A kind of Apatinib intermediate and preparation method thereof

A technology of apatinib and intermediates, which is applied in the field of medicinal chemical synthesis, can solve the problems of difficult to eliminate impurities, difficult separation and purification, and increased cost, and achieves the effects of less impurities, simplified process method, and optimized reaction steps.

Active Publication Date: 2020-08-14
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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  • A kind of Apatinib intermediate and preparation method thereof
  • A kind of Apatinib intermediate and preparation method thereof
  • A kind of Apatinib intermediate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] (A) Preparation of ethyl 4-[(2-chloropyridin-3-yl)carbonylamino]phenylacetate:

[0047] Ethyl 4-aminophenylacetate (55.0g, 0.31mol) was dissolved in N,N-dimethylformamide (1500mL), N,N-diethylaniline (68.7g, 0.46mol) was added, stirred and ice bathed Cool to 5-10°C, add dropwise a solution of 2-chloronicotinoyl chloride (59.4g, 0.34mol) in N,N-dimethylformamide (60mL), after dropping, the reaction mixture rises to 40°C for 10h until the reaction is complete , lowered to room temperature, 1N hydrochloric acid was added dropwise to adjust to pH = 7, the organic solvent was removed by rotary evaporation under reduced pressure, ethyl acetate and water were added for extraction, the organic phase was separated, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and reduced Concentrated to dryness by rotary evaporation, the resulting crude product was recrystallized with isopropanol and dried to give ethyl 4-[(2-chloropyridin-3-yl)carbony...

Embodiment 2

[0053] (A) Preparation of methyl 4-[(2-chloropyridin-3-yl)carbonylamino]phenylacetate:

[0054] Methyl 4-aminophenylacetate (100.0g, 0.61mol) was dissolved in 1,4-dioxane (2500mL), sodium carbonate (128.3g, 1.21mol) was added, stirred and cooled in an ice bath to 5-10°C, Add dropwise a solution of 2-chloronicotinoyl chloride (159.8g, 0.91mol) in 1,4-dioxane (100mL). After dropping, the reaction mixture rises to 60°C and reacts for 6h until the reaction is complete. After cooling down to room temperature, add 1N Hydrochloric acid was adjusted to pH = 7, the organic solvent was removed by rotary evaporation under reduced pressure, ethyl acetate and water were added for extraction, the organic phase was separated, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, concentrated to dryness by rotary evaporation under reduced pressure, the obtained The crude product was recrystallized with isopropanol and dried to obtain methyl 4-[(2-chloropyrid...

Embodiment 3

[0060] (A) Preparation of methyl 4-[(2-chloropyridin-3-yl)carbonylamino]phenylacetate:

[0061] Methyl 4-aminophenylacetate (153.0g, 0.93ol) was dissolved in chloroform (3500mL), added pyridine (131.9g, 1.67mol), stirred and cooled to 5-10°C in an ice bath, and 2-chloronicotinoyl chloride ( 211.9g, 1.20mol) of chloroform (250mL) solution, after dropping, the reaction mixture was incubated at 20°C for 16h until the reaction was complete, then cooled to room temperature, 1N hydrochloric acid was added dropwise to adjust the pH to 7, the organic solvent was removed by rotary evaporation under reduced pressure, and the Extracted with ethyl acetate and water, separated the organic phase, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, concentrated to dryness by rotary evaporation under reduced pressure, the obtained crude product was recrystallized with isopropanol, dried to give 4-[(2 -Chloropyridin-3-yl)carbonylamino]phenylacetic acid meth...

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Abstract

An Apatinib intermediate and its preparation method belong to the technical field of pharmaceutical chemical synthesis. The chemical name of the Apatinib intermediate is 1-{4-[(2-((4-pyridyl methyl)amino)pyridine-3-yl)carbonylamino]phenyl}cyclopentanecarboxylic alkyl ester. The preparation method comprises the following steps: 4-aminophenylacetic alkyl ester and 2-Chloronicotinyl chloride are subjected to an amidation reaction in a system of an acid-binding agent base and a solvent to obtain 4-[(2-chloropyridine-3-yl)carbonylamino]phenylacetic alkyl ester; the product and 4-aminomethylpyridineare subjected to a substitution reaction in a system of an acid-binding agent base and a solvent to obtain 4-{[2-((4-pyridylmethyl)amino)pyridine-3-yl]carbonylamino}phenylacetic alkyl ester; and theproduct and 1,4-dihalogenbutane are subjected to a condensation reaction to obtain a finished product. The technology is simple, is low-cost, is green and environmentally-friendly, and is suitable forindustrial production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to an apatinib intermediate, and also relates to a preparation method thereof. Background technique [0002] The aforementioned Apatinib is a novel targeting vascular growth factor receptor (VEGFR) inhibitor, a national 1.1 new drug independently developed by Jiangsu Hengrui Medicine Co., Ltd., for the treatment of advanced gastric cancer, due to its excellent The curative effect, safety and good tolerance of the drug have attracted the attention and praise of the industry, and it has been approved by the 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 exi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/82
CPCC07D213/82
Inventor 莫国宁钱祥云
Owner SUZHOU FUSHILAI PHARMA CO LTD
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