Apalutamide synthetic method and intermediate

A technology of apalutamide and a synthesis method, applied in the field of medicine and chemical industry, can solve the problems of low atom economy and high material cost, and achieve the effects of good application prospect, easy availability of raw materials and mild reaction conditions

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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route is prepared by APAL-007 through 4 subsequent steps of reaction to obtain apalutamide. APAL-007 is the key material to determine the cost of this route. Route material cost is high

Method used

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  • Apalutamide synthetic method and intermediate
  • Apalutamide synthetic method and intermediate
  • Apalutamide synthetic method and intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Example 1 Preparation of 1-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)cyclobutane-1-carboxylic acid (1)

[0060] Drop into 9.28g 2-fluoro-4-bromo-N-methyl benzylamine amide (0.04mol), 9.1g 1-aminocyclobutyl carboxylate hydrochloride (0.06mol), 16.6g salt of wormwood ( 0.12mol), 1.55g CuI (0.008mol), 60mL DMF, and evacuated 3 times with argon protection at room temperature, stirred at room temperature for 30min, replaced with argon, heated to 110°C to react, the solution quickly turned green, and gray appeared after about 2 hours The solid was suspended, and after 9 hours, the plate was spotted, and the raw materials were completely reacted.

[0061] After cooling to room temperature, 100 mL of ethyl acetate / 200 mL of water was added, stirred for 30 min, and separated. The water layer was taken, and the pH of the water layer was adjusted to 4 with 110 mL of 37% citric acid aqueous solution. Solids precipitated out. After stirring in an ice-water bath for 1 h, suction fi...

Embodiment 2

[0066] Example 2 Preparation of 1-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)cyclobutane-1-carboxylic acid (2)

[0067] Drop into 9.28g 2-fluoro-4-bromo-N-methyl benzylamine amide (0.04mol), 9.1g 1-aminocyclobutyl carboxylate hydrochloride (0.06mol), 16.6g salt of wormwood ( 0.12mol), 0.8g CuCl (0.008mol), 60mL DMF, and evacuated 3 times with argon protection at room temperature, stirred at room temperature for 30min, heated to 110°C to react, the solution quickly turned green, and the raw materials reacted completely after 10h.

[0068] After cooling to room temperature, add 100mL ethyl acetate / 200mL water, stir for 30min, separate the layers, take the water layer, adjust the pH of the water layer to 4 with 110mL of 37% citric acid aqueous solution, and solid precipitates, stir in an ice-water bath for 1h, and then filter with suction. After drying, 7.9 g of 1-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)cyclobutane-1-carboxylic acid was obtained, with a yield of 74.1% and a pu...

Embodiment 3

[0069] Example 3 Preparation of 1-((3-fluoro-4-(methylcarbamoyl)phenyl)amino)cyclobutane-1-carboxylic acid (3)

[0070] Drop into 18.6g 2-fluoro-4-bromo-N-methyl benzylamine amide (0.08mol), 18.0g1-aminocyclobutyl carboxylic acid hydrochloride (0.11mol), 21.2g sodium carbonate (0.20 mol), 1.6g CuCl (0.016mol), 100mL DMF, and evacuate the room with argon protection for 3 times, stir at room temperature for 30min, and heat to 110°C to react. After 10h, the raw materials reacted completely.

[0071] After cooling to room temperature, add 250 mL of ethyl acetate / 400 mL of water, stir for 30 min, separate the layers, and take the water layer; The aqueous layer was adjusted to pH ~ 4 with 10% hydrochloric acid, and solids precipitated out. After stirring in an ice-water bath for 1 h, suction filtration and drying gave 15.8 g of 1-((3-fluoro-4-(methylcarbamoyl)phenyl) Amino)cyclobutane-1-carboxylic acid, yield 74%, liquid phase detection purity 98.4%. Spectrogram detection result i...

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Abstract

The invention provides a novel preparation method of Apalutamide. According to the novel preparation method, 2-fluoro-4-bromo-N-methyl benzene methanamine amide, 1-amino cyclobutyl carboxylate hydrochloride, and the like are taken as initial raw materials, and substitution reaction is carried out so as to obtain 1-((3-fluoro-4-(methyl carbamyl)phenyl)amino) cyclobutane-1-carboxylic acid, wherein synthesis yield is higher than 70%, and purity is higher than 97.2%; then esterification is carried out so as to obtain 1-((3-fluoro-4-(methyl carbamyl)phenyl)amino) cyclobutane-1-carboxylic ester, wherein synthesis yield is higher than 83%, and purity is higher than 97.8%; and at last, ring closing reaction with 2-cyan-3-trifluoromethyl-5-isothiocyano pyridine is carried out so as to obtain Apalutamide, wherein yield is higher than 68%, and purity is higher than 98.1%. The preparation method possesses following advantages: the raw materials are easily available; technology is simple; operationis convenient; yield is high; and cost is low.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a synthesis method and an intermediate of apalutamide. Background technique [0002] Apalutamide (Apalutamide, JNJ-56021927, ARN-509, JNJ-927), chemical structural formula as shown in formula III, is a kind of androgen inhibitor (Androgen receptor (AR) antagonists), developed by Johnson & Johnson, available in the treatment of prostate cancer. Apalutamide is currently in phase III clinical research and has good application prospects. [0003] [0004] The preparation method of apalutamide mainly comprises following two kinds at present: [0005] The synthetic route of method 1 includes route I, route II and route III, which are disclosed in patents WO2007126765, WO2008119015, WO2011103202 and WO2014190895, the contents are as follows: [0006] Compound 4-((1-cyanocyclobutyl)amino)-2-fluoro-N-methylbenzamide (APAL-009) and compound 2-cyano-3-trifluor...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C237/30C07C231/12C07D401/04
CPCC07C231/12C07C237/30C07D401/04
Inventor 唐家邓王小梅茆勇军
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