Preparation method of apatinib

A technology of apatinib and its compounds, which is applied in the field of preparation of apatinib, can solve problems such as unfavorable product purity assurance and impurity control, multiple side reactions in reaction conditions and product degradation, insufficient activation of chlorine atom substitution reactions, etc., to achieve Low cost, stable reaction operation, and less by-products

Active Publication Date: 2018-12-18
XINFA PHARMA
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Problems solved by technology

[0009] The reaction steps of the above-mentioned synthetic route are long, and the price of raw material 2-chloronicotinyl chloride is relatively high; The ortho position of the atom is an amide functional group, which is not enough to activate the chlorine atom to carry out the substitution reaction, and the substitution reaction activity is low, resulting in N-[4-(1-cyanocyclopentyl) phenyl]-2-chloro-3-pyridinecarboxamide and The substitution reaction of 4-aminomethylpyridine requires higher reaction temperature and longer reaction time. The harsher reaction conditions cause more side reactions and product degradation. The purity of Apatinib obtained is only 95-96%, which is not conducive to Product purity assurance and impurity control, and lower yield

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Examples

Experimental program
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Embodiment 1

[0057] Example 1: Preparation of N-(pyridin-4-ylmethyl)-2-amino-3-cyanopyridine (Ⅲ)

[0058] To a 500 ml four-neck flask connected with a stirring, thermometer, and vacuum distillation device, add 180 g of N,N-dimethylformamide, 27.7 g (0.2 moles) of 2-chloro-3-cyanopyridine (II1) , 34.5 grams (0.25 moles) of potassium carbonate, 22.0 grams (0.2 moles) of 4-aminomethylpyridine, 95 to 100 ° C stirring reaction for 4 hours, cooled to 20-25 ° C, filtered, filter cake with 30 grams of N, N- Dimethylformamide was washed, the combined filtrates were distilled under reduced pressure to recover the solvent, and the residue was recrystallized with methyl tert-butyl ether to obtain 38.9 grams of N-(pyridin-4-ylmethyl)-2-amino-3-cyano Pyridine (Ⅲ), yield 92.6%, liquid phase purity 99.72%.

Embodiment 2

[0059] Example 2: Preparation of N-(pyridin-4-ylmethyl)-2-amino-3-cyanopyridine (Ⅲ)

[0060] To a 500 ml four-neck flask connected with a stirring, thermometer, and vacuum distillation device, add 200 g of N,N-dimethylformamide, 36.6 g (0.2 moles) of 2-bromo-3-cyanopyridine (II2) , 34.5 grams (0.25 moles) of potassium carbonate, 22.0 grams (0.2 moles) of 4-aminomethylpyridine, stirred and reacted at 80 to 85 ° C for 5 hours, cooled to 20-25 ° C, filtered, and the filter cake was washed with 30 grams of N, N- Wash with dimethylformamide, combine the filtrates, and distill under reduced pressure to recover the solvent, and the residue is recrystallized with methyl tert-butyl ether to obtain 39.3 grams of N-(pyridin-4-ylmethyl)-2-amino-3-cyano Pyridine (Ⅲ), yield 93.6%, liquid phase purity 99.65%.

Embodiment 3

[0061] Example 3: Preparation of N-(pyridin-4-ylmethyl)-2-amino-3-pyridinecarboxylic acid methyl ester (Ⅳ1)

[0062] In a 500 ml four-neck flask connected with stirring, a thermometer, and a reflux condenser, add 160 grams of methanol, 21.0 grams (0.1 mole) of N-(pyridin-4-ylmethyl)-2-amino- 3-cyanopyridine (Ⅲ), 22.0 grams of 35wt% concentrated hydrochloric acid, stirred and reacted at 60 to 65°C for 5 hours, cooled to 20-25°C, added 100 grams of water, 150 grams of toluene, and adjusted the pH of the system with 5wt% sodium carbonate aqueous solution The value is 7.0-8.0, separate layers, the water layer is extracted twice with toluene, 50 grams of toluene each time, the toluene organic layer is combined, washed once with 30 grams of saturated sodium chloride aqueous solution, methanol and toluene are recovered by atmospheric distillation, and the residue is washed with toluene tert-butyl ether was recrystallized to obtain 21.6 g of methyl N-(pyridin-4-ylmethyl)-2-amino-3-pyr...

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Abstract

The invention provides a preparation method of apatinib. The preparation method comprises that 2-halogenated-3-cyanopyridine as a raw material and 4-aminomethylpyridine undergo a substitution reactionto produce N-(pyridin-4-yl-methyl)-2-amino-3-cyanopyridine, the N-(pyridin-4-yl-methyl)-2-amino-3-cyanopyridine undergoes an esterification reaction to produce N-(pyridin-4-yl-methyl)-2-amino-3-picolinate, and the N-(pyridin-4-yl-methyl)-2-amino-3-picolinate and 1-(4-aminophenyl)cyclopentylformonitrile undergo an amidation reaction to produce apatinib (I). The preparation method has the advantages of low cost and easy availability of raw materials, simple processes, low cost, less waste water generation, safety and environmental protection, easy realization of reaction conditions, high reactivity and selectivity, few side reactions, few apatinib impurities, high purity and high yield.

Description

technical field [0001] The invention relates to a preparation method of apatinib, which belongs to the technical field of medicinal chemistry. Background technique [0002] During the growth and metastasis of malignant tumors, tumor angiogenesis plays a very important role. Inhibiting tumor angiogenesis is an important means of treating tumors. The tyrosine kinase vascular endothelial growth factor (VEGF) and its receptor (VEGFR) play an extremely important role in tumor angiogenesis. Important targets in generation. Apatinib is a new generation of tyrosine kinase inhibitors that can block tumor angiogenesis. Apatinib is the world's first proven safe and effective small-molecule anti-angiogenic targeted drug for the treatment of advanced gastric cancer. It is also a single drug that can significantly prolong the survival of advanced gastric cancer after the failure of standard chemotherapy. At the same time, the drug is the only oral preparation among targeted drugs for g...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/82
CPCC07D213/82
Inventor 崔庆荣刘月盛屈虎吕强三鞠立柱
Owner XINFA PHARMA
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