阅读说明：本技术 一种***癌药物恩杂鲁胺的制备工艺 (Preparation process of prostate cancer drug enzalutamide ) 是由 刘素云 李项 于 2018-09-04 设计创作，主要内容包括：本发明提供一种前列腺癌药物恩杂鲁胺的制备工艺,以N-甲基-4-溴-2-氟-苯甲酰胺为原料,与2-氨基异丁酸在碱性条件下,经催化发生亲核取代反应,生成2-(3-氟-4-(甲基氨基甲酰基)苯基氨基)-2-甲基丙酸,再经酯化反应,生成2-甲氧基乙基2-((3-氟-4-(甲基氨基甲酰基)苯基)氨基)-2-甲基丙酸酯,上述产物与2-三氟甲基-4-异硫氰基苯甲腈发生合环反应,生成终产物4-(3-(4-氰基-3-三氟甲基)苯基)-5,5-二甲基-4-氧代-2-硫代咪唑-1-基)-2-氟-N-甲基苯甲酰胺,即恩杂鲁胺。本发明的方法克服了现有技术存在的主要弊端,避免使用碘甲烷等高毒性试剂,具有反应条件温和,后处理方便简单,总收率提高,反应时间减少,制备成本降低,绿色环保以及适用于工业化大生产的优势。<Image he="129" wi="284" file="DEST_PATH_IMAGE001.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention provides a preparation process of an Enzalutamide serving as a prostate cancer medicament, which comprises the steps of carrying out a nucleophilic substitution reaction on N-methyl-4-bromo-2-fluoro-benzamide and 2-aminoisobutyric acid under an alkaline condition through catalysis to generate 2- (3-fluoro-4- (methylcarbamoyl) phenylamino) -2-methylpropionic acid, carrying out an esterification reaction to generate 2-methoxyethyl 2- ((3-fluoro-4- (methylcarbamoyl) phenyl) amino) -2-methylpropionate, carrying out a cyclization reaction on the product and 2-trifluoromethyl-4-isothiocyanatobenzonitrile to generate a final product 4- (3- (4-cyano-3-trifluoromethyl) phenyl) -5, 5-dimethyl-4-oxo-2-thioimidazol-1-yl) -2-fluoro-N-methylbenzamide, enzalutamide. The method provided by the invention overcomes the main defects in the prior art, avoids using high-toxicity reagents such as methyl iodide and the like, and has the advantages of mild reaction conditions, convenience and simplicity in post-treatment, improvement of total yield, reduction of reaction time, reduction of preparation cost, greenness and environmental friendliness, and suitability for industrial mass production.)

1. A novel preparation process of Enzalutamide (Enzalutamide), which is characterized by comprising the following steps:

a. carrying out a nucleophilic substitution reaction on N-methyl-4-bromo-2-fluoro-benzamide (A) serving as a raw material and 2-aminoisobutyric acid under the alkaline condition through catalysis to generate 2- (3-fluoro-4- (methylcarbamoyl) phenylamino) -2-methylpropanoic acid (B);

b. performing esterification reaction on the compound B to generate 2-methoxyethyl 2- ((3-fluoro-4- (methylcarbamoyl) phenyl) amino) -2-methylpropionate (C);

c. and the compound C and 2-trifluoromethyl-4-isothiocyanatobenzonitrile (D) are subjected to cyclization reaction to generate a final product 4- (3- (4-cyano-3-trifluoromethyl) phenyl) -5, 5-dimethyl-4-oxo-2-thioimidazole-1-yl) -2-fluoro-N-methylbenzamide, namely enzalutamide (API).

2. The process of claim 1, wherein the catalyst of step a is one of CuCl, CuI and CuBr, and the reaction temperature is in the range of 100-130 ℃.

3. The process of claim 1 wherein the base of step a is one of potassium carbonate, lithium carbonate, cesium carbonate.

4. The process according to claim 1, wherein the esterification reaction condition in the step b is ethylene glycol monomethyl ether or 1-bromo-2-methoxyethane.

5. The process of claim 1, wherein the reaction temperature in step b is 20 ℃ to 40 ℃.

6. The process according to claim 1, characterized by the following steps:

adding the compound A (1.0eq), 2-amino-2-methylpropanoic acid (1.5 eq), potassium carbonate (2.5 eq) and CuCl (0.2eq) into a solvent, uniformly stirring, adding 2-acetyl cyclohexanone (0.2eq), and reacting at 110 ℃ for 16 hours under inert gas; after the reaction is completed, the reaction solution is cooled to room temperature, purified water and ethyl acetate are added for extraction, and organic layers are combined; adjusting the pH value of the organic layer to acidity by using a 1N hydrochloric acid solution, stirring and crystallizing at 0-5 ℃, filtering, washing a filter cake by using purified water, and performing forced air drying at 60 ℃ to obtain a compound B;

dissolving the compound B (1.0eq), 1-bromo-2-methoxyethane (1.1 eq) and 1, 8-diazacyclo [5,4,0] undecene-7 (2.0eq) in DMF, and reacting at 30 ℃ overnight under the protection of inert gas; adding purified water into the reaction solution, stirring for 2 hours, filtering, and drying a filter cake by blowing air at 50 ℃ to obtain a compound C;

placing compound C (1.0eq), compound D (2.0eq), DMSO and isopropyl acetate in a reaction flask to react at 85 ℃ for 16 hours; cooling to room temperature, adding isopropyl acetate and purified water, stirring, separating liquid, extracting the water phase with isopropyl acetate, combining organic phases, washing with saturated saline, drying with sodium sulfate, concentrating under reduced pressure to remove organic solvent, adding methanol into the residue, stirring for 5 hours at room temperature, filtering, and drying the filter cake by blowing at 50 ℃ to obtain the final product of enzalutamide.

Technical Field

The invention relates to a preparation process of an enzalutamide serving as a prostate cancer medicament, and belongs to the field of medicament synthesis.

Background

Prostate cancer is the most common malignancy of the male reproductive system, and the incidence and mortality of prostate cancer is second to lung cancer in European and American countries, and is the 2 nd of cancer deaths in men. The incidence of prostate cancer in China is obviously lower than that in Europe and America, but the incidence of prostate cancer is rapidly increased due to the gradual popularization of social aging, population urbanization, western dietary structure and serum Prostate Specific Antigen (PSA) screening in recent 10 years, and the prostate cancer becomes a disease seriously threatening the health of old men in China increasingly.

Prostate cancer is highly heterogeneous and hormone sensitive. Androgen deprivation therapy is the primary treatment for mid-to-late stage prostate cancer, but most patients develop castration-resistant prostate cancer (CRPC) gradually after l4-30 months of treatment, with a median survival time of less than 20 months. At present, the mechanism of development and progression of CRPC is not clear, and the choice of therapeutic strategies remains a clinically very challenging problem. Prostate cancer treatment drugs that have been marketed, in addition to the traditional chemotherapeutic docetaxel, are only abiraterone and the drug Enzalutamide (Enzalutamide, tradename Xtandi @) marketed in 2012.

Enzalutamide is an effective androgen receptor inhibitor (AR inhibitor), has 5-8 times higher affinity to AR than that of the existing antiandrogen drugs such as bicalutamide, and plays a role by inhibiting nuclear translocation of an AR complex and inducing conformational change of AR to prevent the binding of the compound with DNA. Compared with androgen synthesis inhibitors such as abiraterone, enzalutamide has the advantage that corticosteroid is not required to be matched, so that adverse reaction of steroid hormone is reduced. Clinical tests show that the compound has obvious antitumor activity, less adverse reactions and good tolerance, and provides a new means for treating castration prostate cancer.

Enzalutamide (Enzalutamide)

Disclosure of Invention

Aiming at the problems in the prior art, the inventor provides a preparation process of enzalutamide with high yield and high final product purity through a large number of condition experiments, and the method is simple and convenient to operate, does not use substances with large toxicity, is environment-friendly and is suitable for industrial production.

Specifically, the preparation process comprises the following steps:

a. carrying out a nucleophilic substitution reaction on N-methyl-4-bromo-2-fluoro-benzamide (A) serving as a raw material and 2-aminoisobutyric acid under the alkaline condition through catalysis to generate 2- (3-fluoro-4- (methylcarbamoyl) phenylamino) -2-methylpropanoic acid (B);

b. carrying out esterification reaction on 2- (3-fluoro-4- (methylcarbamoyl) phenylamino) -2-methylpropanoic acid (B) to generate 2-methoxyethyl 2- ((3-fluoro-4- (methylcarbamoyl) phenyl) amino) -2-methylpropionate (C);

c. 2-methoxyethyl 2- ((3-fluoro-4- (methylcarbamoyl) phenyl) amino) -2-methylpropionate (C) is subjected to cyclization reaction with 2-trifluoromethyl-4-isothiocyanatobenzonitrile (D) to generate a final product, namely 4- (3- (4-cyano-3-trifluoromethyl) phenyl) -5, 5-dimethyl-4-oxo-2-thioimidazol-1-yl) -2-fluoro-N-methylbenzamide, namely enzalutamide (API).

Preferably, the catalyst in the step a is one of CuCl, CuI and CuBr, and the reaction temperature ranges from 100 ℃ to 130 ℃;

preferably, the base in step a is one of potassium carbonate, lithium carbonate and cesium carbonate;

preferably, the esterification reaction conditions of step b are ethylene glycol monomethyl ether or 1-bromo-2-methoxyethane;

preferably, the reaction temperature of the step b is 20-40 ℃;

more preferably, the preparation process is as follows: adding the compound A (1.0eq), 2-amino-2-methylpropanoic acid (1.5 eq), potassium carbonate (2.5 eq) and CuCl (0.2eq) into a solvent, uniformly stirring, adding 2-acetylcyclohexanone (0.2eq), and reacting at 110 ℃ for 16 hours under inert gas. After the reaction is completed, the reaction solution is cooled to room temperature, purified water and ethyl acetate are added for extraction, and organic layers are combined; adjusting the pH of the organic layer to acidity by using a 1N hydrochloric acid solution, stirring and crystallizing at 0-5 ℃, filtering, washing a filter cake by using purified water, and performing forced air drying at 60 ℃ to obtain a yellow solid B;

dissolving the compound B (1.0eq), 1-bromo-2-methoxyethane (1.1 eq) and 1, 8-diazacyclo [5,4,0] undecene-7 (2.0eq) in DMF, and reacting at 30 ℃ overnight under the protection of inert gas. Adding purified water into the reaction solution, stirring for 2 hours, filtering, and drying a filter cake by blowing air at 50 ℃ to obtain a white-like solid C;

compound C (1.0eq), Compound D (2.0eq), DMSO and isopropyl acetate were placed in a reaction flask and reacted at 85 ℃ for 16 hours. Adding isopropyl acetate and purified water to room temperature, stirring and separating liquid, extracting a water phase with isopropyl acetate, combining organic phases, washing with saturated saline, drying with sodium sulfate, decompressing and concentrating to remove an organic solvent, adding methanol to a residue, stirring for 5 hours at room temperature, filtering, and drying a filter cake by blowing at 50 ℃ to obtain the final product, namely enzalutamide (white powder).

The method provided by the invention overcomes the main defects in the prior art, avoids using high-toxicity reagents such as methyl iodide and the like, and has the advantages of mild reaction conditions, convenience and simplicity in post-treatment, improvement of total yield, reduction of reaction time, reduction of preparation cost, greenness and environmental friendliness, and suitability for industrial mass production.

Detailed Description

The present invention is further illustrated below with reference to specific examples. The present invention includes, but is not limited to, the following examples.