CN115703745A - Preparation method of enzalutamide - Google Patents
Preparation method of enzalutamide Download PDFInfo
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- CN115703745A CN115703745A CN202110915110.0A CN202110915110A CN115703745A CN 115703745 A CN115703745 A CN 115703745A CN 202110915110 A CN202110915110 A CN 202110915110A CN 115703745 A CN115703745 A CN 115703745A
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- carbonyl
- methylamino
- methylalanine
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- WXCXUHSOUPDCQV-UHFFFAOYSA-N enzalutamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1N1C(C)(C)C(=O)N(C=2C=C(C(C#N)=CC=2)C(F)(F)F)C1=S WXCXUHSOUPDCQV-UHFFFAOYSA-N 0.000 title claims abstract description 41
- 229960004671 enzalutamide Drugs 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- -1 alcohol compound Chemical class 0.000 claims abstract description 40
- 238000000034 method Methods 0.000 claims abstract description 39
- IAAHEGARPMZSTJ-UHFFFAOYSA-N 2-[3-fluoro-4-(methylcarbamoyl)anilino]-2-methylpropanoic acid Chemical compound CNC(=O)C1=CC=C(NC(C)(C)C(O)=O)C=C1F IAAHEGARPMZSTJ-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000003960 organic solvent Substances 0.000 claims abstract description 29
- TYXKOMAQTWRDCR-UHFFFAOYSA-N 4-isothiocyanato-2-(trifluoromethyl)benzonitrile Chemical compound FC(F)(F)C1=CC(N=C=S)=CC=C1C#N TYXKOMAQTWRDCR-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000002425 crystallisation Methods 0.000 claims abstract description 25
- 230000008025 crystallization Effects 0.000 claims abstract description 25
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000002994 raw material Substances 0.000 claims abstract description 20
- 238000005406 washing Methods 0.000 claims abstract description 17
- 238000001914 filtration Methods 0.000 claims abstract description 13
- 238000001035 drying Methods 0.000 claims abstract description 7
- 239000003513 alkali Substances 0.000 claims abstract description 6
- 239000007858 starting material Substances 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 97
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 53
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 46
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 30
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 21
- 229940011051 isopropyl acetate Drugs 0.000 claims description 21
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 21
- 239000008367 deionised water Substances 0.000 claims description 16
- 229910021641 deionized water Inorganic materials 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 13
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 13
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 9
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 6
- VOGSDFLJZPNWHY-UHFFFAOYSA-N 2,2-difluoroethanol Chemical compound OCC(F)F VOGSDFLJZPNWHY-UHFFFAOYSA-N 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 4
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 4
- 239000001095 magnesium carbonate Substances 0.000 claims description 4
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 230000036541 health Effects 0.000 abstract description 5
- 230000009286 beneficial effect Effects 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 239000000047 product Substances 0.000 description 32
- 238000001514 detection method Methods 0.000 description 24
- 150000001875 compounds Chemical class 0.000 description 22
- 229940125898 compound 5 Drugs 0.000 description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 13
- 229910052739 hydrogen Inorganic materials 0.000 description 13
- 239000001257 hydrogen Substances 0.000 description 13
- 238000001228 spectrum Methods 0.000 description 11
- 229940126214 compound 3 Drugs 0.000 description 10
- 239000012265 solid product Substances 0.000 description 8
- 238000001816 cooling Methods 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- 239000012065 filter cake Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 238000001291 vacuum drying Methods 0.000 description 7
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 5
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 3
- FOZVXADQAHVUSV-UHFFFAOYSA-N 1-bromo-2-(2-bromoethoxy)ethane Chemical compound BrCCOCCBr FOZVXADQAHVUSV-UHFFFAOYSA-N 0.000 description 3
- 230000003321 amplification Effects 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 229940125797 compound 12 Drugs 0.000 description 3
- 238000003199 nucleic acid amplification method Methods 0.000 description 3
- 238000011895 specific detection Methods 0.000 description 3
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- FUOOLUPWFVMBKG-UHFFFAOYSA-N 2-Aminoisobutyric acid Chemical compound CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 231100000086 high toxicity Toxicity 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000004611 spectroscopical analysis Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- ZQQSRVPOAHYHEL-UHFFFAOYSA-N 4-bromo-2-fluorobenzoic acid Chemical compound OC(=O)C1=CC=C(Br)C=C1F ZQQSRVPOAHYHEL-UHFFFAOYSA-N 0.000 description 1
- 229940123407 Androgen receptor antagonist Drugs 0.000 description 1
- 206010007269 Carcinogenicity Diseases 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000003936 androgen receptor antagonist Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 231100000260 carcinogenicity Toxicity 0.000 description 1
- 230000007670 carcinogenicity Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000009982 effect on human Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- HMZHEECHJWHZJX-UHFFFAOYSA-N methyl 2-amino-2-methylpropanoate Chemical compound COC(=O)C(C)(C)N HMZHEECHJWHZJX-UHFFFAOYSA-N 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
Abstract
The invention relates to a preparation method of enzalutamide, belonging to the technical field of medicine preparation. The method comprises the steps of taking N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine as a starting material, reacting at room temperature in the presence of an organic solvent and N, N-carbonyldiimidazole, reacting with an alcohol compound in the presence of alkali, and crystallizing, filtering, washing and drying to obtain a lipid compound; lipid compounds and 4-isothiocyanato-2- (trifluoromethyl) benzonitrile are mixed in an organic solvent, stirred and heated to react, and the enzalutamide is prepared after concentration, crystallization, filtration, washing and drying. The method can reduce the safety and occupational health risks and is beneficial to large-scale production; the consumption of the raw material 4-isothiocyanato-2- (trifluoromethyl) benzonitrile can also be reduced, thereby reducing the cost.
Description
Technical Field
The invention relates to a preparation method of enzalutamide, belonging to the technical field of medicine preparation.
Background
Enzalutamide is a novel nonsteroidal androgen receptor antagonist for the treatment of prostate cancer, developed by both anslatate and Medivation under the trade name xtani. Enzalutamide is approved by the U.S. Food and Drug Administration (FDA) for marketing at day 31/8 of 2012 for the treatment of prostate cancer. Enzalutamide has the chemical formula of 4- [3- [ 4-cyano-3- (trifluoromethyl) phenyl ] -5, 5-dimethyl-4-oxo-2-thione-1-imidazolidinyl ] -2-fluoro-N-methylbenzamide, and the molecular structural formula is as follows:
at present, the preparation methods of enzalutamide have been reported mainly as follows:
1) Patent WO2011106570 reports a process for the preparation of enzalutamide. The chemical reaction equation of the method is as follows:
wherein, 4-bromo-2-fluorobenzoic acid (compound 1 in the chemical reaction equation) and thionyl chloride (SOCl) are respectively 2 ) And methylamine (MeNH) 2 ) 4-bromo-2-fluoro-N-methylbenzoic acid (compound 2 in the chemical reaction equation) is prepared by reaction; reacting 4-bromo-2-fluoro-N-methylbenzoic acid with 2-methylalanine under the catalysis of CuI to prepare N- [ 3-fluoro-4- [ (methylamino) carbonyl]Phenyl radical]-2-methylalanine (compound 3 in the chemical reaction equation); n- [ 3-fluoro-4- [ (methylamino) carbonyl ] carbonyl]Phenyl radical]Reaction of (E) -2-methylalanine with iodomethane (MeI) to produce N- [ 3-fluoro-4- [ (methylamino) carbonyl]Phenyl radical]-methyl 2-methylalaninate (compound 4 in the chemical reaction equation); n- [ 3-fluoro-4- [ (methylamino) carbonyl]Phenyl radical]The enzalutamide is prepared by reacting methyl-2-methylalaninate and 4-isothiocyanatoyl-2- (trifluoromethyl) benzonitrile (compound 5 in a chemical reaction equation) with the molar ratio of 2. The biggest problem of the method is that methyl iodide which is a chemical substance with carcinogenicity and neurotoxicity is used in the synthesis process, and is not beneficial to safe production.
2) In order to overcome the defects in patent WO2011106570, patent CN110396063 reports a preparation method of enzalutamide. The chemical reaction equation of the method is as follows:
the method comprises the following steps of using N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine (a compound 3 in a chemical reaction equation) as a starting material, using 2-bromoethyl ether or p-methoxybenzyl chloride to replace methyl iodide for esterification to prepare a compound 11 in the chemical reaction equation, and reacting the compound 11 with 4-isothiocyanato-2- (trifluoromethyl) benzonitrile (a compound 5 in the chemical reaction equation) to prepare enzalutamide. In the method, 2-bromoethyl ether is extremely inflammable (flash point is 70 degrees F), and the p-methoxybenzyl chloride has strong stimulation effect on human mucosa and respiratory tract, so that certain safety and occupational health risks exist in scale-up production; the mol ratio of the raw material 4-isothiocyanato-2- (trifluoromethyl) benzonitrile (compound 5 in the chemical reaction equation) to the compound 11 is 2.1-2.2, and the compound 5 has high production cost due to high market price.
3) CN107690427 reports a preparation method of enzalutamide, the chemical reaction equation of the method is as follows:
wherein N- [ 3-fluoro-4- [ (methylamino) carbonyl group]Phenyl radical]2-methyl alanine (compound 3 in the chemical reaction equation) is used as a starting material and is firstly reacted with ethylamine (EtNH) under the action of 1-ethyl-3 (3-dimethylpropylamine) carbodiimide (EDCI) and 1-hydroxybenzotriazole (HOBt) 2 ) The amide compound 12 is prepared by reaction in a solvent DMF, and the enzalutamide is prepared by reaction of the amide compound 12 and 4-isothiocyanato-2- (trifluoromethyl) benzonitrile (compound 5 in the chemical reaction equation). In the method, a high-toxicity and volatile ethylamine raw material is needed, which is not beneficial to the amplification production; prepared enzalutamideThe yield was 47.3%, relatively low; the molar ratio of the raw material 4-isothiocyanato-2- (trifluoromethyl) benzonitrile (compound 5 in the chemical reaction equation) to the compound 12 is 2.2-5.4, which is relatively high and the use amount is large, and the market price of the 4-isothiocyanato-2- (trifluoromethyl) benzonitrile (compound 5) is expensive, so that the production cost is high.
Disclosure of Invention
In order to solve the problems of high safety, occupational health risk, high production cost and the like existing in the preparation method of enzalutamide in the prior art, the invention aims to provide the preparation method of the enzalutamide, the method can reduce the safety and occupational health risk, and is favorable for large-scale production; meanwhile, the method can reduce the consumption of the raw material 4-isothiocyanato-2- (trifluoromethyl) benzonitrile, thereby reducing the production cost.
In order to achieve the purpose of the invention, the following technical scheme is provided.
A preparation method of enzalutamide comprises the following steps:
(1) N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine (compound 3 in a chemical reaction equation) is used as a starting material, the reaction is carried out for 1h to 2h at room temperature in the presence of an organic solvent and N, N-Carbonyldiimidazole (CDI), then the reaction is carried out for 4h to 10h with an alcohol compound (ROH in the chemical reaction equation) at the temperature of 20 ℃ to 60 ℃ in the presence of alkali, and then the lipid compound (compound II in the chemical reaction equation) is prepared after crystallization, filtration, washing and drying.
(2) Lipid compounds and 4-isothiocyanato-2- (trifluoromethyl) benzonitrile (compound 5 in the chemical reaction equation) are mixed in an organic solvent, stirred and heated for reaction for 10-20 h at the temperature of 75-95 ℃, and the enzalutamide (compound I in the chemical reaction equation) is prepared by concentration, crystallization, filtration, washing and drying.
The chemical equation of the method is as follows:
in the step (1):
the organic solvent is N, N-dimethylformamide, N-dimethylacetamide, acetonitrile or tetrahydrofuran, and preferably is N, N-dimethylformamide or N, N-dimethylacetamide.
Preferably, the mass ratio of the volume of the organic solvent to the reaction raw material N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine is 2 mL-10mL, and more preferably is 4 mL.
Preferably the molar ratio of N, N-Carbonyldiimidazole (CDI) to N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine is 1 to 2, more preferably 1.2.
The alcohol compound is 2, 2-trifluoroethanol or 2, 2-difluoroethanol.
Preferably, the molar ratio of the alcohol compound to N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine is 1 to 5, preferably 1.9.
Preferably, the base is potassium carbonate, calcium carbonate, sodium carbonate, magnesium carbonate, N-diisopropylethylamine, N-methylmorpholine, triethylamine or pyridine, more preferably, the base is pyridine.
Preferably, the molar ratio of the base to N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine is from 1 to 5, more preferably 2.
The crystallization is a process of adding water to separate out lipid compound crystals after the reaction is finished.
The volume ratio of water to organic solvent in the crystallization is preferably 1 to 10, more preferably 3 to 5.
The water in the crystallization is preferably water with a purity higher than that of deionized water.
In the step (2):
preferably, the molar ratio of 4-isothiocyanato-2- (trifluoromethyl) benzonitrile to the lipid compound is 1.6 to 1.9, more preferably 1.6.
The organic solvent is a mixture of dimethyl sulfoxide and ethyl acetate, a mixture of dimethyl sulfoxide and isopropyl acetate, a mixture of N, N-dimethylformamide and ethyl acetate or a mixture of N, N-dimethylformamide and isopropyl acetate; preferably a mixture of dimethyl sulfoxide and isopropyl acetate; the volume ratio of isopropyl acetate to dimethyl sulfoxide is preferably 1-7.
The concentration crystallization is that after the reaction is finished, the organic solvent is removed under reduced pressure, isopropanol is added, the temperature is raised to 75-90 ℃, and then the temperature is lowered for crystallization; the ratio of the volume of the isopropanol to the lipid compound mass is 3 mL-10mL, and is preferably 6 mL-7mL.
Advantageous effects
1. The invention provides a preparation method of enzalutamide, high-toxicity chemical raw materials such as methyl iodide and ethanolamine, extremely flammable raw materials such as 2-bromoethyl ether and the like which are not beneficial to amplification production are not used in the preparation process, and 2, 2-trifluoroethanol and 2, 2-difluoroethanol which are relatively low in toxicity and relatively high in safety are used, so that the safety and occupational health risks are reduced, and the amplification production is facilitated.
2. The invention provides a preparation method of enzalutamide, which adopts cheap and easily-obtained N, N-carbonyl diimidazole as a condensing agent, so that a brand new lipid compound can be simply and conveniently prepared, and the enzalutamide can be efficiently prepared; the method has the advantages that the nucleophilicity of the byproduct 2, 2-trifluoroethanol or 2, 2-difluoroethanol is weaker in the reaction process of the lipid compound and the 4-isothiocyanato-2- (trifluoromethyl) benzonitrile, the side reaction with the 4-isothiocyanato-2- (trifluoromethyl) benzonitrile can be effectively reduced by the characteristic, and the usage amount of the required high-valence raw material 4-isothiocyanato-2- (trifluoromethyl) benzonitrile is finally reduced. Through calculation, 1kg of enzalutamide is produced, 1.19 kg-2.28 kg of 4-isothiocyanato-2- (trifluoromethyl) benzonitrile required by the prior art is produced, and 0.98kg of the invention is produced; meanwhile, in the process of producing the 4-isothiocyanato-2- (trifluoromethyl) benzonitrile, thiophosgene which is a highly toxic substance is needed to be used, the usage amount of the 4-isothiocyanato-2- (trifluoromethyl) benzonitrile is reduced, the safety and environmental protection pressure can be further reduced, and the large-scale production is facilitated.
Detailed Description
The invention will be described in more detail with reference to specific examples, which should not be construed as limiting the scope of the invention.
In order that the technical features and contents of the present invention can be understood in detail, preferred embodiments of the present invention will be described in more detail below. While the preferred embodiments of the present invention have been described in the examples, it should be understood that the present invention may be embodied in various forms and should not be limited by the embodiments set forth herein.
Example 1
10.0g (39.3 mmol) of N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine (compound 3 in the chemical reaction equation), 8.0g (49.3 mmol) of N, N-Carbonyldiimidazole (CDI) and 40mL of N, N-dimethylformamide as raw materials were taken in a reaction flask, stirred at room temperature for 1.5h, then 6.4g (80.9 mmol) of pyridine and 7.5g (74.9 mmol) of 2, 2-trifluoroethanol were added, reacted at 25 ℃ for 10h, 160mL of deionized water was poured into the reaction solution, crystals were precipitated, filtered, washed 3 times with deionized water, 20mL each time, and dried under vacuum at 60 ℃ to obtain 12.2g of the product in 92% yield.
The chemical reaction equation of the method is as follows:
and (3) performing nuclear magnetic hydrogen spectrum detection on the product, wherein the detection result proves that the product is a lipid compound as shown by a compound II-a in a chemical reaction equation. The specific detection result data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ7.69–7.62(m,1H),7.46(t,J=8.9Hz,1H), 6.88(s,1H),6.31(dd,J=8.7,2.3Hz,1H),6.14(dd,J=14.5,2.3Hz,1H),4.81(q,J =9.0Hz,2H),2.73(d,J=4.5Hz,3H),1.52(s,6H);HRMS(ESI)Calcd for C14H16F4N2O5Na[M+Na] + 359.0989,found:359.0986.
example 2
10.0g (39.3 mmol) of N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine (compound 3 in the chemical reaction equation), 12.7g (78.3 mmol) of N, N-Carbonyldiimidazole (CDI) and 40mL of N, N-dimethylformamide as raw materials are taken in a reaction bottle, stirred for 1.5h at room temperature, then 15.5g (196.0 mmol) of pyridine and 19.6g (195.9 mmol) of 2, 2-trifluoroethanol are added, reaction is carried out for 10h at 25 ℃, 160mL of deionized water is poured into the reaction liquid, crystals are separated out, the reaction liquid is filtered, washed with deionized water for 3 times, 20mL each time, and dried in vacuum at 60 ℃ to obtain 11.9g of the product, and the yield is 90%.
The chemical reaction equation of the method is as follows:
the product was subjected to nuclear magnetic hydrogen spectroscopy, and the results of the detection were the same as those in example 1, demonstrating that the product structure is represented by compound II-a in the chemical reaction equation, which is a lipid compound.
Example 3
10.0g (39.3 mmol) of N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine (compound 3 in the chemical reaction equation), 8.0g (49.3 mmol) of N, N-Carbonyldiimidazole (CDI) and 40mL of N, N-dimethylformamide as raw materials were taken in a reaction flask, stirred at room temperature for 1.5h, then 6.4g (80.9 mmol) of pyridine and 7.5g (74.9 mmol) of 2, 2-trifluoroethanol were added, the temperature was raised to 60 ℃ and reacted for 4h, 160mL of deionized water was poured into the reaction solution, crystals were precipitated, filtered, washed with deionized water 3 times, each time at 20mL, and vacuum-dried at 60 ℃ to obtain 12.7g of a product in 96% yield.
The chemical reaction equation of the method is as follows:
the nuclear magnetic hydrogen spectrum detection is carried out on the product, and the detection result is the same as that in example 1, which proves that the product structure is shown as a compound II-a in a chemical reaction equation and is a lipid compound.
Example 4
10.0g (39.3 mmol) of N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine (compound 3 in the chemical reaction equation), 8.0g (49.3 mmol) of N, N-Carbonyldiimidazole (CDI) and 40mL of N, N-dimethylformamide as raw materials were taken in a reaction flask, stirred at room temperature for 1.5h, then 6.4g (80.9 mmol) of pyridine and 7.5g (74.9 mmol) of 2, 2-trifluoroethanol were added, the temperature was raised to 60 ℃ and reacted for 4h, 120mL of deionized water was poured into the reaction solution to precipitate crystals, which were filtered, washed with deionized water 3 times, each time with 20mL, and vacuum-dried at 60 ℃ to obtain 11.5g of a product with a yield of 87%.
The chemical reaction equation of the method is as follows:
the nuclear magnetic hydrogen spectrum detection is carried out on the product, and the detection result is the same as that in example 1, which proves that the product structure is shown as a compound II-a in a chemical reaction equation and is a lipid compound.
Example 5
10.0g (39.3 mmol) of N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine (compound 3 in the chemical reaction equation), 8.0g (49.3 mmol) of N, N-Carbonyldiimidazole (CDI) and 40mL of N, N-dimethylformamide are taken as raw materials, the raw materials are stirred for 1.5h at room temperature, 6.4g (80.9 mmol) of pyridine and 7.5g (74.9 mmol) of 2, 2-trifluoroethanol are added, the temperature is increased to 60 ℃ for reaction for 4h, 200mL of deionized water is poured into the reaction liquid, crystals are separated out, the mixture is filtered, washed 3 times with deionized water, each time, 20mL is added, and vacuum drying is carried out at 60 ℃ to obtain 12.8g of the product, and the yield is 97%.
The chemical reaction equation of the method is as follows:
the product was subjected to nuclear magnetic hydrogen spectroscopy, and the results of the detection were the same as those in example 1, demonstrating that the product structure is represented by compound II-a in the chemical reaction equation, which is a lipid compound.
Example 6
10.0g (39.3 mmol) of N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine (compound 3 in the chemical reaction equation), 8.0g (49.3 mmol) of N, N-Carbonyldiimidazole (CDI) and 40mL of N, N-dimethylformamide as raw materials were taken in a reaction flask, stirred at room temperature for 1.5h, then 6.4g (80.9 mmol) of pyridine and 6.2g (75.6 mmol) of 2, 2-difluoroethanol were added, the temperature was raised to 60 ℃ for reaction for 4h, 160mL of deionized water was poured into the reaction solution, crystals were precipitated, filtered, washed with deionized water 3 times, each time at 20mL, and dried under vacuum at 60 ℃ to obtain 11.8g of a product in a yield of 94%.
The chemical reaction equation of the method is as follows:
and (3) performing nuclear magnetic hydrogen spectrum detection on the product, wherein the detection result proves that the product is a lipid compound as shown by a compound II-b in a chemical reaction equation. The specific detection result data are as follows:
1 H NMR(400MHz,Chloroform-d)δ7.90(t,J=9.0Hz,1H),6.57(d,J=12.0 Hz,1H),6.36(dd,J=8.7,2.4Hz,1H),6.16(dd,J=14.9,2.4Hz,1H),5.84(tt,J=54.9,3.9Hz,1H),4.55(s,1H),4.31(td,J=13.6,4.0Hz,2H),2.98(dd,J=4.8,1.2 Hz,3H),1.62(s,6H).HRMS(ESI)Calcd for C14H17F3N2O5Na[M+Na] + 341.1083,found:341.1081.
example 7
4.0g (11.9 mmol) of the compound II-a prepared in the example, 5.1g (22.3 mmol) of 4-isothiocyanato-2- (trifluoromethyl) benzonitrile (compound 5 in the chemical reaction equation), 6mL of isopropyl acetate and 3mL of dimethyl sulfoxide are mixed, heated to 85 ℃, stirred and heated for reaction for 14h; concentrating under reduced pressure to remove most of organic solvent, adding 25mL of isopropanol, stirring at 85 ℃ for 2h, cooling to 5 ℃ for crystallization, filtering, washing the filter cake with isopropanol 3 times, wherein the washing amount is 10mL each time, and vacuum-drying at 60 ℃ for 8h to obtain 4.6g of white solid product, wherein the yield is 83%.
The chemical reaction equation of the method is as follows:
and (3) performing nuclear magnetic hydrogen spectrum detection on the product, wherein the detection result proves that the product is enzalutamide with the structure shown as a compound I in a chemical reaction equation. The specific detection result data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.46(br,1H),8.42-8.40(d,J=8.0Hz,1H), 8.29(s,1H),8.10-8.08(d,J=8.0Hz,1H),7.81-7.76(t,J=8.0Hz,1H),7.46-7.42 (dd,J=8.4Hz,J=1.6Hz,1H),7.35-7.31(dd,J=8.4Hz,J=1.6Hz,1H),2.81-2.78 (d,J=8.0Hz,1H),1.54(s,6H)。
example 8
4.0g (11.9 mmol) of the compound II-a prepared in the above example, 4.4g (19.3 mmol) of 4-isothiocyanato-2- (trifluoromethyl) benzonitrile (compound 5 in the chemical reaction equation), 6mL of isopropyl acetate (IPAc) and 3mL of dimethyl sulfoxide (DMSO) were mixed, heated to 85 ℃ and stirred for 14 hours of reaction; concentrating under reduced pressure to remove most of solvent, adding isopropanol 25mL, stirring at 85 deg.C for 2h, cooling to 5 deg.C for crystallization, filtering, washing the filter cake with isopropanol 3 times, each time at 10mL, and vacuum drying at 60 deg.C for 8h to obtain white solid product 4.5g with 82% yield.
The chemical reaction equation of the method is as follows:
the nuclear magnetic hydrogen spectrum detection is carried out on the product, and the detection result is the same as that in example 7, which proves that the product structure is shown as a compound I in a chemical reaction equation and is enzalutamide.
Example 9
4.0g (11.9 mmol) of the compound II-a prepared in the above example, 4.4g (19.3 mmol) of 4-isothiocyanato-2- (trifluoromethyl) benzonitrile (compound 5 in the chemical reaction equation), 6mL of Ethyl Acetate (EA) and 3mL of dimethyl sulfoxide (DMSO) are mixed, heated to 75 ℃, stirred and heated for reaction for 14h; concentrating under reduced pressure to remove most of the solvent, adding 25mL of isopropanol, stirring at 85 ℃ for 2h, cooling to 5 ℃ for crystallization, filtering, washing the filter cake with isopropanol 3 times, wherein the washing amount is 10mL each time, and vacuum-drying at 60 ℃ for 8h to obtain 3.9g of white solid product, wherein the yield is 71%.
The chemical reaction equation of the method is as follows:
the nuclear magnetic hydrogen spectrum detection is carried out on the product, and the detection result is the same as that in example 7, which proves that the product structure is shown as a compound I in a chemical reaction equation and is enzalutamide.
Example 10
4.0g (11.9 mmol) of the compound II-a prepared in the above example, 4.4g (19.3 mmol) of 4-isothiocyanato-2- (trifluoromethyl) benzonitrile (compound 5 in the chemical reaction equation), 6mL of Ethyl Acetate (EA) and 3mL of N, N-Dimethylformamide (DMF) are mixed, heated to 75 ℃, stirred and heated for reaction for 14h; concentrating under reduced pressure to remove most of solvent, adding isopropanol 25mL, stirring at 85 deg.C for 2h, cooling to 5 deg.C for crystallization, filtering, washing the filter cake with isopropanol 3 times, each time at 10mL, and vacuum drying at 60 deg.C for 8h to obtain white solid product 2.8g with yield of 51%.
The chemical reaction equation of the method is as follows:
the nuclear magnetic hydrogen spectrum detection is carried out on the product, and the detection result is the same as that in example 7, which proves that the product structure is shown as a compound I in a chemical reaction equation and is enzalutamide.
Example 11
4.0g (11.9 mmol) of the compound II-a prepared in the above example, 4.4g (19.3 mmol) of 4-isothiocyanato-2- (trifluoromethyl) benzonitrile (compound 5 in the chemical reaction equation), 6mL of isopropyl acetate (IPAc) and 1mL of dimethyl sulfoxide (DMSO) are mixed, heated to 85 ℃, stirred and heated for reaction for 14h; concentrating under reduced pressure to remove most of the solvent, adding 25mL of isopropanol, stirring at 85 ℃ for 2h, cooling to 5 ℃ for crystallization, filtering, washing the filter cake with isopropanol 3 times, wherein the washing amount is 10mL each time, and vacuum-drying at 60 ℃ for 8h to obtain 3.2g of white solid product, wherein the yield is 58%.
The chemical reaction equation of the method is as follows:
the nuclear magnetic hydrogen spectrum detection is carried out on the product, and the detection result is the same as that in example 7, which proves that the product structure is shown as a compound I in a chemical reaction equation and is enzalutamide.
Example 12
Taking 3.8g (11.9 mmol) of the lipid compound prepared in example 6 (compound II-b in the chemical reaction equation), 5.0g (21.9 mmol) of 4-isothiocyanato-2- (trifluoromethyl) benzonitrile (compound 5 in the chemical reaction equation), 6mL of isopropyl acetate (IPAc) and 3mL of dimethyl sulfoxide (DMSO), mixing, heating to 85 ℃, stirring and heating for reaction for 14h; concentrating under reduced pressure to remove most of solvent, adding isopropanol 25mL, stirring at 85 deg.C for 2h, cooling to 5 deg.C for crystallization, filtering, washing the filter cake with isopropanol 3 times, each time at 10mL, and vacuum drying at 60 deg.C for 8h to obtain white solid product 4.5g with 82% yield.
The chemical reaction equation of the method is as follows:
the nuclear magnetic hydrogen spectrum detection is carried out on the product, and the detection result is the same as that in example 7, which proves that the product structure is shown as a compound I in a chemical reaction equation and is enzalutamide.
Example 13
Taking 3.8g (11.9 mmol) of the lipid compound prepared in the example 6 (the compound II-b in the chemical reaction equation), 4.4g (19.3 mmol) of 4-isothiocyanato-2- (trifluoromethyl) benzonitrile (the compound 5 in the chemical reaction equation), 6mL of isopropyl acetate (IPAc) and 3mL of dimethyl sulfoxide (DMSO), mixing, heating to 85 ℃, stirring and heating for reaction for 14h; concentrating under reduced pressure to remove most of the solvent, adding 25mL of isopropanol, stirring at 85 ℃ for 2h, cooling to 5 ℃ for crystallization, filtering, washing the filter cake with isopropanol 3 times, wherein the washing amount is 10mL each time, and drying at 60 ℃ for 8h in vacuum to obtain a white solid product, namely 4.4g of the white solid product, wherein the yield is 79%.
The chemical reaction equation of the method is as follows:
the nuclear magnetic hydrogen spectrum detection is carried out on the product, and the detection result is the same as that in example 7, which proves that the product structure is shown as a compound I in a chemical reaction equation and is enzalutamide.
While embodiments of the present invention have been described above, the above description is illustrative, not exhaustive, and not limited to the disclosed embodiments. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments.
Claims (10)
1. The preparation method of enzalutamide is characterized by comprising the following steps: the method comprises the following steps:
(1) Taking N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine as a starting material, reacting for 1-2 h at room temperature in the presence of an organic solvent and N, N-carbonyldiimidazole, then reacting with an alcohol compound for 4-10 h at 20-60 ℃ in the presence of alkali, and then crystallizing, filtering, washing and drying to obtain a lipid compound;
(2) Mixing a lipid compound and 4-isothiocyanato-2- (trifluoromethyl) benzonitrile in an organic solvent, stirring and heating for reaction for 10-20 h at 75-95 ℃, and performing concentration crystallization, filtration, washing and drying to prepare enzalutamide;
in the step (1):
the organic solvent is N, N-dimethylformamide, N-dimethylacetamide, acetonitrile or tetrahydrofuran;
the alcohol compound is 2, 2-trifluoroethanol or 2, 2-difluoroethanol;
in the step (2):
the organic solvent is a mixture of dimethyl sulfoxide and ethyl acetate, a mixture of dimethyl sulfoxide and isopropyl acetate, a mixture of N, N-dimethylformamide and ethyl acetate or a mixture of N, N-dimethylformamide and isopropyl acetate.
2. The method for preparing enzalutamide according to claim 1, characterized in that:
in the step (1):
the organic solvent is N, N-dimethylformamide or N, N-dimethylacetamide;
the alkali is potassium carbonate, calcium carbonate, sodium carbonate, magnesium carbonate, N-diisopropylethylamine, N-methylmorpholine, triethylamine or pyridine;
the water in the crystallization is water with the purity higher than that of deionized water;
in the step (2):
the organic solvent is a mixture of dimethyl sulfoxide and isopropyl acetate.
3. The method of claim 2, wherein the step of preparing enzalutamide comprises:
in the step (1): the base is pyridine.
4. The method for preparing enzalutamide according to claim 1, characterized in that:
in the step (1):
the mass ratio of the volume of the organic solvent to the reaction raw material N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine is 2 mL-10mL;
the molar ratio of N, N-carbonyldiimidazole to N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine is 1-2;
the mol ratio of the alcohol compound to N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine is 1-5;
the molar ratio of the base to N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine is 1-5;
the volume ratio of water to the organic solvent in crystallization is 1-10;
in the step (2):
the mol ratio of the 4-isothiocyanato-2- (trifluoromethyl) benzonitrile to the lipid compound is 1.6-1.9;
the volume ratio of the isopropyl acetate to the dimethyl sulfoxide is 1-7.
5. The method of claim 4, wherein the step of preparing enzalutamide comprises:
in the step (1):
the mass ratio of the volume of the organic solvent to the reaction raw material N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine is 4 mL;
the molar ratio of N, N-carbonyldiimidazole to N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine is 1.2;
the molar ratio of the alcohol compound to the N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine is 1.9;
the molar ratio of the base to N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine is 2;
the volume ratio of water to the organic solvent in crystallization is 3-5;
in the step (2):
the molar ratio of 4-isothiocyanato-2- (trifluoromethyl) benzonitrile to lipid compound was 1.6.
6. The method of claim 1, wherein the step of preparing enzalutamide comprises:
in the step (1):
the organic solvent is N, N-dimethylformamide or N, N-dimethylacetamide;
the alkali is potassium carbonate, calcium carbonate, sodium carbonate, magnesium carbonate, N-diisopropylethylamine, N-methylmorpholine, triethylamine or pyridine;
the water in the crystallization is water with the purity higher than that of deionized water;
the mass ratio of the volume of the organic solvent to the reaction raw material N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine is 2 mL-10mL;
the molar ratio of N, N-carbonyldiimidazole to N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine is 1-2;
the molar ratio of the alcohol compound to the N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine is 1-5;
the molar ratio of the base to N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine is 1-5;
the volume ratio of water to the organic solvent in crystallization is 1-10;
in the step (2):
the organic solvent is a mixture of dimethyl sulfoxide and isopropyl acetate;
the mol ratio of the 4-isothiocyanato-2- (trifluoromethyl) benzonitrile to the lipid compound is 1.6-1.9;
the volume ratio of the isopropyl acetate to the dimethyl sulfoxide is 1-7.
7. The method of claim 1, wherein the step of preparing enzalutamide comprises:
in the step (1):
the organic solvent is N, N-dimethylformamide or N, N-dimethylacetamide;
the alkali is potassium carbonate, calcium carbonate, sodium carbonate, magnesium carbonate, N-diisopropylethylamine, N-methylmorpholine, triethylamine or pyridine;
the water in the crystallization is water with the purity higher than that of deionized water;
the mass ratio of the volume of the organic solvent to the reaction raw material N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine is 4 mL;
the molar ratio of N, N-carbonyldiimidazole to N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine is 1.2;
the molar ratio of the alcohol compound to N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine is 1.9;
the molar ratio of the base to N- [ 3-fluoro-4- [ (methylamino) carbonyl ] phenyl ] -2-methylalanine is 2;
the volume ratio of water to the organic solvent in crystallization is 3-5;
in the step (2):
the organic solvent is a mixture of dimethyl sulfoxide and isopropyl acetate;
the molar ratio of 4-isothiocyanato-2- (trifluoromethyl) benzonitrile to lipid compound is 1.6;
the volume ratio of the isopropyl acetate to the dimethyl sulfoxide is 1-7.
8. The method of claim 7, wherein the step of preparing enzalutamide comprises:
in the step (1): the base is pyridine.
9. The process for preparing enzalutamide according to any one of claims 1 to 8, wherein: in the step (2): the concentration crystallization is that after the reaction is finished, the organic solvent is removed under reduced pressure, isopropanol is added, the temperature is raised to 75-90 ℃, and then the temperature is lowered for crystallization; the ratio of the volume of the isopropanol to the lipid compound mass is 3 mL-10mL.
10. The method of claim 9, wherein the step of preparing enzalutamide comprises: in the step (2): the ratio of the volume of the isopropanol to the lipid compound mass is 6 mL-7mL.
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