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High-selectivity simple preparation method of apatinib

A technology of apatinib and the first amide, applied in the field of medicinal chemistry, can solve the problems of high price of 2-chloronicotinyl chloride, complicated steps, large amount of nitrification reaction wastewater, etc., and achieves high addition reaction activity and technological process. Simple, highly active methylene effect

Active Publication Date: 2019-05-28
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The synthesis route has long reaction steps, and the price of raw material 2-chloronicotinoyl chloride is relatively high; 6.0 equivalents of sodium hydride is required for the condensation of phenylacetonitrile and 1,4-dibromobutane, and the amount of sodium hydride is large, which is not conducive to cost reduction and safe operation; nitration reaction The amount of waste water is large, which is not conducive to environmental protection; the condensation temperature of the last step and 4-aminomethylpyridine is high, which is not conducive to product purity assurance and impurity control
[0009] In summary, the existing synthetic technology of apatinib has problems such as cumbersome steps, poor safety and environmental protection, high cost, many impurities, poor selectivity and purity.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1: Preparation of N-(4-pyridine)methyl-N'-4-(1-cyanocyclopentyl)phenylmalonamide (V)

[0047] Into a 250 ml four-necked flask connected with a stirrer, a thermometer and a reflux condenser, add 120 g of dimethyl malonate and 18.6 g (0.1 mol) of 1-(4-aminophenyl)cyclopentylcarbonitrile II , Stir the dealcoholization reaction at 100~105℃ for 4 hours (first amidation reaction), recover the excess dimethyl malonate by distillation under reduced pressure, cool to 60-70℃, add 13.0g (0.12mol) 4-ammonia The methyl pyridine IV was stirred and dealcoholized at 110-115°C for 4 hours (the second amidation reaction). Cool to 30-40°C, add 80 g of isopropanol to the residue, recrystallize, filter, and dry to obtain 33.5 g of N-(4-pyridine)methyl-N'-4-(1-cyanocyclopentan Yl)phenylmalonamide, the yield is 92.6%, and the liquid phase purity is 99.8%.

Embodiment 2

[0048] Example 2: Preparation of N-(4-pyridine)methyl-N'-4-(1-cyanocyclopentyl)phenylmalonamide (V)

[0049] Into a 250 ml four-necked flask connected with a stirrer, a thermometer and a reflux condenser, add 150 g of diethyl malonate and 18.6 g (0.1 mol) of 1-(4-aminophenyl)cyclopentylcarbonitrile II , Stirring dealcoholization reaction at 105~110℃ for 4 hours (first amidation reaction), recovering excess diethyl malonate by distillation under reduced pressure, cooling to 60-70℃, adding 13.0g (0.12mol) of 4-ammonia The methyl pyridine IV was stirred and dealcoholized at 110-115°C for 4 hours (the second amidation reaction). Cool to 30-40°C, add 80 g of isopropanol to the residue, recrystallize, filter, and dry to obtain 33.1 g of N-(4-pyridine)methyl-N'-4-(1-cyanocyclopentan Base) phenylmalonamide, the yield is 91.3%, and the liquid phase purity is 99.9%.

Embodiment 3

[0050] Example 3: Preparation of N-(4-pyridine)methyl-N'-4-(1-cyanocyclopentyl)phenylmalonamide (V)

[0051] Into a 250 ml four-necked flask connected with a stirrer, a thermometer and a reflux condenser, 150 g of di-tert-butyl malonate and 18.6 g (0.1 mol) of 1-(4-aminophenyl)cyclopentylcarbonitrile were added Ⅱ. Stir the dealcoholization reaction at 110~115℃ for 4 hours (the first amidation reaction), recover the excess di-tert-butyl malonate by distillation under reduced pressure, cool to 60-70℃, add 13.0 g (0.12 mole) 4 -Aminomethylpyridine IV, at 120-125°C for 4 hours with stirring and dealcoholization (second amidation reaction). Cool to 30-40°C, add 80 g of isopropanol to the residue, recrystallize, filter, and dry to obtain 32.6 g of N-(4-pyridine)methyl-N'-4-(1-cyanocyclopentan Yl)phenylmalonamide, the yield is 90.1%, and the liquid phase purity is 99.7%.

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Abstract

The invention provides a high-selectivity simple preparation method of apatinib. The high-selectivity simple preparation method comprises the following steps: carrying out first-time amidation reaction on 1-(4-aminophenyl)cyclopentyl carbonitrile II and excessive malonate diester to prepare N-4-(1-cyanocyclopentyl)phenyl monomalonate monoamide III; decompressing, distilling and recycling the excessive malonate diester; adding 4-aminomethylpyridine IV into residues and carrying out second-time amidation reaction to obtain N-(4-pyridine)-methyl-N'-4-(1-cyanocyclopentyl)phenyl malonamide V; carrying out addition-elimination-condensation reaction on a formula shown as a formula V, 2-halogenated acrylaldehyde and ammonia to obtain the apatinib I. The high-selectivity simple preparation method provided by the invention has the advantages that raw materials are cheap and easy to obtain, a technological flow is simple and convenient, the wastewater amount is less, the method is green, safe andenvironmentally friendly and the cost is low; the preparation method provided by the invention has high selectivity and the prepared apatinib has the advantages of few impurities and high purity.

Description

Technical field [0001] The invention relates to a simple and convenient preparation method of apatinib with high selectivity, and belongs to the technical field of medicinal chemistry. Background technique [0002] Inhibition of tumor angiogenesis is an important means to treat tumors. Tyrosine kinase vascular endothelial growth factor (VEGF) and its receptor play an extremely important role in the process of tumor angiogenesis. Apatinib is a new generation Tyrosine kinase inhibitors can block tumor angiogenesis. Apatinib is the world's first safe and effective small molecule anti-angiogenesis targeted drug that has been proven to treat advanced gastric cancer. It is also a single drug that can significantly prolong survival after standard chemotherapy for advanced gastric cancer fails. At the same time, the drug is the only oral preparation among targeted drugs for gastric cancer, which can effectively improve patient compliance with treatment and significantly reduce treatment...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/82C07D213/40C07C253/30C07C255/46
Inventor 戚聿新范岩森鞠立柱
Owner XINFA PHARMA
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