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Preparation method of axitinib intermediate

A technology of axitinib and intermediates, applied in the field of pharmaceutical synthesis, can solve the problems of high production cost, low purity and high technical requirements, and achieve the effects of mild reaction conditions, high reaction yield and high product purity

Pending Publication Date: 2021-01-12
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] In order to solve the problems of low yield, low purity, high technical requirements, serious environmental pollution and high production cost in the preparation process of 2-mercapto-N-methylbenzamide, an important intermediate of axitinib in the prior art, the present invention provides A new method for the preparation of 2-mercapto-N-methylbenzamide has been developed. The preparation method is novel, the raw materials are readily available, the operation is simple, the reaction conditions are milder, the economy is environmentally friendly and the yield is high, and it is suitable for industrial production

Method used

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  • Preparation method of axitinib intermediate
  • Preparation method of axitinib intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0039] Dissolve 30.23g (0.2mol) of 2-hydroxy-N-methylbenzamide in tetrahydrofuran (50ml), slowly add 29.66g (0.24mol) of dimethylaminothioformyl chloride and 31.39g (0.28mol) of triethylene Diamine, temperature control 40 ℃ reaction, after TLC detects reaction, add ethyl acetate and purified water (V 乙酸乙酯 :V 纯化水 =3: 1) 40ml, the organic layer was concentrated under reduced pressure to obtain 2-mercapto-N-methylbenzamide with a yield of 97.2% and a purity of 99.95% by HPLC.

Embodiment 2

[0041] Dissolve 30.23g (0.2mol) of 2-hydroxy-N-methylbenzamide in acetonitrile (50ml), slowly add 27.20g (0.22mol) of dimethylaminothioformyl chloride and 36.19g (0.28mol) of N, N-diisopropylethylamine, warming up to 40 ° C, after the TLC detection reaction is completed, the reaction solution is down to room temperature, ethyl acetate and purified water (V 乙酸乙酯 :V 纯化水 =3:1) 40ml, the organic layer was concentrated under reduced pressure to obtain 2-mercapto-N-methylbenzamide with a yield of 94.4% and a purity of 99.88% by HPLC.

Embodiment 3

[0043] Dissolve 30.23g (0.2mol) of 2-hydroxy-N-methylbenzamide in N,N-dimethylformamide (40ml), slowly add 24.72g (0.2mol) of dimethylaminothioformyl chloride and 34.21g (0.28mol) of 4-dimethylaminopyridine was heated up to 60°C for reaction. After the reaction was detected by TLC, the reaction solution was cooled to room temperature, and ethyl acetate and purified water (V 乙酸乙酯 :V 纯化水=3:1) 40ml, the organic layer was concentrated under reduced pressure to obtain 2-mercapto-N-methylbenzamide with a yield of 92.3% and a purity of 99.90% by HPLC.

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Abstract

The present invention belongs to the field of medicine synthesis, and particularly relates to a preparation methodof an axitinib intermediate 2-sulfydryl-N-methylbenzamide, the method comprises the following steps: the intermediate compound S-(2-(methylcarbamoyl) phenyl) dimethylthioformate is synthesized by taking 2-hydroxy-N-methylbenzamide as a raw material under the action of a catalyst, and the new intermediate is further synthesized into the 2-sulfydryl-N-methylbenzamide under the action of alkali. The synthesis method provided by the invention is short in route and simple to operate, and the obtained 2-sulfydryl-N-methylbenzamide is high in yield, high in purity and more suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, and in particular relates to a preparation method of an axitinib intermediate. Background technique [0002] The chemical name of Axitinib is N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indol-6-ylsulfonyl]-benzene Formamide; molecular formula: C 22 h 18 N 4 OS; molecular weight: 386.47; CAS registration number: 319463-51-9, the structural formula is as follows: [0003] [0004] Axitinib is an oral tyrosine kinase inhibitor developed by Pfizer that acts on vascular endothelial growth factor VEGF1 receptor, VECF2 receptor and VECF3 receptor. Adult patients with advanced renal cell carcinoma (RCC) who have failed treatment with a tyrosine kinase inhibitor or cytokine. Axitinib comprehensively prevents tumor progression by inhibiting the vascular endothelial growth factor receptor signaling system. It was approved by the FDA in 2012. Its trade name is Inlyta. It is used for the treatm...

Claims

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Application Information

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IPC IPC(8): C07C319/02C07C323/62C07C333/04
CPCC07C319/02C07C333/04
Inventor 刘建设翟立海安坤宋端正
Owner LUNAN PHARMA GROUP CORPORATION
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