CN115960085A - Preparation method of fluoro-oxindole heterocyclic compound - Google Patents
Preparation method of fluoro-oxindole heterocyclic compound Download PDFInfo
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- -1 fluoro-oxindole heterocyclic compound Chemical class 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 60
- 238000000034 method Methods 0.000 claims abstract description 19
- 229910052684 Cerium Inorganic materials 0.000 claims abstract description 11
- GWXLDORMOJMVQZ-UHFFFAOYSA-N cerium Chemical compound [Ce] GWXLDORMOJMVQZ-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000003054 catalyst Substances 0.000 claims abstract description 10
- VYLVYHXQOHJDJL-UHFFFAOYSA-K cerium trichloride Chemical compound Cl[Ce](Cl)Cl VYLVYHXQOHJDJL-UHFFFAOYSA-K 0.000 claims abstract description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- 238000005406 washing Methods 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 15
- 238000001035 drying Methods 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 13
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 12
- 229910052794 bromium Inorganic materials 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 12
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 12
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 12
- 239000003208 petroleum Substances 0.000 claims description 12
- 125000001246 bromo group Chemical group Br* 0.000 claims description 11
- 125000001041 indolyl group Chemical group 0.000 claims description 8
- 239000011259 mixed solution Substances 0.000 claims description 8
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 6
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 claims description 6
- 229930185107 quinolinone Natural products 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 238000001291 vacuum drying Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
- BTEJSUVVNDDTPL-UHFFFAOYSA-N n-fluoro-n-phenylbenzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(=O)N(F)C1=CC=CC=C1 BTEJSUVVNDDTPL-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 239000003599 detergent Substances 0.000 claims description 2
- 150000002148 esters Chemical group 0.000 claims description 2
- 238000000967 suction filtration Methods 0.000 claims 1
- 238000005859 coupling reaction Methods 0.000 abstract description 4
- 238000003682 fluorination reaction Methods 0.000 abstract description 4
- 230000003197 catalytic effect Effects 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 239000002253 acid Substances 0.000 abstract description 2
- 125000000524 functional group Chemical group 0.000 abstract description 2
- 229910052751 metal Inorganic materials 0.000 abstract description 2
- 239000002184 metal Substances 0.000 abstract description 2
- 125000001424 substituent group Chemical group 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 239000010970 precious metal Substances 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 34
- 239000000243 solution Substances 0.000 description 22
- 238000005481 NMR spectroscopy Methods 0.000 description 14
- 239000000047 product Substances 0.000 description 13
- 239000012074 organic phase Substances 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- 238000009987 spinning Methods 0.000 description 5
- CHPVQLYVDDOWNT-UHFFFAOYSA-N 1-methylquinoxalin-2-one Chemical compound C1=CC=C2N=CC(=O)N(C)C2=C1 CHPVQLYVDDOWNT-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 238000012512 characterization method Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- BLRHMMGNCXNXJL-UHFFFAOYSA-N 1-methylindole Chemical compound C1=CC=C2N(C)C=CC2=C1 BLRHMMGNCXNXJL-UHFFFAOYSA-N 0.000 description 3
- DGKOFMLBEWYZLR-UHFFFAOYSA-N 1-prop-2-ynylquinoxalin-2-one Chemical compound C1=CC=C2N(CC#C)C(=O)C=NC2=C1 DGKOFMLBEWYZLR-UHFFFAOYSA-N 0.000 description 3
- XZCNHDAUOLXBPV-UHFFFAOYSA-N 6-bromo-1-methylquinolin-2-one Chemical compound C1=C(Br)C=C2C=CC(=O)N(C)C2=C1 XZCNHDAUOLXBPV-UHFFFAOYSA-N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- HIOJKWCIURECFH-UHFFFAOYSA-N 1-(cyclohexylmethyl)indole Chemical compound C1=CC2=CC=CC=C2N1CC1CCCCC1 HIOJKWCIURECFH-UHFFFAOYSA-N 0.000 description 2
- 101100074846 Caenorhabditis elegans lin-2 gene Proteins 0.000 description 2
- 101100497386 Mus musculus Cask gene Proteins 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- XEEANGGQJOWRTG-UHFFFAOYSA-N 1h-indol-2-ylmethanol Chemical compound C1=CC=C2NC(CO)=CC2=C1 XEEANGGQJOWRTG-UHFFFAOYSA-N 0.000 description 1
- GTQFGAJYMBBUSO-UHFFFAOYSA-N 2-diazoacetamide Chemical compound NC(=O)C=[N+]=[N-] GTQFGAJYMBBUSO-UHFFFAOYSA-N 0.000 description 1
- OBIVZIJHRGYOPJ-UHFFFAOYSA-N 2h-oxireno[2,3-b]indole Chemical compound N1C2=CC=CC=C2C2=C1O2 OBIVZIJHRGYOPJ-UHFFFAOYSA-N 0.000 description 1
- MXIRBQGJHHAAIX-UHFFFAOYSA-N 3-fluoro-1,3-dihydroindol-2-one Chemical class C1=CC=C2C(F)C(=O)NC2=C1 MXIRBQGJHHAAIX-UHFFFAOYSA-N 0.000 description 1
- UJSHYNUSRWUTAS-UHFFFAOYSA-N 3-fluoroindol-2-one Chemical class C1=CC=CC2=NC(=O)C(F)=C21 UJSHYNUSRWUTAS-UHFFFAOYSA-N 0.000 description 1
- SBOITLSQLQGSLO-UHFFFAOYSA-N 5-bromo-1-methylindole Chemical compound BrC1=CC=C2N(C)C=CC2=C1 SBOITLSQLQGSLO-UHFFFAOYSA-N 0.000 description 1
- VXWVFZFZYXOBTA-UHFFFAOYSA-N 5-bromo-1h-indole Chemical compound BrC1=CC=C2NC=CC2=C1 VXWVFZFZYXOBTA-UHFFFAOYSA-N 0.000 description 1
- YLAFBGATSQRSTB-UHFFFAOYSA-N 6-bromo-1h-quinolin-2-one Chemical compound N1C(=O)C=CC2=CC(Br)=CC=C21 YLAFBGATSQRSTB-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- PCKPVGOLPKLUHR-UHFFFAOYSA-N OH-Indolxyl Natural products C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- LDDQLRUQCUTJBB-UHFFFAOYSA-N ammonium fluoride Chemical compound [NH4+].[F-] LDDQLRUQCUTJBB-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- UUWSLBWDFJMSFP-UHFFFAOYSA-N bromomethylcyclohexane Chemical compound BrCC1CCCCC1 UUWSLBWDFJMSFP-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- QNLOWBMKUIXCOW-UHFFFAOYSA-N indol-2-one Chemical class C1=CC=CC2=NC(=O)C=C21 QNLOWBMKUIXCOW-UHFFFAOYSA-N 0.000 description 1
- WRIRWRKPLXCTFD-UHFFFAOYSA-N malonamide Chemical compound NC(=O)CC(N)=O WRIRWRKPLXCTFD-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000002379 progesterone receptor modulator Substances 0.000 description 1
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229940095745 sex hormone and modulator of the genital system progesterone receptor modulator Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Indole Compounds (AREA)
Abstract
The invention relates to a preparation method of a fluorooxindole heterocyclic compound, which adopts a cheap and small-dose cerium catalyst to synthesize a series of fluorooxindole heterocyclic compounds by a mild and efficient photo-promoted cerium catalytic method. Compared with the traditional process for synthesizing the 3-fluorooxoindole heterocyclic ring, the process has the advantages that the cerium chloride and the N-fluorobisbenzenesulfonamide which are cheap and efficient are used as the catalyst and the fluorination reagent, so that the use of precious metals is avoided, the metal consumption is reduced, the reaction condition is milder, economic and efficient, and the industrialization possibility of a reaction system is promoted; the coupling reaction is promoted by utilizing visible light, so that the use of strong acid in the traditional coupling reaction is avoided, and the method is more environment-friendly; 3- (3-fluoro-2-oxoindol-3-yl) -quinolinone compounds with different substituents are efficiently expanded, a reaction system has better functional group compatibility and provides higher yield, and the yield of a target product can reach more than 90%.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of a fluoro-oxindole heterocyclic compound.
Background
The oxindole heterocyclic compound widely exists in natural products and important medicine molecular structures, has a remarkable biological property in the field of pharmacy, and has been widely applied to treatment of diseases, such as medicines for resisting neurological disorders, resisting stroke, progesterone receptor modulators and the like.
The traditional method for preparing the 3-fluorooxoindole derivatives can be mainly divided into two methods, one method is to respectively perform fluorooxidation or nucleophilic fluorination on indole or oxoindole derivatives, the method needs a difficult-to-prepare substrate such as 2-hydroxymethyl indole and spiro epoxyindole as the substrate, uses a hazardous fluorination reagent such as ammonium hydrofluoride salt as a fluorine source, and even additionally adds an oxidant and alkali to promote the reaction, so that the reaction conditions are harsh and the steps are complex; another conventional method uses malonamide or diazoacetamide, which is difficult to prepare, as a cyclization substrate, and adds expensive organometallic complexes and other additives to promote the cyclization reaction, thereby increasing the preparation cost and environmental burden, and being unsuitable for industrialization. The conventional preparation method remarkably reduces the practicability due to higher preparation cost, complicated synthesis steps, lower safety and more wastes, so that a high-efficiency, environment-friendly and economic preparation method of the fluorooxindole heterocyclic compound, particularly the 3-fluorooxindole derivative, is required to be developed to be better suitable for the field of practical application.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides a preparation method of a fluorooxoindole heterocyclic compound (3- (3-fluoro-2-oxoindol-3-yl) -quinolinone derivative), which is simple and convenient to operate and high in efficiency.
The technical scheme adopted by the invention is as follows:
a preparation method of a fluoro-oxoindole heterocyclic compound is disclosed, wherein the structural formula of the fluoro-oxoindole heterocyclic compound is shown as the following formula (I):
wherein R is 1 Is any one of H, methyl, cyclohexylmethyl and propargyl; r 2 Any one selected from the following groups: H. bromine substituted at the 5-position of indole, cyano and ester substituted at the 6-position of indole; r 3 Any one selected from the following groups: H. methyl and benzyl; r 4 Is any one of chlorine and bromine substituted by H and quinolinone 6 site;
the preparation method of the fluoro-oxygenated indole heterocyclic compound comprises the following steps:
(1) Preparing a compound shown as a structural formula (II);
(2) Preparing a compound shown as a structural formula (III);
(3) Adding a compound with a structural formula shown as (II), a compound with a structural formula shown as (III) and a cerium catalyst into a reaction container, adding a solvent, and stirring for reaction under the condition of room temperature blue light irradiation; then adding N-fluoro-diphenyl sulfonamide, and continuously stirring for reaction at the temperature of 35-65 ℃; to obtain the product shown in the structural formula (I).
The invention uses a photo-promoted cerium catalytic method to prepare fluorooxindole heterocyclic compounds (3- (3-fluoro-2-oxoindol-3-yl) -quinolinone derivatives), and the reaction process is as follows:
preferably, R 1 Is methyl or cyclohexylmethyl; r is 2 Is H or bromine substituted at the 5-position of indole; r 3 Is methyl; r is 4 Is H or bromine substituted at the 6-position of quinolinone.
Preferably, the cerium catalyst is anhydrous cerium chloride.
Preferably, the solvent is acetonitrile or dichloroethane.
Preferably, the mol ratio of the compound shown in the structural formula (II), the compound shown in the structural formula (III), the N-fluoro-diphenyl sulfonamide and the cerium catalyst is 1:1.1:1.5: 0.005-0.01.
Preferably, the temperature for continuing the stirring reaction is 50 ℃.
Preferably, after the reaction is finished, the solvent is dried by spinning, the mixed solution of ethanol and water is used for recrystallization, then the filtration is carried out, the detergent is selected from the mixed solution of petroleum ether/ethyl acetate for washing three times, and the product is obtained by vacuum drying.
The preparation method of the 3- (3-fluoro-2-oxoindol-3-yl) -quinolinone derivative provided by the invention is scientific and reasonable, adopts a cheap and small-dose cerium catalyst, and synthesizes a series of 3- (3-fluoro-2-oxoindol-3-yl) -quinolinone derivatives by a mild and efficient photo-promoted cerium catalytic method.
The invention has the beneficial effects that:
(1) Compared with the traditional process for synthesizing 3-fluorooxoindole heterocyclic ring, the method has the advantages that the cheap and efficient cerium chloride and N-fluorobisbenzenesulfonamide are used as the catalyst and the fluorination reagent, the use of noble metal is avoided, the metal consumption is reduced, the reaction condition is milder, economic and efficient, and the possibility of industrialization of the reaction system is promoted;
(2) The coupling reaction is promoted by utilizing visible light, so that the use of strong acid in the traditional coupling reaction is avoided, and the method is more environment-friendly;
(3) 3- (3-fluoro-2-oxoindol-3-yl) -quinolinone compounds with different substituents are efficiently expanded, a reaction system has better functional group compatibility and provides higher yield, and the yield of a target product can reach more than 90%.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of 3- (3-fluoro-1-cyclohexylmethyl-2-oxoindol-3-yl) -1-methylquinolin-2 (1H) -one prepared in example 1.
Detailed Description
The invention is further illustrated by the following examples, without limiting the scope of the invention. Those skilled in the art can and should understand that any simple changes or substitutions based on the spirit of the present invention should fall within the protection scope of the present invention.
Example 1
Preparation of N-cyclohexylmethylindole (R in structural formula (II)) 1 Is cyclohexylmethyl, R 2 Is H)
Indole (13.2mmol, 1.55g), potassium hydroxide (46.2mmol, 2.60g) and 15mL of N, N-Dimethylformamide (DMF) were added to a 50mL round-bottomed flask, followed by stirring in an ice bath, then a solution of (bromomethyl) cyclohexane (15.84mmol, 2.80g) in DMF was added dropwise to the round-bottomed flask, and after completion of the addition, the reaction was continued at room temperature for 3 hours, followed by TLC detection. After the reaction is finished, washing the reaction solution with a saturated ammonium chloride solution, extracting with ethyl acetate, washing the organic phase with brine again, separating out the organic phase, drying, spin-drying, purifying by using a petroleum ether and ethyl acetate (80.
Preparation of N-methylquinoxalinone (R in structural formula (III)) 3 Is methyl, R 4 Is H)
2-hydroxyquinoxalinone (12mmol, 1.75g), potassium carbonate (24mmol, 3.31g) and 15mL of N, N-Dimethylformamide (DMF) are respectively added into a 100mL round-bottomed flask, stirred under ice bath, then a DMF solution of methyl iodide (14.4 mmol, 2g) is dropwise added into the round-bottomed flask, after the dropwise addition is finished, the reaction is continued for 6 hours at room temperature, and the reaction is detected by TLC. After the reaction is finished, washing the reaction solution with saturated ammonium chloride solution, extracting with ethyl acetate, washing the organic phase with brine again, separating out the organic phase, spin-drying to obtain a crude product, and recrystallizing the crude product with ethyl acetate/petroleum ether (1:4) to obtain the purer N-methylquinoxalinone.
Preparation of 3- (3-fluoro-1-cyclohexylmethyl-2-oxoindol-3-yl) -1-methylquinolin-2 (1H) -one (formula (I) R 1 Is cyclohexylmethyl, R 2 Is H, R 3 Is methyl, R 4 Is H)
Respectively adding N-cyclohexyl methyl indole (0.2mmol, 42.7mg), N-methyl quinoxalinone (0.22mmol, 35.2mg), anhydrous cerium chloride (0.001mmol, 0.25mg) and 3mL acetonitrile into a 25mL reaction flask, and reacting for 1 hour under the condition of blue light irradiation at room temperature; subsequently, N-fluorobisbenzenesulfonamide (0.3mmol, 94.6 mg) was slowly added to the reaction system, and the reaction was continued at 50 ℃ for 3 hours, as checked by TLC. After the reaction is finished, drying acetonitrile by spinning, adding ethanol to dissolve the mixture, slowly dropwise adding water until the reaction solution is gradually turbid, cooling to 0 ℃, continuously stirring for 20min for material precipitation, filtering, washing a filter cake by using a petroleum ether/ethyl acetate (3/1) mixed solution for three times, and performing vacuum drying to obtain the target product 3- (3-fluoro-1-cyclohexylmethyl-2-oxoindol-3-yl) -1-methylquinoline-2 (1H) -ketone, wherein the yield is 95%.
Structural characterization of 3- (3-fluoro-1-cyclohexylmethyl-2-oxoindol-3-yl) -1-methylquinolin-2 (1H) -one nuclear magnetic resonance data are shown in figure 1: 1 H NMR(400MHz,DMSO-d 6 )δ8.04(dd,J＝8.1,1.5Hz,1H),7.76(ddd,J＝8.6,7.3,1.6Hz,1H),7.64(d,J＝8.5Hz,1H),7.54–7.45(m,2H),7.27–7.21(m,2H),7.02(t,J＝7.5Hz,1H),3.61(dd,J＝7.0,2.0Hz,2H),3.57(s,3H),1.87(dt,J＝12.4,3.5Hz,2H),1.80–1.69(m,3H),1.66–1.60(m,1H),1.26–1.17(m,3H),1.08(tt,J＝11.9,6.4Hz,2H)； 13 C NMR(101MHz,DMSO-d 6 )δ152.12,146.32,133.70,132.56,132.24,132.13,130.41,125.04,124.70,124.32,123.07,115.69,110.48,46.43,36.41,30.69,29.40,26.39,25.81； 19 F NMR(471MHz,DMSO-d 6 )δ-159.67.
the analysis result shows that the obtained target product is correct.
Example 2
The yield of the target product prepared by substituting dichloroethane for acetonitrile was 90%.
Example 3
The target product was prepared in 72% yield by substituting N, N-Dimethylformamide (DMF) for acetonitrile.
Example 4
Preparation of 5-bromo-1-methyl-1H-indolePreparation of (R in the formula (II)) 1 Is methyl, R 2 Is bromine substituted in the 5-position of the indole)
5-bromo-1H-indole (13.2 mmol,2.6 g), potassium hydroxide (46.2 mmol, 2.60g) and 15mL of N, N-Dimethylformamide (DMF) were added to a 50mL round-bottomed flask, followed by stirring in an ice bath, dropwise addition of a solution of methyl iodide (15.84mmol, 2.2 g) in DMF to the round-bottomed flask, further reaction at room temperature for 3 hours after completion of the dropwise addition, and detection by TLC was performed. After the reaction is finished, washing the reaction solution with a saturated ammonium chloride solution, extracting with ethyl acetate, washing the organic phase with brine again, separating out the organic phase, drying, spin-drying, purifying by column chromatography with a ratio of petroleum ether to ethyl acetate (80.
Preparation of 3- (5-bromo-3-fluoro-1-methyl-2-oxoindolin-3-yl) -1-methylquinolin-2 (1H) -one (R in formula (I)) 1 Is methyl, R 2 Is bromine, R substituted at the 5-position of indole 3 Is methyl, R 4 Is H)
Respectively adding 5-bromo-1-methyl-1H-indole (0.2mmol, 42mg), N-methylquinoxalinone (0.22mmol, 35.2mg), anhydrous cerium chloride (0.002mmol, 0.25mg) and 3mL acetonitrile into a 25mL reaction flask, and reacting for 3 hours under the condition of blue light irradiation at room temperature; subsequently, N-fluorobisbenzenesulfonamide (0.3mmol, 94.6 mg) was slowly added to the reaction system, and the reaction was continued at 50 ℃ for 3 hours, followed by TLC detection. After the reaction is finished, drying acetonitrile by spinning, adding ethanol to dissolve the mixture, slowly dropwise adding water until the reaction solution is gradually turbid, cooling to 0 ℃, continuously stirring for 20min for material precipitation, filtering, washing a filter cake by using a petroleum ether/ethyl acetate (3/1) mixed solution for three times, and performing vacuum drying to obtain the target product 3- (5-bromo-3-fluoro-1-methyl-2-oxoindolin-3-yl) -1-methylquinoline-2 (1H) -one, wherein the yield is 92%.
Structural characterization of 3- (5-bromo-3-fluoro-1-methyl-2-oxoindolin-3-yl) -1-methylquinolin-2 (1H) -one nuclear magnetic resonance data: 1 H NMR(400MHz,Chloroform-d)δ8.14(dd,J＝8.0,1.5Hz,1H),7.69(ddd,J＝8.6,7.2,1.5Hz,1H),7.57(dt,J＝8.3,2.0Hz,1H),7.53–7.46(m,1H),7.43–7.36(m,2H),6.86(dd,J＝8.3,1.2Hz,1H),3.64(d,J＝1.6Hz,3H),3.37(s,3H)； 13 C NMR(101MHz,Chloroform-d)δ169.64,152.36,151.51,145.18,145.13,134.82,134.79,133.37,132.56,131.85,131.16,127.95,125.95,124.51,115.43,115.39,113.91,110.53,90.34,29.09,26.79； 19 F NMR(376MHz,Chloroform-d)δ-163.51.
the analysis result shows that the obtained target product is correct.
Example 5
Preparation of N-methylindole (R in structural formula (II)) 1 Is methyl, R 2 Is H)
Indole (13.2mmol, 1.55g), potassium hydroxide (46.2mmol, 2.60g) and 15mL of N, N-Dimethylformamide (DMF) were added to a 50mL round-bottomed flask, and stirred in an ice bath, then a solution of iodomethane (15.84mmol, 2.25g) in DMF was added dropwise to the round-bottomed flask, and after completion of the addition, the reaction was continued at room temperature for 3 hours, and the reaction was checked by TLC. After the reaction is finished, washing the reaction solution with a saturated ammonium chloride solution, extracting with ethyl acetate, washing the organic phase with brine again, separating out the organic phase, drying, spin-drying, purifying by using a petroleum ether and ethyl acetate (80.
Preparation of 6-bromo-1-methylquinolin-2 (1H) -one (R in formula (III)) 3 Is methyl, R 4 Is bromine substituted in the 6-position of quinolinone
6-bromoquinolin-2 (1H) -one (12mmol, 2.7 g), potassium carbonate (24mmol, 3.31g) and 15mL of N, N-Dimethylformamide (DMF) were added to a 100mL round-bottomed flask, followed by stirring in ice, dropwise addition of a solution of methyl iodide (14.4 mmol, 2g) in DMF to the round-bottomed flask, completion of the dropwise addition, continuation of the reaction at room temperature for 6 hours, and the reaction was checked by TLC. After the reaction is finished, washing the reaction solution with saturated ammonium chloride solution, extracting with ethyl acetate, washing the organic phase with brine, separating out the organic phase, spin-drying to obtain a crude product, and recrystallizing the crude product with ethyl acetate/petroleum ether (1:3) to obtain the pure 6-bromo-1-methylquinolin-2 (1H) -one.
Preparation of 6-bromo-3- (3-fluoro-1-methyl-2-oxoindolin-3-yl) -1-methylquinolin-2 (1H) -one (R in structural formula (I)) 1 Is methyl, R 2 Is H, R 3 Is methyl, R 4 Bromine substituted in position 6 for quinolinone
Respectively adding N-methylindole (0.2mmol, 26.2mg), 6-bromo-1-methylquinolin-2 (1H) -one (0.22mmol, 52.6 mg), anhydrous cerium chloride (0.002mmol, 0.25mg) and 3mL of acetonitrile into a 25mL reaction flask, and reacting for 3 hours under the condition of blue light irradiation at room temperature; subsequently, N-fluorobisbenzenesulfonamide (0.3mmol, 94.6 mg) was slowly added to the reaction system, and the reaction was continued at 50 ℃ for 3 hours, as checked by TLC. After the reaction is finished, drying acetonitrile by spinning, adding ethanol to dissolve the mixture, slowly dropwise adding water until the reaction solution is gradually turbid, cooling to 0 ℃, continuously stirring for 20min for material precipitation, filtering, washing a filter cake by using a petroleum ether/ethyl acetate (3/1) mixed solution for three times, and performing vacuum drying to obtain the target product 6-bromo-3- (3-fluoro-1-methyl-2-oxoindolin-3-yl) -1-methylquinoline-2 (1H) -one, wherein the yield is 93%.
Structural characterization of 6-bromo-3- (3-fluoro-1-methyl-2-oxoindolin-3-yl) -1-methylquinolin-2 (1H) -one nuclear magnetic resonance data: 1 H NMR(400MHz,Chloroform-d)δ8.30(s,1H),7.76(d,J＝8.8Hz,1H),7.46(t,J＝7.7Hz,1H),7.25(d,J＝8.9Hz,2H),7.05(t,J＝7.5Hz,1H),6.97(d,J＝7.8Hz,1H),3.60(s,3H),3.38(s,3H)； 13 C NMR(101MHz,Chloroform-d)δ153.78,152.05,134.32,133.40,133.26,132.51,132.28,132.25,124.79,123.90,123.72,123.07,123.04,116.97,115.29,109.13,92.75,29.20,26.70； 19 F NMR(376MHz,Chloroform-d)δ-163.49.
the analysis result shows that the obtained target product is correct.
Example 6
Preparation of N-propargyl quinoxalinone (R in structural formula (II)) 1 Is propargyl, R 2 Is H)
2-hydroxyquinoxalinone (12mmol, 1.75g), potassium carbonate (24mmol, 3.31g) and 15mL of N, N-Dimethylformamide (DMF) are respectively added into a 100mL round-bottomed flask, stirred under ice bath, then a DMF solution of 3-bromopropyne (14.4 mmol, 1.71g) is dropwise added into the round-bottomed flask, and after the dropwise addition is finished, the reaction is continued for 6 hours at room temperature, and the reaction is detected by TLC. After the reaction is finished, washing the reaction solution with saturated ammonium chloride solution, extracting with ethyl acetate, washing the organic phase with brine, separating out the organic phase, drying, spin-drying to obtain a crude product, and recrystallizing the crude product with ethyl acetate/petroleum ether (1:4) to obtain the pure N-propargyl quinoxalinone.
Preparation of 3- (3-fluoro-1-methyl-2-oxoindol-3-yl) -1-propargylquino lin-2 (1H) -one (R in structural formula (I)) 1 Is propargyl, R 2 Is H, R 3 Is methyl, R 4 Is H)
Respectively adding N-methylindole (0.2mmol, 26.2mg), N-propargyl quinoxalinone (0.22mmol, 40.5mg), anhydrous cerium chloride (0.001mmol, 0.25mg) and 3mL acetonitrile into a 25mL reaction tube, and reacting for 1 hour under the condition of blue light irradiation at room temperature; subsequently, N-fluorobisbenzenesulfonamide (0.3mmol, 94.6 mg) was slowly added to the reaction system, and the reaction was continued at 50 ℃ for 3 hours, as checked by TLC. After the reaction is finished, drying acetonitrile by spinning, adding ethanol to dissolve a mixture, slowly dropwise adding water until a reaction solution is gradually turbid, cooling to 0 ℃, continuously stirring for 20min for material precipitation, filtering, washing a filter cake by using a mixed solution of petroleum ether/ethyl acetate (3/1) for three times, and performing vacuum drying to obtain a target product 3- (3-fluoro-1-methyl-2-oxoindol-3-yl) -1-propargyl quinoxaline-2 (1H) -one, wherein the yield is 92%.
Structural characterization of 3- (3-fluoro-1-methyl-2-oxoindol-3-yl) -1-propargylquino lin-2 (1H) -one nuclear magnetic resonance data are shown below: 1 H NMR(400MHz,Chloroform-d)δ8.16(d,J＝8.0Hz,1H),7.64(t,J＝7.8Hz,1H),7.49–7.43(m,2H),7.38–7.31(m,2H),7.05(t,J＝7.5Hz,1H),6.97(d,J＝7.8Hz,1H),5.90–5.79(m,1H),4.85–4.79(m,2H),3.39(s,3H).
the analysis result shows that the obtained target product is correct.
It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the concept of the present application, and these are all within the scope of protection of the present application.
Claims (7)
1. A preparation method of fluoro-oxindole heterocyclic compounds is characterized by comprising the following steps: the structural formula of the fluoro-oxoindole heterocyclic compound is shown as the following formula (I):
wherein R is 1 Is any one of H, methyl, cyclohexylmethyl and propargyl; r 2 Any one selected from the following groups: H. bromine substituted at the 5-position of indole, cyano-group and ester substituted at the 6-position of indole; r 3 Any one selected from the following groups: H. methyl and benzyl; r is 4 Is any one of chlorine and bromine substituted by H and quinolinone 6 site;
the preparation method of the fluorinated oxoindole heterocyclic compound comprises the following steps:
(1) Preparing a compound shown as a structural formula (II);
(2) Preparing a compound shown as a structural formula (III);
(3) Adding a compound with a structural formula shown as (II), a compound with a structural formula shown as (III) and a cerium catalyst into a reaction container, adding a solvent, and stirring for reaction under the condition of blue light irradiation at room temperature; then adding N-fluoro-diphenyl sulfonamide, and continuously stirring for reaction at the temperature of 35-65 ℃; to obtain the product with the structural formula shown in (I).
2. The process for producing a fluorinated oxoindole heterocyclic compound according to claim 1, comprising: r 1 Is methyl or cyclohexylmethyl; r 2 Is H or bromine substituted at the 5-position of indole; r is 3 Is methyl; r 4 Is H or bromine substituted at the 6-position of quinolinone.
3. The process for producing a fluorinated oxoindole heterocyclic compound according to claim 1, comprising: the cerium catalyst is anhydrous cerium chloride.
4. The process for producing a fluorinated oxoindole heterocyclic compound according to claim 1, comprising: the solvent is acetonitrile or dichloroethane.
5. The process for producing a fluorooxyindole heterocyclic compound according to claim 1, characterized in that: the mol ratio of the compound shown as the structural formula (II) to the compound shown as the structural formula (III) to the N-fluoro-bis-benzenesulfonamide to the cerium catalyst is 1:1.1:1.5: 0.005-0.01.
6. The process for producing a fluorinated oxoindole heterocyclic compound according to claim 1, comprising: the temperature for further stirring was 50 ℃.
7. The process for producing a fluorinated oxoindole heterocyclic compound according to claim 1, comprising: and after the reaction is finished, spin-drying the solvent, recrystallizing by using a mixed solution of ethanol and water, then carrying out suction filtration, washing the detergent by using a mixed solution of petroleum ether/ethyl acetate for three times, and carrying out vacuum drying to obtain the product.
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