Method for synthesizing apalutamide and intermediate thereof

A technology of apalutamide and a synthetic method, applied in the field of medicine and chemical industry, can solve the problems of the cost of amplifying the production route, long linear steps, complicated process operation, etc., and achieves the advantages of reducing the process cost, reducing the generation of by-products, and simplifying the process operation. Effect

Active Publication Date: 2018-08-10
HANGZHOU CHEMINSPIRE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The linear steps of this route are too long, highly toxic sodium cyanide is used in the route, the process operation is relatively cumbersome, and the multi-step reaction needs to be catalyzed by precious metal palladium, and the cost of enlarging the production route is high

Method used

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  • Method for synthesizing apalutamide and intermediate thereof
  • Method for synthesizing apalutamide and intermediate thereof
  • Method for synthesizing apalutamide and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039]

[0040] Add N-methyl-2-fluoro-4-bromo-benzamide 1a (23.21g, 100mmol), cyclobutanine hydrochloride 2 (15.16 100mmol) and N,N-dimethylacetamide into the three-necked flask (116mL), copper iodide (1.90g, 10mmol) and cesium carbonate (71.68g, 220mmol) were added under nitrogen protection, stirred evenly and heated to 90-95°C overnight. After the reaction was completed, water (232 mL) and isopropyl acetate (232 mL) were added, stirred and separated, the aqueous phase was collected and adjusted to pH 3-4 with 4N hydrochloric acid, a large amount of solid was precipitated, and compound 3 (17.88 g, 79%) was obtained by filtration and drying. MS(ESI)m / z=227.2[M+H] + .

[0041] The cuprous iodide here can be replaced by cuprous chloride or cuprous bromide; the alkaline substance cesium carbonate can be replaced by potassium carbonate and sodium carbonate; the solvent N,N-dimethylacetamide can be replaced by N,N-dimethylformamide Amide, N-methylpyrrolidone instead.

[0042]...

Embodiment 2

[0044]

[0045] Add compound 3 (26.63g, 100mmol) and methanol (133mL) into a three-neck flask, stir well, then slowly add thionyl chloride (17.85g, 150mmol), then heat to 40-45°C for 6-8 hours. At the end of the reaction, part of the methanol was spun off, water (266 mL) was slowly added to make a slurry, and filtered. The crude product was then slurried with a mixed solvent of methanol and petroleum ether, filtered and dried to obtain compound 4a (25.79 g, 92%). MS(ESI)m / z=281.2[M+H] +1 H NMR(400MHz,DMSO-d6)δ7.67-7.45(m,2H),6.80(s,1H),6.22-6.41(m,1H),5.98-6.17(m,1H),3.62(s,3H ), 2.82-2.67 (m, 5H), 2.62-2.50 (m, 2H), 2.32-2.26 (m, 1H), 1.82-1.67 (m, 1H) ppm.

Embodiment 3

[0047]

[0048]Add 7 (28.03g, 100mmol) and 75% methanol (280mL) into the three-necked flask, stir well and add potassium thiocyanate (23.00g, 120mmol) and diisopropylethylamine (25.85g, 200mmol). Reflux reaction for 6-8 hours. After the reaction was completed, part of the water was spun off, water (248 mL) was added to make a slurry, recrystallized with a mixed solvent of ethyl acetate and petroleum ether, filtered, and dried to obtain compound 5 (27.56 g, 85%). MS(ESI)m / z=308.0[M+H] +1 HNMR(400MHz,DMSO-d6)δ9.32(br,1H),δ7.70-7.55(m,2H),6.82-6.70(m,1H),6.12(br,1H),2.84-2.65(m, 5H), 2.63-2.50 (m, 2H), 2.35-2.25 (m, 1H), 1.85-1.65 (m, 1H) ppm.

[0049] Here potassium thiocyanate can be replaced by sodium thiocyanate; alkaline substance diisopropylethylamine can be replaced by triethylamine, pyridine, DMAP, DBU or DABCO; solvent methanol can be replaced by N,N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, ethanol, isopropanol, acetonitrile, tetrahydrofuran,...

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Abstract

The invention discloses a method for synthesizing apalutamide. The method includes carrying out condensation on N-methyl-2-fluorine-4-halogenated-benzamide compounds 1 and amino-1-cyclobutanecarboxylic acid hydrochloride 2 by means of Ullmann reaction to obtain to obtain intermediate compounds 3 and esterifying the intermediate compounds 3 to obtain intermediate compounds 4; carrying out cyclization by means of reaction on the intermediate compounds 4 and thiocyanide to obtain compounds 5; carrying out condensation by means of coupling the compounds 5 to obtain the apalutamide. The N-methyl-2-fluorine-4-halogenated-benzamide compounds 1 and the amino-1-cyclobutanecarboxylic acid hydrochloride 2 are used as starting materials. A path is shown, an R in the path represents alkyl, includes butis not limited to methyl or ethyl. The method has the advantages that route steps can be shortened to a great extent, the route efficiency can be improved, precious metal catalysts are omitted, and accordingly the process cost can be lowered; byproduct generation can be reduced, and accordingly the method is favorable for improving the purity of ultimate products.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to a new synthesis method for preparing apalutamide and related intermediates. Background technique [0002] Apalutamide (code-named ARN-509) is a second-generation androgen receptor signaling inhibitor developed by Aragon Pharmaceuticals of the United States and later acquired by Johnson & Johnson of the United States. The drug is used to treat castration-resistant prostate cancer, and has a good effect on inhibiting the survival and growth of cancer cells. The current phase III clinical trial is also progressing smoothly. If approved, it will be able to meet the needs of many prostate cancer patients and has great market prospects. [0003] Apalutamide chemical name: 4-(7-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-8-oxo-6-thio-5,7-diazepine Heterospiro[3.4]oct-5-yl)-2-fluoro-N-methylbenzamide, the structural formula is as follows: [0004] [0005] PCT patent WO200...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C237/30C07C231/12C07D235/02C07D401/04
CPCC07C231/12C07C237/30C07D235/02C07D401/04C07C2601/04
Inventor 郑旭春张一平
Owner HANGZHOU CHEMINSPIRE TECH CO LTD
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