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Synthetic method for cabozantinib

A technology of cabozantinib and its synthetic method, which is applied in the field of preparation of raw drug cabozantinib, can solve the problems of unfavorable environment and human health, unfavorable industrial production, etc., achieve good purity and yield, be beneficial to industrial production, and avoid Effect of acyl chloride reagents

Inactive Publication Date: 2018-01-09
深圳万乐药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The method uses corrosive acid chloride reagents such as thionyl chloride and oxalyl chloride in multiple steps, which is harmful to the environment and human health.
[0012] Not conducive to industrial production

Method used

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  • Synthetic method for cabozantinib
  • Synthetic method for cabozantinib
  • Synthetic method for cabozantinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Preparation of Example 1N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-1-formamide-cyclopropyl-1-carboxylic acid

[0024] Add triethylamine (48.5mL, 0.345mol) to a solution of 1,1-cyclopropyldicarboxylic acid (44.9g, 0.345mol) in tetrahydrofuran (350ml), and stir the solution at room temperature for 40 minutes under nitrogen protection, then add chlorine Sulfoxide (25mL, 0.344mol), LC / MS monitors the reaction, monitors the conversion rate of monoacyl chloride (monocarboxylate methyl ester is monitored after the reaction solution is quenched with methanol), after stirring at room temperature for 3 hours, successively add 4-[ (6,7-dimethoxy-4-quinoline) oxy]aniline (102g, 0.344mol) and tetrahydrofuran (150ml), continue to stir at room temperature for 16 hours, add ethyl acetate (1000ml) to dilute the reaction slurry , extracted with 1N sodium hydroxide solution. Filter the two-phase slurry thick liquid, adjust the pH of the water phase to 6 with hydrochloric acid and filter...

Embodiment 2

[0029] Add 1-[4-(6,7-dimethoxyquinoline-4-oxyl group) phenylcarbamoyl]-cyclopropyl-1-carboxylic acid (4.08g, 10mmol) in reaction flask, add N,N-Dimethylformamide was dissolved, then 1-hydroxybenzotriazole (HOBt, 2.43g, 18mmol), HB TU (4.55g, 12mmol) and N,N-diisopropylethylamine (1.55 g, 12mmol), after stirring evenly, add 4-fluoroaniline (1.11g, 10mmol), stir the reaction at room temperature overnight until the reaction is complete, add water (800ml) to dilute, stir and crystallize, filter, and filter the cake through 1N hydrochloric acid tetrahydrofuran solution respectively (800ml), 1N sodium hydroxide solution in tetrahydrofuran (800ml) and aqueous solution of tetrahydrofuran (800ml) were slurry washed and crystallized, filtered and dried to obtain 4.6g of cabozantinib base with a yield of 91.8% and a purity of 99.1%. MS: m / z 501[M+H] + . IR: 3442cm -1 、3244cm -1 、3071cm -1 、3021cm -1 、2959cm -1 、2836cm -1 、1672cm -1 、1642cm -1 、1618cm -1 、1589cm -1 、1567cm -1...

Embodiment 3

[0031] Add 1-[4-(6,7-dimethoxyquinoline-4-oxyl group) phenylcarbamoyl]-cyclopropyl-1-carboxylic acid (4.08g, 10mmol) in reaction flask, add N , N-dimethylformamide was dissolved, then added 1-hydroxybenzotriazole (HOBt, 2.43g, 18mmol), 2-(7-azobenzotriazole)-N,N,N',N '-Tetramethyluronium hexafluorophosphate (HATU, 4.56g, 12mmol) and N,N-diisopropylethylamine (1.55g, 12mmol), after stirring evenly, add 4-fluoroaniline (1.11g, 10mmol ), stirred at room temperature and reacted overnight until the reaction was complete, added water (800ml) for dilution, stirred and crystallized, filtered, and the filter cake was subjected to 1N hydrochloric acid tetrahydrofuran solution (800ml), 1N sodium hydroxide tetrahydrofuran solution (800ml) and tetrahydrofuran aqueous solution (800ml) respectively. After slurry washing and crystallization, filter and dry to obtain 4.3 g of cabozantinib base with a yield of 85.8% and a purity of 99.0%.

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Abstract

The invention provides a synthetic method for cabozantinib. The method comprises the following steps: 1,1-cyclopropanedicarboxylic acid is used a starting raw material, acylation is performed, condensation is performed on an acylation product and 4-[6,7-dimethoxy-4-quinolinyl]oxy]aniline, condensation is further performed on an obtained product and 4-fluoroaniline under effects of a polypeptide condensing agent, and therefore the cabozantinib is obtained. According to the method, the reaction conditions are mild, a chlorinating reagent is used just in one step, and the method is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the field of antineoplastic drugs, and in particular relates to a method for preparing a raw material cabozantinib suitable for treating medullary thyroid cancer (MTC). Background technique [0002] Cabozantinib chemical name N-[4-[6,7-dimethoxy-4-quinolyl]oxy]phenyl]-N-(4-fluorophenyl)-1,1 -Cyclopropanedicarboxamide, cabozantinib malate is a tyrosine kinase inhibitor developed by Exelixis Pharmaceuticals of the United States, which was launched in the United States in 2012 under the trade name 20mg and 80mg capsule formulations. Clinically, it is mainly used for the treatment of advanced and metastatic medullary thyroid carcinoma. At present, there is no cabozantinib malate on the market in China. [0003] The structural formula of cabozantinib malate is as follows: [0004] [0005] Cabozantinib is suitable for the treatment of advanced and metastatic medullary thyroid carcinoma (MTC). It is a multi-target inhibitor o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/22
Inventor 朱勇李瑞远孙朋杰袁庆柏江涛雷光华
Owner 深圳万乐药业有限公司
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