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Synthesis method of apatinib for treating stomach cancer

A synthesis method and apatinib technology, applied in the field of drug synthesis, can solve the problems of harsh reaction conditions, difficult purification of products and yields, etc., and achieve the effects of few reaction steps, simple reaction and mild reaction conditions.

Inactive Publication Date: 2017-08-18
QINGDAO CHENDA BIOLOGICAL SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The purpose of the present invention is to overcome the problems of harsh reaction conditions, difficult purification of product and low yield in the existing synthetic method of Apatinib, and provide a new synthetic method of Apatinib

Method used

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  • Synthesis method of apatinib for treating stomach cancer
  • Synthesis method of apatinib for treating stomach cancer
  • Synthesis method of apatinib for treating stomach cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Synthesis of compounds shown in formula I

[0029] 37.7g (220mmol) of methyl 2-chloro-3-pyridinecarboxylate and 127.2g (1.2mol) of sodium carbonate were mixed in 240ml mixed solvent at room temperature, and said mixed solvent was acetonitrile and A mixed solution of water, then 23.8g (200mmol) of 4-diazomethyl-pyridine was added to the system to carry out a contact reaction for 3 hours, and the reaction was monitored, and the reaction liquid was added with water, extracted with dichloromethane, and dried over anhydrous sodium sulfate , concentrated under reduced pressure, recrystallized from petroleum ether, and dried to obtain 39.6 g of the compound represented by formula I, with a yield of 87.6% and a HPLC purity of 99.31%. MS(ESI):m / z[M+H] + 227.10.

[0030] 1 HNMR (400MHz, CDCl 3 ): δ10.17(s,1H),8.26-8.19(d,2H),8.15-8.09(d,1H),7.79-7.71(d,1H),7.48-7.44(d,2H),6.76-6.70 (m, 1H), 4.57-5.49 (d, 2H).

Embodiment 2

[0032] Synthesis of compounds shown in formula I

[0033] 20.6g (120mmol) of methyl 2-chloro-3-pyridinecarboxylate was mixed with 55.2g (400mmol) of potassium carbonate in 160ml mixed solvent at room temperature, and the mixed solvent was acetonitrile and water with a volume ratio of 8:1 Then 11.9g (100mmol) of 4-diazomethyl-pyridine was added to the system for contact reaction for 3.5 hours, and the reaction was monitored. Water was added to the reaction solution, extracted with dichloromethane, and dried over anhydrous sodium sulfate. Concentrate under reduced pressure, recrystallize from petroleum ether, and dry to obtain 20 g of the compound represented by formula I, with a yield of 88.3% and a purity of 99.22% by HPLC.

Embodiment 3

[0035] Synthesis of compounds shown in formula I

[0036] 18.9g (110mmol) of methyl 2-chloro-3-pyridinecarboxylate and 41.4g (300mmol) of potassium carbonate were mixed in 180ml mixed solvent at room temperature, and the mixed solvent was acetonitrile and water with a volume ratio of 10:1 4-diazomethyl-pyridine 11.9g (100mmol) was then added to the system for contact reaction for 3 hours, monitored until the reaction was complete, adding water to the reaction solution, extracting with dichloromethane, drying over anhydrous sodium sulfate, Concentrate under reduced pressure, recrystallize from petroleum ether, and dry to obtain 19.6 g of the compound represented by formula I, with a yield of 86.8% and an HPLC purity of 99.40%.

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Abstract

The invention discloses a synthesis method of apatinib for treating stomach cancer, which comprises the following steps: (1) carrying out contact reaction between 2-chloro-3-methyl picolinate and 4-diazomethyl-pyridine in a mixed solution in the presence of an alkali to obtain a compound shown as formula I; (2) reacting the compound obtained in step (2) with the compound shown as formula II under stirring and under catalysis of tert-butyl alcohol, filtering reaction solution, concentrating filtrate, pouring into a sodium bisulfite solution, continuing stirring for reaction, regulating pH to 8-9 with saturated sodium bicarbonate after the reaction is complete to obtain apatinib. The method of the invention provides a new route for synthesis of apatinib, and has the following advantages: few reaction steps are involved, the yield of the target product is high, the raw materials are easily-accessible, the product purification is simple, and the method is suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a method for synthesizing Apatinib, a drug for treating gastric cancer. Background technique [0002] Apatinib is a novel tyrosine kinase inhibitor with the chemical name N-[4-(1-cyanocyclopentyl)phenyl]-2-(4-pyridylmethyl)amino-3-pyridine Formamide, the specific structure is as follows: [0003] [0004] As a new generation of tyrosine kinase inhibitors, apatinib has been clinically proven to be effective, safe and well tolerated in the treatment of patients with advanced gastric cancer. The drug is the first to demonstrate the efficacy of anti-angiogenic small molecule targeted drugs in gastric cancer. Tyrosine kinase vascular endothelial growth factor (VEGF) and its receptor (VEGFR) play an extremely important role in tumor angiogenesis, and are important targets in blocking tumor angiogenesis. Vascular endothelial growth factor is the most important r...

Claims

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Application Information

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IPC IPC(8): C07D213/82A61P35/00
CPCC07D213/82
Inventor 陈令浩
Owner QINGDAO CHENDA BIOLOGICAL SCI & TECH
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