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The preparation method of Apatinib

A technology of apatinib and alkyl cyclopentanecarboxylate, which is applied in the field of medicinal chemical synthesis, can solve the problems of difficult separation and purification, difficult to eliminate impurities, and reduced yield, and achieves cost reduction, less impurities, and less side reactions. control effect

Active Publication Date: 2020-08-07
SUZHOU FUSHILAI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] The amidation reaction involved also requires an expensive condensing agent, which not only increases the cost, but also makes separation and purification difficult, impurities are difficult to eliminate, and the yield decreases

Method used

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  • The preparation method of Apatinib
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  • The preparation method of Apatinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] A) Preparation of methyl 1-[4-(tert-butoxycarbonylamino)phenyl]cyclopentanecarboxylate:

[0054] Add 60% sodium hydride (5.7g, 141.3mmol), chloroform (300mL) and methyl 4-(tert-butoxycarbonylamino)phenylacetate (25.0g, 94.2mmol) to the reaction flask, stir for 10min, add dropwise 1,4 -Dibromobutane (24.4g, 113.1mmol) in chloroform (20mL) solution, the reaction mixture was stirred and reacted at 60°C for 12h, after the reaction was completed, the reaction solution was lowered to 5°C, dilute hydrochloric acid was added dropwise to adjust the pH=7, and the reaction solution reduced Remove the organic solvent by rotary evaporation, add ethyl acetate for extraction, dry over magnesium sulfate, concentrate to dryness by rotary evaporation, recrystallize from isopropanol, and dry to obtain 1-[4-(tert-butoxycarbonylamino)phenyl]cyclopentane Methyl formate, off-white to white solid (26.8g), yield 89.0%;

[0055] B) Preparation of methyl 1-(4-aminophenyl)cyclopentanecarboxylate:...

Embodiment 2

[0066] A) Preparation of ethyl 1-[4-(tert-butoxycarbonylamino)phenyl]cyclopentanecarboxylate:

[0067] Potassium hydride (49.5g, 1.23mol), toluene (1400mL) and ethyl 4-(tert-butoxycarbonylamino)phenylacetate (123.0g, 0.44mol) were added to the reaction flask, stirred for 10min, and 1,4-bis Bromobutane (190.1g, 0.88mol) in toluene (200mL) solution, the reaction mixture was stirred and reacted at 80°C for 10h, after the reaction was completed, the reaction solution was lowered to 5°C, dilute hydrochloric acid was added dropwise to adjust the pH=7, the reaction solution was decompressed and spun Remove the organic solvent by evaporation, extract with ethyl acetate, dry over magnesium sulfate, concentrate to dryness by rotary evaporation, recrystallize from isopropanol, and dry to obtain ethyl 1-[4-(tert-butoxycarbonylamino)phenyl]cyclopentanecarboxylate Ester, off-white to white solid (128.5g), yield 87.5%;

[0068] B) Preparation of ethyl 1-(4-aminophenyl)cyclopentanecarboxylat...

Embodiment 3

[0079] A) Preparation of methyl 1-[4-(tert-butoxycarbonylamino)phenyl]cyclopentanecarboxylate:

[0080] Potassium tert-butoxide (296.1g, 2.64mol), N,N-dimethylformamide (5000mL) and methyl 4-(tert-butoxycarbonylamino)phenylacetate (200.0g, 0.75mol) were added to the reaction flask, Stir for 10 min, add dropwise a solution of 1,4-dichlorobutane (239.4g, 1.88mol) in N,N-dimethylformamide (300mL), and raise the reaction mixture to 100°C and stir for 6h. After the reaction is complete, the reaction solution Decrease to 5°C, add dilute hydrochloric acid dropwise to adjust the pH to 7, remove the organic solvent by rotary evaporation under reduced pressure, add ethyl acetate for extraction, dry over magnesium sulfate, concentrate to dryness by rotary evaporation, recrystallize from isopropanol, and dry to obtain 1 -[4-(tert-butoxycarbonylamino)phenyl]cyclopentanecarboxylic acid methyl ester, off-white to white solid (219.1g), yield 91.0%;

[0081] B) preparation of 1-(4-aminophenyl...

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Abstract

The invention relates to a preparation method for apatinib. The preparation method comprises the following steps: performing condensation reaction on 4-(tert-butoxycarbonyl group) alkyl phenylacetateand 1,4-butane dihalide, thereby acquiring 1-[4-(tert-butoxycarbonyl group) phenyl] alkyl cyclopentane formate; performing deprotection reaction on the acquired product, thereby acquiring 1-(4-aminophenyl) alkyl cyclopentane formate; performing amidation reaction on the acquired product and 2-chloronicotinoyl chloride, thereby acquiring 1-{4-[(2-chlorine pyridine-3-group) carbonyl amino] phenyl} alkyl cyclopentane formate; performing substitution reaction on the acquired product and 4-aminomethyl pyridine, thereby acquiring 1-{4-[(2-((4-pyridyl methyl) amino) pyridine-3-group) carbonyl amino]phenyl} alkyl cyclopentane formate; performing amidation reaction on the acquired product, thereby acquiring 1-{4-[(2-((4-pyridyl methyl) amino) pyridine-3-group) carbonyl amino] phenyl} cyclopentaneformamide; lastly, dehydrating, thereby acquiring an end product.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a preparation method of Apatinib. Background technique [0002] The aforementioned Apatinib (Apatinib) is a novel targeting vascular growth factor receptor (VEGFR) inhibitor. It is a national 1.1 new drug independently developed by Jiangsu Hengrui Medicine Co., Ltd. and is used for the treatment of advanced gastric cancer. Excellent curative effect, safety and good tolerance, so it has attracted the attention and praise of the industry, and has been approved by the national FDA for marketing. The sales of apatinib are growing rapidly, and the sales in 2017 reached more than 1.8 billion yuan, and the market prospect is very promising. 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 are existing patent reports on the p...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/82
Inventor 莫国宁钱祥云
Owner SUZHOU FUSHILAI PHARMA CO LTD
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