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Preparation process of prostatic cancer medicine Enzalutamide

A preparation process and technology of enzalutamide, applied in the field of drug synthesis, can solve problems such as being unsuitable for industrial production, and achieve the effects of reduced preparation cost, convenient and simple post-processing, and reduced reaction time

Active Publication Date: 2020-03-10
BEIJING KAILAI TIANCHENG MEDICINE TECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0020] The above-mentioned methods all have certain problems in the preparation process and are not suitable for industrialized production. Therefore, it is necessary to develop a new method to solve the problems encountered in the above-mentioned route, avoid the use of highly toxic compounds, and improve the yield and the purity of the final product

Method used

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  • Preparation process of prostatic cancer medicine Enzalutamide
  • Preparation process of prostatic cancer medicine Enzalutamide
  • Preparation process of prostatic cancer medicine Enzalutamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1: Synthesis of 2-(3-fluoro-4-(methylcarbamoyl)phenylamino)-2-methylpropionic acid

[0037]

[0038] N-methyl-4-bromo-2-fluoro-benzamide (A) (600g, 2.6mol, 1.0eq), 2-amino-2-methylpropionic acid (400g, 3.9mol, 1.5eq), Potassium carbonate (893g, 6.5mol, 2.5eq), CuCl (51g, 0.52mol, 0.2eq), was added to DMF (3600ml), stirred well, and 2-acetylcyclohexanone (73g, 0.52mol, 0.2eq ), react at 110°C for 16 hours under inert gas. After the reaction was complete, the reaction liquid was cooled to room temperature, purified water and ethyl acetate were added to extract twice, and the organic layers were combined. The organic layer was adjusted to acidic pH with 1N hydrochloric acid solution, stirred and crystallized at 0-5°C, filtered, the filter cake was washed with purified water, and air-dried at 60°C to obtain 583g of a yellow solid, with a yield of 88.7%.

Embodiment 2

[0039] Example 2: Synthesis of 2-methoxyethyl 2-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)-2-methylpropionate

[0040]

[0041]2-(3-fluoro-4-(methylcarbamoyl)phenylamino)-2-methylpropionic acid (200g, 0.79mol), ethylene glycol monomethyl ether (124mL, 0.16mol, 2.0eq) , 1-hydroxybenzotriazole (HOBt, 127g, 0.95mmol, 1.2eq), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCHCl, 181g, 0.95mol , 1.2eq) into 1L of dichloromethane, under the protection of an inert gas, react overnight at room temperature. Purified water (3 L) was added to the reaction solution, stirred and separated, the organic layer was washed once with water and brine, dried over sodium sulfate, concentrated under reduced pressure to remove the organic solvent, and dried in vacuo overnight to obtain 225 g of off-white solid with a yield of 91.3%. ESI-MS m / z: 313.16[M+H] + , 1 H-NMR (DMSO-d 6 ) (ppm): 7.97(d, 1H, J=10.0Hz, -Ph),6.61(s, 1H, -NH), 6.57(dd, 1H, J 1 =5.0Hz,J 2 =10.0Hz, -Ph), 6.4...

Embodiment 3

[0042] Example 3: Synthesis of 2-methoxyethyl 2-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)-2-methylpropionate

[0043]

[0044] 2-(3-fluoro-4-(methylcarbamoyl)phenylamino)-2-methylpropionic acid (200g, 0.79mol), 1-bromo-2-methoxyethane (82mL, 0.87 mol, 1.1eq), 1,8-diazacyclo[5,4,0]undecene-7 (238g, 1.57mol, 2.0eq), dissolved in DMF (1.5L), under inert gas protection, React overnight at 30°C. Purified water (3 L) was added to the reaction solution, stirred for 2 hours, filtered, and the filter cake was air-dried at 50°C to obtain 228 g of off-white solid, with a yield of 92.6%. ESI-MS m / z: 313.16[M+H] + , 1 H-NMR (DMSO-d 6 ) (ppm): 7.97(d, 1H, J=10.0Hz, -Ph), 6.61(s, 1H, -NH), 6.57(dd,1H, J 1 =5.0Hz,J 2 =10.0Hz, -Ph), 6.43(dd, 1H, J 1 =5.0Hz,J 2 =10.0Hz, -Ph), 4.46(s,1H, -NH), 4.21(t, 2H, J=5.0Hz, -CH 2 ), 3.69(t, 2H, J=5.0Hz, -CH 2 ), 3.37(s, 3H,-CH 3 ), 2.76(s, 3H, -CH 3 ), 1.56(s, 6H, -CH 3 ).

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Abstract

The invention provides a preparation process of a prostatic cancer medicine Enzalutamide. The preparation process includes: with N-methyl-4-bromo-2-fluoro-benzamide being a raw material, performing acatalytic nucleophilic substitution reaction with 2-amino isobutyric acid under alkaline condition to generate 2-(3-fluoro-4-(methylcarbamoyl)phenylamino)-2-methylpropionic acid; performing esterification to generate 2-methoxyethyl-2-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)-2-methylpropionate; performing a ring closing reaction on the product with 2-trifluoromethyl-4-isothiocyanobenzonitrile togenerate the finish product 4-(3-(4-cyano-3-trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-sulfoimidazole-1-yl)-2-fluoro-N-methylbenzamide, namely, Enzalutamide. The method overcomes the major defectsin the prior art and avoids use of high-toxic reagent such as iodomethane, is gentle in reaction conditions and is convenient and simple in after treatment, is improved in total yield and reduced in reaction time, is reduced in preparation cost, is green and environment-friendly, and is suitable for industrial large-scale production.

Description

technical field [0001] The invention relates to a preparation process of a prostate cancer drug enzalutamide, which belongs to the field of drug synthesis. Background technique [0002] Prostate cancer is the most common malignant tumor of the male reproductive system, and its morbidity and mortality are second only to lung cancer in European and American countries, ranking second in male cancer deaths. The incidence of prostate cancer in my country is significantly lower than that in Europe and the United States, but in the past 10 years, due to the aging of the society, urbanization of the population, Westernization of dietary structure, and the gradual promotion of serum prostate specific antigen (PSA) screening, the incidence of prostate cancer has increased. Rapid growth is increasingly becoming a disease that seriously threatens the health of elderly men in our country. [0003] Prostate cancer is highly heterogeneous and hormone sensitive. For advanced prostate cance...

Claims

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Application Information

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IPC IPC(8): C07D233/86
CPCC07D233/86
Inventor 刘素云李项
Owner BEIJING KAILAI TIANCHENG MEDICINE TECH CO LTD
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