CN112159372A - Preparation method of bicalutamide - Google Patents
Preparation method of bicalutamide Download PDFInfo
- Publication number
- CN112159372A CN112159372A CN202011138941.3A CN202011138941A CN112159372A CN 112159372 A CN112159372 A CN 112159372A CN 202011138941 A CN202011138941 A CN 202011138941A CN 112159372 A CN112159372 A CN 112159372A
- Authority
- CN
- China
- Prior art keywords
- reaction
- bicalutamide
- preparation
- filtering
- fatty acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 title claims abstract description 28
- 229960000997 bicalutamide Drugs 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 54
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- VTIIJXUACCWYHX-UHFFFAOYSA-L disodium;carboxylatooxy carbonate Chemical compound [Na+].[Na+].[O-]C(=O)OOC([O-])=O VTIIJXUACCWYHX-UHFFFAOYSA-L 0.000 claims abstract description 21
- 229940045872 sodium percarbonate Drugs 0.000 claims abstract description 21
- 238000006735 epoxidation reaction Methods 0.000 claims abstract description 19
- 238000003756 stirring Methods 0.000 claims abstract description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000001914 filtration Methods 0.000 claims abstract description 18
- HHWDZLSGDDXUSM-UHFFFAOYSA-N n-[4-cyano-3-(trifluoromethyl)phenyl]-2-methylprop-2-enamide Chemical compound CC(=C)C(=O)NC1=CC=C(C#N)C(C(F)(F)F)=C1 HHWDZLSGDDXUSM-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000001816 cooling Methods 0.000 claims abstract description 14
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 14
- 229930195729 fatty acid Natural products 0.000 claims abstract description 14
- 239000000194 fatty acid Substances 0.000 claims abstract description 14
- 238000005406 washing Methods 0.000 claims abstract description 14
- 238000001035 drying Methods 0.000 claims abstract description 9
- 239000003208 petroleum Substances 0.000 claims abstract description 9
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims abstract description 9
- 235000019345 sodium thiosulphate Nutrition 0.000 claims abstract description 9
- 238000010438 heat treatment Methods 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 6
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 4
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims abstract description 4
- 150000004665 fatty acids Chemical class 0.000 claims abstract description 4
- 239000012074 organic phase Substances 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 15
- -1 fatty acid ester Chemical class 0.000 claims description 15
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 12
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 239000007810 chemical reaction solvent Substances 0.000 abstract description 4
- 239000012044 organic layer Substances 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 238000002390 rotary evaporation Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 4
- 230000001590 oxidative effect Effects 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- 239000004593 Epoxy Substances 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- MPRWIVBRDAXEAF-UHFFFAOYSA-N acetyloxy ethaneperoxoate Chemical compound CC(=O)OOOC(C)=O MPRWIVBRDAXEAF-UHFFFAOYSA-N 0.000 description 2
- 239000003098 androgen Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- PMDYLCUKSLBUHO-UHFFFAOYSA-N 4-amino-2-(trifluoromethyl)benzonitrile Chemical compound NC1=CC=C(C#N)C(C(F)(F)F)=C1 PMDYLCUKSLBUHO-UHFFFAOYSA-N 0.000 description 1
- GKLHGXQYDYSCIC-UHFFFAOYSA-N 4-fluoro-2-phenylbenzenethiol Chemical compound FC1=CC(=C(C=C1)S)C1=CC=CC=C1 GKLHGXQYDYSCIC-UHFFFAOYSA-N 0.000 description 1
- 102000006771 Gonadotropins Human genes 0.000 description 1
- 108010086677 Gonadotropins Proteins 0.000 description 1
- LKJPYSCBVHEWIU-UHFFFAOYSA-N N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide Chemical compound C=1C=C(C#N)C(C(F)(F)F)=CC=1NC(=O)C(O)(C)CS(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000002622 gonadotropin Substances 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 150000002484 inorganic compounds Chemical class 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000003956 nonsteroidal anti androgen Substances 0.000 description 1
- 150000001451 organic peroxides Chemical group 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000002910 solid waste Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/48—Compounds containing oxirane rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/02—Synthesis of the oxirane ring
- C07D301/03—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds
- C07D301/12—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with hydrogen peroxide or inorganic peroxides or peracids
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Pyrrole Compounds (AREA)
- Epoxy Compounds (AREA)
Abstract
The invention provides a preparation method of bicalutamide, which comprises the following steps: dissolving N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -2-methacrylamide in a lower fatty acid ester solvent, sequentially adding sodium percarbonate and acetic anhydride, stirring and heating, and carrying out epoxidation reaction to obtain a reaction liquid; filtering the reaction solution, washing an organic phase by using a sodium thiosulfate solution, and recovering the solvent under reduced pressure; adding petroleum ether, cooling, crystallizing, filtering and drying to obtain the bicalutamide. The preparation method of bicalutamide provided by the invention has the advantages of mild reaction conditions, high reaction yield, high epoxidation efficiency and recyclable reaction solvent.
Description
Technical Field
The invention relates to the technical field of biological pharmacy, in particular to a preparation method of bicalutamide.
Background
Bicalutamide (Bicalutamide), chemical name: n- [ 4-cyano-3- (trifluoromethyl) phenyl ] -3- [ (4-fluorophenyl) sulfonyl ] -2-methyl-2-hydroxypropionamide. Bicalutamide is successfully developed by AstraZeneca company of UK, can feedback and inhibit the secretion of gonadotropin from anterior pituitary and reduce the production of androgen but has almost no androgen activity as a non-steroidal anti-androgen compound, and is clinically used for treating prostatic cancer. The bicalutamide has strong drug effect, convenient administration and little side effect, and is the most clinically applied anti-androgen malignant prostate cancer treatment drug at present.
In the related art, a literature (Howard Tucker j. med. chem.1988,31,954-959, USP463605) discloses a method for synthesizing bicalutamide, wherein 4-cyano-3-trifluoromethylaniline and 2-methacryloyl chloride are acylated to obtain amide 1, m-chloroperoxybenzoic acid is used for oxidizing 1 to obtain epoxy compound 2, p-fluorophenylthiophenol is subjected to ring opening to obtain 3, and m-chloroperoxybenzoic acid is used for oxidizing to obtain bicalutamide 4, and the reaction formula is shown as follows:
in the synthesis method, m-chloroperoxybenzoic acid is adopted as an epoxidizing agent, an oxidant easily generates a large amount of solid waste, so that the great environmental pollution is caused, and the peroxy acid has explosiveness, is unsafe to use and has high requirements on safe production operation; dichloroethane is used as a solvent, and the dichloroethane has high toxicity, so that residual products are difficult to remove, and the product quality is influenced.
Therefore, there is a need to provide a new preparation method of bicalutamide to solve the above problems.
Disclosure of Invention
The invention aims to overcome the technical problems and provide a preparation method of bicalutamide, which has the advantages of mild reaction conditions, high reaction yield, high epoxidation efficiency and recyclable reaction solvent.
In order to achieve the above object, the present invention provides a method for preparing bicalutamide, comprising the steps of:
dissolving N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -2-methacrylamide in a lower fatty acid ester solvent, sequentially adding sodium percarbonate and acetic anhydride, stirring and heating, and carrying out epoxidation reaction to obtain a reaction liquid;
filtering the reaction solution, washing an organic phase by using a sodium thiosulfate solution, and recovering the solvent under reduced pressure;
adding petroleum ether, cooling, crystallizing, filtering and drying to obtain the bicalutamide.
Preferably, the lower fatty acid ester is an aliphatic ester which is liquid at normal temperature and has 2 to 6 carbon atoms.
Preferably, the lower fatty acid ester is one of methyl formate, ethyl formate, methyl acetate and ethyl acetate.
Preferably, the lower fatty acid ester is ethyl acetate or ethyl formate.
Preferably, the reaction temperature of the epoxidation reaction is 10-50 ℃.
Preferably, the reaction temperature of the epoxidation reaction is 35-45 ℃.
Preferably, the molar ratio of the N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -2-methacrylamide to the sodium percarbonate is 1 (1.1-1.5).
Preferably, the molar ratio of the sodium percarbonate to the acetic anhydride is 1 (0.3-0.8).
Preferably, the reaction time of the epoxidation reaction is 1-12 h.
Compared with the prior art, the preparation method of bicalutamide provided by the invention has the advantages of mild reaction conditions, high reaction yield, high epoxidation efficiency and recyclable reaction solvent.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The invention provides a preparation method of bicalutamide, which comprises the following steps:
dissolving N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -2-methacrylamide in a lower fatty acid ester solvent, sequentially adding sodium percarbonate and acetic anhydride, stirring and heating, and carrying out epoxidation reaction to obtain a reaction liquid;
filtering the reaction solution, washing an organic phase by using a sodium thiosulfate solution, and recovering the solvent under reduced pressure;
adding petroleum ether, cooling, crystallizing, filtering and drying to obtain the bicalutamide.
The preparation method provided by the invention takes N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -2-methacrylamide (intermediate 1) as a raw material, sodium percarbonate as an oxygen source and lower fatty acid ester as a solvent, and epoxidizes the intermediate 1 to generate an intermediate 2 at a reaction temperature of 10-50 ℃, wherein the reaction formula is as follows:
the lower fatty acid ester is an aliphatic ester which is liquid at normal temperature and has 2-6 carbon atoms. Preferably, the lower fatty acid ester is one of methyl formate, ethyl formate, methyl acetate and ethyl acetate. Further, the lower fatty acid ester is ethyl acetate or ethyl formate.
The epoxidation reaction is endothermic, and the reaction temperature is 10-50 ℃. Preferably, the reaction temperature of the epoxidation reaction is 35-45 ℃, and the reaction time is 1-12 h.
Sodium percarbonate is an inorganic compound, white powder, with an available oxygen content of 12 to 13%, which is insoluble in organic solvents. The mechanism of the epoxidation reaction is: firstly, sodium percarbonate and acetic anhydride generate an organic peroxide compound intermediate, and then the organic peroxide compound intermediate reacts with N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -2-methacrylamide to generate an epoxy compound. The essence of the method is that the epoxidation reagents such as peroxyacetic anhydride and the like are prepared by the action of sodium percarbonate and acetic anhydride, and react with N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -2-methacrylamide while acting in the reaction process, so that the defects of instability and easy decomposition of organic peroxide are avoided, the reaction is stable, and the operation is safe.
The epoxidation reaction of sodium percarbonate and acetic anhydride is a solid-liquid two-phase reaction, and in order to ensure the complete reaction, the molar ratio of the N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -2-methacrylamide to the sodium percarbonate is 1 (1.1-1.5).
The function of acetic anhydride is to react with sodium percarbonate to form peracetic anhydride, which itself is reduced to acetic anhydride after transfer of the oxygen atom to N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -2-methacrylamide. Therefore, acetic anhydride can be recycled. In order to accelerate the reaction speed, the molar ratio of the sodium percarbonate to the acetic anhydride is 1 (0.3-0.8) in practical operation.
Example one
Adding 150ml of ethyl acetate, 18.84g of sodium percarbonate (0.12 mol) and 25.4g of N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -2-methacrylamide (0.10 mol) into a 500ml three-necked bottle, stirring, dropwise adding acetic anhydride (7.14g and 0.07mol) at the temperature of 35-40 ℃, slowly heating to 45 ℃ after dropwise adding, stirring for 5 hours, tracking the reaction process by TLC (thin layer chromatography), cooling to room temperature after the reaction is finished, filtering the reaction system, washing an organic layer once by using a sodium thiosulfate solution, washing the organic layer for 2 times by using saturated saline, carrying out reduced pressure rotary evaporation to recover the ethyl acetate, adding 80ml of petroleum ether after the ethyl acetate is recovered, stirring, cooling, crystallizing, filtering and drying to obtain 24.6g of bicalutamide white solid with the yield of 91.1%.
Example two
Adding 180ml of methyl formate, 23.55g of sodium percarbonate (0.15 mol) and 25.4g of N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -2-methacrylamide (0.10 mol) into a 500ml three-necked bottle, stirring, dropwise adding acetic anhydride (7.65g, 0.075mol) at the temperature of 35-40 ℃, slowly heating to 50 ℃ after dropwise adding, stirring for 6h, tracking the reaction process by TLC, cooling to room temperature after the reaction is finished, filtering the reaction system, washing an organic layer once by using a sodium thiosulfate solution, washing the organic layer for 2 times by using saturated saline, carrying out reduced pressure rotary evaporation to recover the methyl formate, adding 100ml of petroleum ether after the methyl formate is recovered, stirring, cooling, crystallizing, filtering, drying to obtain 24.92g of bicalutamide white solid, wherein the yield is 92.3%.
EXAMPLE III
Adding 200ml of methyl acetate, 21.98g of sodium percarbonate (0.14 mol) and 25.4g of N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -2-methacrylamide (0.10 mol) into a 500ml three-necked bottle, stirring, dropwise adding acetic anhydride (8.16g and 0.08mol) at the temperature of 30-35 ℃, slowly heating to 45 ℃ after dropwise adding, stirring for 8 hours, tracking the reaction process by TLC, cooling to room temperature after the reaction is finished, filtering the reaction system, washing an organic layer once by using a sodium thiosulfate solution, washing the organic layer for 2 times by using saturated saline, carrying out reduced pressure rotary evaporation to recover the methyl acetate, adding 85ml of petroleum ether after the methyl acetate is recovered, stirring, cooling, crystallizing, filtering and drying to obtain 25.2g of bicalutamide white solid with the yield of 93.3%.
Example four
Adding 180ml of ethyl acetate, 20.4g of sodium percarbonate (0.13 mol) and 25.4g of N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -2-methacrylamide (0.10 mol) into a 500ml three-necked bottle, stirring, dropwise adding acetic anhydride (6.12g, 0.06mol) at the temperature of 35-40 ℃, stirring for 8 hours at the temperature of 40-45 ℃ after dropwise adding, tracking the reaction process by TLC, cooling to room temperature after the reaction is finished, filtering the reaction system, washing an organic layer once with a sodium thiosulfate solution, washing 2 times with saturated saline, carrying out reduced pressure rotary evaporation to recover ethyl acetate, adding 100ml of petroleum ether after recovering the ethyl acetate, stirring, cooling, crystallizing, filtering, drying to obtain 24.78g of bicalutamide white solid, wherein the yield is 91.8%.
EXAMPLE five
Adding 200ml of ethyl formate, 21.98g of sodium percarbonate (0.14 mol) and 25.4g of N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -2-methacrylamide (0.10 mol) into a 500ml three-necked bottle, stirring, dropwise adding acetic anhydride (10.2g, 0.10mol) at the temperature of 30-35 ℃, heating to 40-45 ℃ after dropwise adding, stirring for 10 hours, tracking the reaction process by TLC, cooling to room temperature after the reaction is finished, filtering the reaction system, washing an organic layer once by using a sodium thiosulfate solution, washing the organic layer for 2 times by using saturated saline, carrying out reduced pressure rotary evaporation to recover the ethyl formate, adding 100ml of petroleum ether after the ethyl formate is recovered, stirring, cooling, crystallizing, filtering and drying to obtain 25.36g of bicalutamide white solid with the yield of 93.9%.
The fifth embodiment of the present invention shows that the yield of the bicalutamide provided by the present invention can reach more than 91%.
Compared with the prior art, the preparation method of bicalutamide provided by the invention has the advantages of mild reaction conditions, high reaction yield, high epoxidation efficiency and recyclable reaction solvent.
While the foregoing is directed to embodiments of the present invention, it will be understood by those skilled in the art that various changes may be made without departing from the spirit and scope of the invention.
Claims (9)
1. The preparation method of bicalutamide is characterized by comprising the following steps:
dissolving N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -2-methacrylamide in a lower fatty acid ester solvent, sequentially adding sodium percarbonate and acetic anhydride, stirring and heating, and carrying out epoxidation reaction to obtain a reaction liquid;
filtering the reaction solution, washing an organic phase by using a sodium thiosulfate solution, and recovering the solvent under reduced pressure;
adding petroleum ether, cooling, crystallizing, filtering and drying to obtain the bicalutamide.
2. The method according to claim 1, wherein the lower fatty acid ester is an aliphatic ester having 2 to 6 carbon atoms, which is liquid at normal temperature.
3. The method according to claim 2, wherein the lower fatty acid ester is one of methyl formate, ethyl formate, methyl acetate and ethyl acetate.
4. The method according to claim 3, wherein the lower fatty acid ester is ethyl acetate or ethyl formate.
5. The method according to claim 1, wherein the reaction temperature of the epoxidation reaction is 10 to 50 ℃.
6. The method according to claim 5, wherein the reaction temperature of the epoxidation reaction is 35 to 45 ℃.
7. The preparation method according to claim 1, wherein the molar ratio of the N- [ 4-cyano-3- (trifluoromethyl) phenyl ] -2-methacrylamide to the sodium percarbonate is 1 (1.1-1.5).
8. The preparation method according to claim 1, wherein the molar ratio of the sodium percarbonate to the acetic anhydride is 1 (0.3-0.8).
9. The preparation method according to claim 1, wherein the reaction time of the epoxidation reaction is 1 to 12 hours.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011138941.3A CN112159372A (en) | 2020-10-22 | 2020-10-22 | Preparation method of bicalutamide |
| PCT/CN2021/088332 WO2022083082A1 (en) | 2020-10-22 | 2021-04-20 | Method for preparing bicalutamide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011138941.3A CN112159372A (en) | 2020-10-22 | 2020-10-22 | Preparation method of bicalutamide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN112159372A true CN112159372A (en) | 2021-01-01 |
Family
ID=73864575
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011138941.3A Pending CN112159372A (en) | 2020-10-22 | 2020-10-22 | Preparation method of bicalutamide |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN112159372A (en) |
| WO (1) | WO2022083082A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022083082A1 (en) * | 2020-10-22 | 2022-04-28 | 怀化宝华生物科技有限公司 | Method for preparing bicalutamide |
Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030073742A1 (en) * | 2002-10-02 | 2003-04-17 | Synthon B.V. | Process for making bicalutamide and intermediates thereof |
| CN1422853A (en) * | 2002-11-28 | 2003-06-11 | 复旦大学 | Method for preparing epoxy pinane using sodium percarbonate as reagent |
| WO2004039791A1 (en) * | 2002-10-30 | 2004-05-13 | Instytut Farmaceutyczny | A process for the production of n-(4-cyano-3-trifluoromethylphenyl)-2,3-epoxy-2-methylpropanamide |
| US20070027211A1 (en) * | 2005-07-26 | 2007-02-01 | Apotex Pharmachem Inc. | Process for production of bicalutamide |
| CN101003522A (en) * | 2006-11-30 | 2007-07-25 | 上海力智生化科技有限公司 | Method for preparing epoxy myrcene |
| CN101801945A (en) * | 2007-09-26 | 2010-08-11 | 株式会社Adeka | Oxidizing agent composition for epoxidation and oxidation method thereof |
| CN101891663A (en) * | 2010-07-21 | 2010-11-24 | 杭州民生药业有限公司 | Preparation method of bicalutamide intermediate |
| CN102249874A (en) * | 2011-05-26 | 2011-11-23 | 浙江新化化工股份有限公司 | Method for producing hydratropic aldehyde |
| WO2016079521A1 (en) * | 2014-11-20 | 2016-05-26 | University College Cardiff Consultants Limited | Androgen receptor modulators and their use as anti-cancer agents |
| CN106543108A (en) * | 2016-09-29 | 2017-03-29 | 成都丽凯手性技术有限公司 | A kind of industrialized process for preparing of 3 propyIoxirane, 2 carbonyl ring propionic acid amide. |
| CN106905265A (en) * | 2017-03-09 | 2017-06-30 | 常州沃腾化工科技有限公司 | N [4 cyano group 3（Trifluoromethyl）Phenyl] methyl propanamide of 2,3 epoxy 2 preparation method |
| CN109336798A (en) * | 2018-11-19 | 2019-02-15 | 启东华拓药业有限公司 | A kind of preparation method of Bicalutamide sulfide intermediate |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112159372A (en) * | 2020-10-22 | 2021-01-01 | 怀化宝华生物科技有限公司 | Preparation method of bicalutamide |
-
2020
- 2020-10-22 CN CN202011138941.3A patent/CN112159372A/en active Pending
-
2021
- 2021-04-20 WO PCT/CN2021/088332 patent/WO2022083082A1/en active Application Filing
Patent Citations (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030073742A1 (en) * | 2002-10-02 | 2003-04-17 | Synthon B.V. | Process for making bicalutamide and intermediates thereof |
| WO2004039791A1 (en) * | 2002-10-30 | 2004-05-13 | Instytut Farmaceutyczny | A process for the production of n-(4-cyano-3-trifluoromethylphenyl)-2,3-epoxy-2-methylpropanamide |
| CN1422853A (en) * | 2002-11-28 | 2003-06-11 | 复旦大学 | Method for preparing epoxy pinane using sodium percarbonate as reagent |
| US20070027211A1 (en) * | 2005-07-26 | 2007-02-01 | Apotex Pharmachem Inc. | Process for production of bicalutamide |
| CN101003522A (en) * | 2006-11-30 | 2007-07-25 | 上海力智生化科技有限公司 | Method for preparing epoxy myrcene |
| CN101801945A (en) * | 2007-09-26 | 2010-08-11 | 株式会社Adeka | Oxidizing agent composition for epoxidation and oxidation method thereof |
| CN101891663A (en) * | 2010-07-21 | 2010-11-24 | 杭州民生药业有限公司 | Preparation method of bicalutamide intermediate |
| CN102249874A (en) * | 2011-05-26 | 2011-11-23 | 浙江新化化工股份有限公司 | Method for producing hydratropic aldehyde |
| WO2016079521A1 (en) * | 2014-11-20 | 2016-05-26 | University College Cardiff Consultants Limited | Androgen receptor modulators and their use as anti-cancer agents |
| CN106543108A (en) * | 2016-09-29 | 2017-03-29 | 成都丽凯手性技术有限公司 | A kind of industrialized process for preparing of 3 propyIoxirane, 2 carbonyl ring propionic acid amide. |
| CN106905265A (en) * | 2017-03-09 | 2017-06-30 | 常州沃腾化工科技有限公司 | N [4 cyano group 3（Trifluoromethyl）Phenyl] methyl propanamide of 2,3 epoxy 2 preparation method |
| CN109336798A (en) * | 2018-11-19 | 2019-02-15 | 启东华拓药业有限公司 | A kind of preparation method of Bicalutamide sulfide intermediate |
Non-Patent Citations (2)
| Title |
|---|
| BANG-CHI CHEN等: "Nucleophilic Aromatic Substitution of Methacrylamide Anion and Its Application to the Synthesis of the Anticancer Drug Bicalutamide" * |
| HOWARD TUCKER ET AL.: "Nonsteroidal Antiandrogens. Synthesis and Structure-Activity Relationships of 3-Substituted Derivatives of 2-Hydroxypropionanilides" * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022083082A1 (en) * | 2020-10-22 | 2022-04-28 | 怀化宝华生物科技有限公司 | Method for preparing bicalutamide |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2022083082A1 (en) | 2022-04-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP3992186B1 (en) | Safe, environmentally friendly and controllable process for synthesizing diepoxide | |
| CN109232696A (en) | A kind of preparation method of 16a- hydroxy prednisonlone product | |
| CN112159372A (en) | Preparation method of bicalutamide | |
| CN112028799B (en) | Preparation method of 1, 4-dithiothreitol | |
| CN109081861A (en) | A kind of preparation method of 16a- hydroxy prednisonlone | |
| CN109206396B (en) | Preparation method of 2-C-methyl-4,5-O- (1-methylvinyl) -D-arabinonic acid ethyl ester | |
| FR2660923A1 (en) | Reagent and process for the perhaloalkylation of a nucleophile using sulphur dioxide | |
| CN116239508B (en) | Preparation method of aryl thioimine compound | |
| JPS58116435A (en) | Preparation of 4-hydroxy-2,4,6-trimethylcyclohexa-2, 5-dien-1-one | |
| NL2030589B1 (en) | Preparation method of bicalutamide | |
| JP3836518B2 (en) | Method for producing 3-mercaptopropionitrile and 3-mercaptopropionic acid | |
| CN101817768B (en) | New process of preparing bicalutamide by utilizing air for oxidizing bicalutamide thioether intermediate | |
| CN109336798B (en) | Preparation method of bicalutamide thioether intermediate | |
| EP0020281B1 (en) | Preparation of benzoxazolone | |
| CN114957056A (en) | Process for preparing methyl 3-methyl-2-chloro-4-methylsulfonylbenzoate and intermediates thereof | |
| CN106316824A (en) | Novel 2-fluorocyclopropane carboxylic acid synthesis method | |
| CN112250600A (en) | Process method for improving yield of N, N' -diisopropylcarbodiimide product | |
| JP2005089329A (en) | 2-Adamantanone production method | |
| CN109320442B (en) | Method for synthesizing bicalutamide | |
| CN113880759B (en) | Preparation method of boscalid | |
| Ballini et al. | A New Modulated Oxidative Ring Cleavage of α-Nitrocycloalkanones by Oxone®: Synthesis of α, ω-Dicarboxylic Acids and α, ω-Dicarboxylic Acid Monomethyl Esters | |
| JPS6160822B2 (en) | ||
| CN110172041B (en) | Novel method for synthesizing hexazinone | |
| CN109384685A (en) | A kind of preparation method of amino-acid ester | |
| CN115385855B (en) | Method for preparing quinclorac by two-step oxidation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |