 53%) as a brown solid.
Example 21: preparation of Compound A17
The mixture of A17 and A17' obtained by separation is subjected to preparative resolution by High Performance Liquid Chromatography (HPLC), wherein the resolution operation refers to the conventional resolution operation in the field, and the specific chromatographic conditions are the same as those in example 15. The yield of the isolated compound a17 was 42% and the yield of the compound a17' was 39%.
Example 22: preparation of Xofluza
The preparation method and nuclear magnetic data of the compound Xofluza refer to WO2016175224.
Comparative example 1: preparation of a mixture of Compounds A17 and A17
Compound A16 (1.23g, 1.93mmol) was dissolved in a mixed solvent of 12.3mL acetonitrile, 12.3mL water and 3.7mL methanesulfonic acid, heated to 60 deg.C, reacted for 43 hours, and LCMS monitored to show very little product formation.
Comparative example 2: preparation of a mixture of Compounds A17 and A17
Compound A16 (1.23g, 1.93mmol) was dissolved in a mixed solvent of 12.3mL of methylene chloride and 3.7mL of boron trifluoride etherate at 0 ℃ and warmed to room temperature for 18 hours, and the reaction was not allowed to proceed as monitored by LCMS.
Comparative example 3: preparation of a mixture of Compounds A17 and A17
P-toluenesulfonic acid monohydrate was dissolved in 12.3mL of dichloromethane, and Compound A16 (1.23g, 1.93mmol) was added and reacted at room temperature for 15 hours, and LCMS monitoring showed that no reaction occurred.
Comparative example 4: preparation of a mixture of Compounds A17 and A17
Compound A16 (1.23g, 1.93mmol) was dissolved in a mixed solvent of 12.3mL tetrahydrofuran and 3.7mL hydrochloric acid, reacted at room temperature for 45 hours, and LCMS monitored showed no reaction.
Comparative example 5: preparation of a mixture of Compounds A17 and A17
Compound A16 (1.23g, 1.93mmol) was combined with 3.7mL of trifluoroacetic acid, heated to 60 deg.C, reacted for 24 hours, and LCMS monitored showed no reaction.
Comparative example 6: preparation of a mixture of Compounds A17 and A17
Compound A16 (1.23g, 1.93mmol) was mixed with 3.7mL formic acid, heated to 50 ℃ and reacted for 15 minutes, with LCMS monitoring showing no reaction.
Comparative example 7: preparation of a mixture of Compounds A17 and A17
Stannous chloride (1.5 g) was dissolved in dichloromethane (10 mL) and compound a16 (1.23g, 1.93mmol) was added and reacted at room temperature for 22 hours with LCMS monitoring showing no reaction.
Comparative example 8: preparation of a mixture of Compounds A17 and A17
Compound A16 (1.23g, 1.93mmol) was dissolved in 12.3mL of a mixed solvent of acetonitrile and formic acid (19.3 mmol), warmed to 60 deg.C, reacted for 23 hours, and LCMS monitored to show no reaction.
Claims (15)
1. A process for the preparation of compound a, characterized in that it comprises the following steps: in an organic solvent, under the action of formic acid, performing cyclization reaction on a compound shown as a formula A16; the compound A is a compound shown as a formula A17, a compound shown as a formula A17', or a mixture of the compounds shown as the formula A17 and the formula A17';
wherein R is 2 And R 3 Independently is C 1 -C 4 Alkyl groups of (a);
the molar volume ratio of the compound shown as the formula A16 to the formic acid is 0.3-1.7mol/L;
the organic solvent is one or more of nitrile solvent, ether solvent and acid solvent.
2. A process for the preparation of compound A as claimed in claim 1, wherein R is 2 And R 3 Independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
and/or the volume ratio of the formic acid to the organic solvent is 1:2-1;
and/or the molar concentration of the compound shown as the formula A16 in the organic solvent is 0.1-0.5mol/L;
and/or the reaction temperature is 50-70 ℃;
and/or the reaction time is 31 hours to 5 days.
3. A process for the preparation of compound A as claimed in claim 2, wherein R is 2 And R 3 Independently is methyl;
and/or, when the organic solvent is a nitrile solvent, the nitrile solvent is acetonitrile;
and/or, when the organic solvent is an ether solvent, the ether solvent is tetrahydrofuran;
and/or, when the organic solvent is an acid solvent, the acid solvent is C 2 -C 4 A straight chain saturated monobasic fatty acid of (1);
and/or the molar volume ratio of the compound shown as the formula A16 to the formic acid is 0.4-0.6mol/L;
and/or the volume ratio of the formic acid to the organic solvent is 1:3-1;
and/or the molar concentration of the compound shown as the formula A16 in the organic solvent is 0.1-0.2mol/L;
and/or the reaction time is 31-42 hours;
and/or, the cyclization reaction comprises the following steps: adding the compound shown as the formula A16 into a mixed solvent of formic acid and an organic solvent, and carrying out the cyclization reaction at the temperature of 50-70 ℃.
4. The process for preparing compound a according to claim 3, wherein when the organic solvent is an acid-based solvent, the acid-based solvent is acetic acid;
and/or the volume ratio of the formic acid to the organic solvent is 1:2-1:4.
5. The method according to claim 1, wherein the method for producing the compound represented by the formula a16 is one or two of the following methods:
the first method comprises the following steps: in an organic solvent, carrying out amidation reaction on a compound shown as a formula A12 and a compound shown as a formula A15 under the action of a condensing agent;
the second method comprises the following steps: reacting a compound shown as a formula A12 with dimethyl sulfoxide in an organic solvent to prepare corresponding acyl chloride, and performing amidation reaction on the acyl chloride and a compound shown as a formula A15 in the presence of alkali to obtain the compound;
wherein R is 2 And R 3 The method according to any one of claims 1 to 4.
6. The method according to claim 5, wherein in the first method, the organic solvent is an ether solvent and/or an amide solvent;
and/or, in the first method, the condensing agent is a carbodiimide type condensing agent and/or a urea positive ion type condensing agent;
and/or, in the first method, the molar ratio of the condensing agent to the compound shown in formula A12 is 1.0;
and/or, in the first method, the molar concentration of the compound shown as the formula A12 in the organic solvent is 0.1-0.3mol/L;
and/or, in the first method, the molar ratio of the compound shown in the formula A15 to the compound shown in the formula A12 is 1:1-3:1;
and/or, in the first method, the temperature of the reaction is 20-30 ℃;
and/or, in the first method, the reaction time is 4-40 hours.
7. The method according to claim 6, wherein in the first method, when the organic solvent is an ether solvent, the ether solvent is tetrahydrofuran;
and/or, in the first method, when the organic solvent is an amide solvent, the amide solvent is N, N-dimethylformamide;
and/or, in the first method, the condensing agent is a carbodiimide type condensing agent and a urea positive ion type condensing agent;
and/or, in the first method, when the condensing agent comprises a carbodiimide-type condensing agent, the carbodiimide-type condensing agent is one or more of dicyclohexylcarbodiimide, N' -diisopropylcarbodiimide, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride;
and/or, in the first method, when the condensing agent comprises a urea cationic condensing agent, the urea cationic condensing agent is one or more of 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate, O-benzotriazole-tetramethylurea hexafluorophosphate, 1-hydroxy-7-azobenzotriazole and 1-hydroxybenzotriazole;
and/or, in the first method, when the condensation agent is a carbodiimide type condensation agent and a urea positive ion type condensation agent, the molar ratio of the carbodiimide type condensation agent to the urea positive ion type condensation agent is 1:1.5;
and/or, in the first method, the molar ratio of the condensing agent to the compound shown in formula A12 is 2.0;
and/or the amidation reaction is carried out under the action of a base, wherein the base is one or more of triethylamine, N-diisopropylethylamine and 4-dimethylaminopyridine;
and/or the amidation reaction is carried out under the action of a base, and the molar ratio of the base to the compound shown in the formula A12 is 1:1-4:1.
8. The method of claim 7, wherein in the first method, when the condensing agent comprises a carbodiimide-type condensing agent, the carbodiimide-type condensing agent is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride;
and/or, in the first method, when the condensing agent comprises a urea cationic condensing agent, the urea cationic condensing agent is 1-hydroxybenzotriazole;
and/or, in the first method, when the condensing agent is a carbodiimide type condensing agent and a urea cationic type condensing agent, the molar ratio of the carbodiimide type condensing agent to the urea cationic type condensing agent is 1;
and/or the amidation reaction is carried out under the action of a base, wherein the base is N, N-diisopropylethylamine;
and/or the amidation reaction is carried out under the action of a base, wherein the molar ratio of the base to the compound shown in the formula A12 is 1.2.
9. The method according to claim 5, wherein the method for preparing the compound represented by the formula a12 comprises the following steps: in a solvent, under the action of alkali, carrying out hydrolysis reaction on a compound shown as a formula A4 as shown in the specification;
wherein R is 1 Is C 1 -C 4 The alkyl group of (1).
10. A process for the preparation of compound A as claimed in claim 9, wherein R is 1 Is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
and/or, the base is an alkali metal hydroxide;
and/or the solvent is water and an organic solvent, and the organic solvent is ethanol and/or tetrahydrofuran;
and/or the molar concentration of the compound shown as the formula A4 in the solvent is 0.1-0.3mol/L;
and/or the molar ratio of the alkali to the compound shown in the formula A4 is 1:1-3:1;
and/or the reaction temperature is 20-30 ℃;
and/or the reaction time is 16-19 hours.
11. The method of claim 10, wherein the base is one or more of sodium hydroxide, potassium hydroxide, and lithium hydroxide.
12. The process for the preparation of compound a according to any one of claims 9 to 11, wherein the process for the preparation of compound a, as represented by formula A4, comprises the following steps: in an organic solvent, under the action of acid, carrying out substitution reaction on a compound shown as a formula A8 and a compound shown as a formula A3 as shown in the specification;
wherein R is 1 The method of any one of claims 9-11.
13. A compound of formula I, having the structure:
wherein R is 4 is-OR 5 Or
R 5 、R 6 And R 7 Independently is H or C 1 -C 4 An alkyl group.
14. The compound of formula I according to claim 13, wherein C is 1 -C 3 Alkylene is
And/or, C 1 -C 3 Alkylene is
And/or when R 5 Is C 1 -C 4 When alkyl, said C 1 -C 4 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
and/or when R 6 Is C 1 -C 4 When alkyl, said C 1 -C 4 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
and/or when R 7 Is C 1 -C 4 When alkyl, said C 1 -C 4 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
15. The compound of formula I according to claim 14, wherein said compound of formula I has any one of the following structures:
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