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Preparation method and intermediate of apatinib

A technology of apatinib and intermediates, applied in the field of drug synthesis, can solve problems such as unfavorable industrial production, difficult preparation, and difficulty in purchasing, and achieve high yield and purity, optimized reaction process, and less impurities in the product Effect

Active Publication Date: 2018-08-31
江苏美迪克化学品有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Its method uses 4-diazomethyl-pyridine and 1-(4-bromophenyl)-1-cyanocyclopentane as raw materials, but it is not easy to buy in the market, the preparation difficulty is also relatively large, and the cost is relatively high , is not conducive to the promotion of industrial production

Method used

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  • Preparation method and intermediate of apatinib
  • Preparation method and intermediate of apatinib
  • Preparation method and intermediate of apatinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] The synthetic route is as follows:

[0054]

[0055] A) Preparation of 2-[(pyridine-4-methyl)amino]nicotinic acid methyl ester (compound (II), R is methyl):

[0056] Methyl 2-chloronicotinate (18.8g, compound (Ⅲ), R is methyl, X 1 Chloro) was dissolved in chloroform (220mL), piperidine (15.9g) was added, stirred and cooled in an ice bath to 5-10°C, a solution of 4-(aminomethyl)pyridine (14.2g) in chloroform (15mL) was added dropwise, Raise to 35°C and react for 8 hours until the reaction is complete, then lower to room temperature, add 200ml of water, adjust to neutral with 1N hydrochloric acid, separate the organic phase, wash with water and saturated brine successively, dry over anhydrous sodium sulfate, and concentrate to dryness by rotary evaporation under reduced pressure , the obtained crude product was recrystallized from ethanol to obtain methyl 2-[(pyridine-4-methyl)amino]nicotinate, 25.1 g of off-white solid, yield 94.2%, and purity 99.1%.

[0057] B) Pre...

Embodiment 2

[0060] The synthetic route is as follows:

[0061]

[0062] A) Preparation of ethyl 2-[(pyridine-4-methyl)amino]nicotinate (compound (II), R is ethyl):

[0063] 2-Bromonicotinic acid ethyl ester (25.0g, compound (Ⅲ), R is ethyl, X 1 Bromine) was dissolved in isopropanol (270mL), lithium hydroxide (6.8g) was added, stirred and cooled in an ice bath to 5-10°C, and 4-(aminomethyl)pyridine (16.5g) was added dropwise in isopropanol (20mL) solution, raised to 45°C and reacted for 5h until the reaction was complete, lowered to room temperature, adjusted to neutrality with 1N hydrochloric acid, removed the organic solvent by rotary evaporation under reduced pressure, added dichloromethane and water for extraction, separated the organic phase, followed by water Wash with saturated brine, dry over anhydrous sodium sulfate, concentrate to dryness by rotary evaporation under reduced pressure, and recrystallize the obtained crude product with ethanol to obtain ethyl 2-[(pyridine-4-meth...

Embodiment 3

[0067] The synthetic route is as follows:

[0068]

[0069] A) Preparation of ethyl 2-[(pyridine-4-methyl)amino]nicotinate (compound (II), R is ethyl):

[0070] Ethyl 2-aminonicotinate (55.0g, compound (IV), R is ethyl) was put into toluene (700mL), N,N-diisopropylethylamine (85.5g) was added, stirred and cooled in an ice bath To 5~10 ℃, dropwise add 4-chloromethylpyridine (46.5g, compound (Ⅴ), X 2 Chlorine) in toluene (65mL) solution, heated to 40°C and reacted for 9h until the reaction was complete, cooled to room temperature, adjusted to neutral with 1N hydrochloric acid, removed the organic solvent by rotary evaporation under reduced pressure, added dichloromethane and water for extraction, separated The organic phase was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, concentrated to dryness by rotary evaporation under reduced pressure, and the obtained crude product was recrystallized with ethanol to obtain ethyl 2-[(pyridine-...

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Abstract

The invention discloses a preparation method and an intermediate of apatinib. The preparation method comprises the steps as follows: the intermediate 2-[(pyridine-4-methyl)amino]alkane nicotinate and1-(4-aminophenyl)-1-cyanocyclopentane are subjected to an amidation reaction in the presence of an alkaline substance in a reaction solvent to produce apatinib. By the means of the method, the reaction process can be milder, the operation is simple, no pollutants are produced, and more ideal yield and purity can be realized.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of apatinib and an intermediate thereof. Background technique [0002] Apatinib, a novel targeting vascular growth factor receptor (VEGFR) inhibitor, is a national 1.1 new drug for the treatment of advanced gastric cancer. Its excellent efficacy, safety and good tolerance have attracted the attention of the industry. It is well received and has been approved by the national FDA for marketing. The chemical name of Apatinib is N-[4-(1-cyanocyclopentyl)phenyl]-2-[(4-pyridylmethyl)amino]-3-pyridinecarboxamide, and its chemical structure is: [0003] [0004] There have been patent reports on the preparation method of Apatinib, such as the preparation process route of Apatinib disclosed in patent US20040259916 and CN1281590C. The first method is to use phenylacetonitrile and 1,4-dibromobutane as raw materials, through cyclization , nitration, and red...

Claims

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Application Information

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IPC IPC(8): C07D213/82C07D213/80
CPCC07D213/80C07D213/82
Inventor 杨盟徐肖洁景亚婷
Owner 江苏美迪克化学品有限公司
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