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Preparation method of N-(2,4-fluorobenzoyl)-4-methoxyl-3-oxobutyrylamide

A technology of oxobutyramide and fluorobenzoyl, which is applied in the field of preparation of N--4-methoxy-3-oxobutanamide, can solve the problems of harsh reaction conditions, long reaction steps, difficult industrialized operation and the like , to achieve the effect of simple and easy-to-obtain raw materials, few reaction processes, and easy operation.

Active Publication Date: 2018-04-20
ZHEJIANG LANGHUA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Yet in this method route, used raw material 2-methoxy ethyl acetoacetate is expensive, and reaction step is long simultaneously, and reaction condition is very harsh, causes industrialized operation difficulty, is not suitable for industrialized production

Method used

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  • Preparation method of N-(2,4-fluorobenzoyl)-4-methoxyl-3-oxobutyrylamide
  • Preparation method of N-(2,4-fluorobenzoyl)-4-methoxyl-3-oxobutyrylamide

Examples

Experimental program
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Effect test

Embodiment 1

[0054] Add 14.2g cyclo(ethylene)isopropyl malonate (Formula I), 300ml dichloromethane, and 20.2g triethylamine into a 500mL reaction flask, stir and cool to 0-10°C, add dropwise 13g methoxyethyl Acyl chloride, rise to room temperature reaction after dropwise addition, until the raw material reaction is complete;

[0055] Then, filter, the organic phase is washed 2 times with 100g water, discard the water layer, and the organic layer is concentrated to dryness to obtain 21.3g of crude product comprising the compound of formula III, and the crude yield of the product is 100%, which can be directly used in the next step without purification operate.

Embodiment 2

[0057] Add 14.2g of cyclo(ethylene)isopropyl malonate (formula I), 200ml of tetrahydrofuran, 20.2g of N-methylmorpholine into a 500mL reaction flask, stir and cool to 0-10°C, add dropwise 20g of methoxyacetic anhydride , After the dropwise addition is completed, it is raised to room temperature and reacted until the reaction of the raw materials is completed;

[0058] Then, filter, concentrate the organic layer to dryness, add 300ml of dichloromethane for extraction, wash the organic phase twice with 100g water, discard the water layer, concentrate the organic layer to dryness, and recrystallize to obtain 18.2g of the compound of formula III, with a yield of 85.0% .

Embodiment 3

[0060] Add 14.2g of cyclo(ethylene)isopropyl malonate (Formula I) and 200ml of tetrahydrofuran into a 500mL reaction flask, stir and cool to 0-10°C, add 8.2g of sodium methoxide, and then dropwise add 13.5g of methyl methoxyacetate Esters, after the dropwise addition, rise to room temperature and react until the reaction of the raw materials is complete;

[0061] Then, add 5% hydrochloric acid dropwise to adjust the pH to neutral, add 300ml of toluene for extraction, wash the organic phase twice with 100g of water, discard the water layer, concentrate the organic layer to dryness, and recrystallize to obtain 16.8g of the compound of formula III. 78.5%.

[0062] Preparation of N-(2,4-fluorobenzoyl)-4-methoxy-3-oxobutanamide (compound of formula IV)

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Abstract

The invention provides a preparation method of N-(2,4-fluorobenzoyl)-4-methoxyl-3-oxobutyrylamide. In the preparation method provided by the invention, Meldrum's acid is adopted as a raw material which is simple and easily available; moreover, the reaction process is short, the reaction conditions are mild, thus the preparation method is suitable for industrial and large-scale production of a Dolutegravir intermediate compound N-(2,4-fluorobenzoyl)-4-methoxyl-3-oxobutyrylamide.

Description

technical field [0001] The present invention relates to the field of pharmaceutical intermediates, in particular to a preparation method of N-(2,4-fluorobenzoyl)-4-methoxy-3-oxobutyramide. Background technique [0002] Human immunodeficiency virus (human immunodeficiency virus, HIV) was first discovered in the United States in 1981. It is a lentivirus that infects cells of the human immune system and is a type of retrovirus. This virus destroys the immune ability of the human body, causes the immune system to lose resistance, thereby causes various diseases and cancers to survive in the human body, and finally causes AIDS (acquired immunodeficiency syndrome), and there is still no effective treatment so far. [0003] Dolutegravir (DTG, trade name: TIVICAY) was approved by the US Food and Drug Administration on August 12, 2013. It is a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor ( INSTI), suitable for the treatment of HIV-1 infection in ad...

Claims

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Application Information

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IPC IPC(8): C07C235/80C07C231/02C07D309/32C07D498/14
CPCC07C231/02C07D309/32C07D498/14C07C235/80
Inventor 林邦平曹兆江陈丹峰樊应波
Owner ZHEJIANG LANGHUA PHARMA
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