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A kind of convenient preparation method of highly selective 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: 2020-06-23
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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  • A kind of convenient preparation method of highly selective Apatinib
  • A kind of convenient preparation method of highly selective Apatinib
  • A kind of convenient preparation method of highly selective Apatinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

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

[0047] In a 250 ml four-neck flask connected with a stirrer, a thermometer, and a reflux condenser, add 120 g of dimethyl malonate, 18.6 g (0.1 mole) of 1-(4-aminophenyl) cyclopentylcarbonitrile II , stirred at 100-105°C for dealcoholization reaction for 4 hours (the first amidation reaction), recovered excess dimethyl malonate by distillation under reduced pressure, cooled to 60-70°C, and added 13.0 grams (0.12 moles) of 4-ammonia Pyridine IV, 110-115°C stirred dealcoholization reaction 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-cyanocyclopentyl Base) phenylmalonamide, yield 92.6%, liquid phase purity 99.8%.

Embodiment 2

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

[0049] In a 250 ml four-neck flask connected with a stirrer, a thermometer, and a reflux condenser, add 150 g of diethyl malonate, 18.6 g (0.1 mole) of 1-(4-aminophenyl) cyclopentylcarbonitrile II , 105-110°C stirring dealcoholization reaction for 4 hours (the first amidation reaction), vacuum distillation to recover excess diethyl malonate, cooling to 60-70°C, adding 13.0 grams (0.12 moles) of 4-ammonia Pyridine IV, 110-115°C stirred dealcoholization reaction for 4 hours (the second amidation reaction). Cool to 30-40°C, add 80 grams of isopropanol to the residue, recrystallize, filter, and dry to obtain 33.1 grams of N-(4-pyridine)methyl-N'-4-(1-cyanocyclopentyl Base) phenylmalonamide, yield 91.3%, liquid phase purity 99.9%.

Embodiment 3

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

[0051] In the 250 milliliter four-necked flask that is connected with stirrer, thermometer, reflux condenser, add 150 grams of di-tert-butyl malonate, 18.6 grams (0.1 mole) 1-(4-aminophenyl) cyclopentylcarbonitrile Ⅱ, 110-115°C stirring dealcoholization reaction for 4 hours (the first amidation reaction), vacuum distillation to recover excess di-tert-butyl malonate, cooling to 60-70°C, adding 13.0 g (0.12 moles) 4 -Aminomethylpyridine IV, 120-125° C. stirring dealcoholization reaction for 4 hours (the second amidation reaction). Cool to 30-40°C, add 80 grams of isopropanol to the residue, recrystallize, filter, and dry to obtain 32.6 grams of N-(4-pyridine)methyl-N'-4-(1-cyanocyclopentyl Base) phenylmalonamide, yield 90.1%, liquid phase purity 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 highly selective apatinib, which belongs to the technical field of medicinal chemistry. Background technique [0002] Inhibiting tumor angiogenesis is an important means of treating tumors. The tyrosine kinase vascular endothelial growth factor (VEGF) and its receptors 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 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 gastric cancer, which can effectively improve patients' compliance with treatment and significantly...

Claims

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Application Information

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Patent Type & Authority Patents(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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