Preparation method of 2-amino-4,6-dichloro-5-carboxamidopyrimidine

A technology of formamide and pyrimidine, applied in the field of chemical pharmacy, can solve the problems of complex operation, difficult process control, by-products, etc., and achieve the effects of improving reaction yield, eliminating by-products, and simplifying operation.

Active Publication Date: 2015-07-29
SUZHOU KAIYUAN MINSHENG SCI & TECH CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Such as patent No. WO2004103979, CN101003511, etc., the operation is more complicated, especially in the step-by-step hydrolysis step, the process is difficult to master, and by-products are easily generated

Method used

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  • Preparation method of 2-amino-4,6-dichloro-5-carboxamidopyrimidine
  • Preparation method of 2-amino-4,6-dichloro-5-carboxamidopyrimidine

Examples

Experimental program
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Effect test

Embodiment 1

[0034] Synthesis of diethyl isonitrosomalonate (I):

[0035] Add acetic acid: 92ml, diethyl malonate: 80g into a 500ml four-necked bottle, stir and cool to below 10 degrees, slowly add 40% sodium nitrite aqueous solution: 250g, keep the temperature at 5-10 degrees during the dropping After the dropwise addition, the temperature was slowly raised to 40-45° C. for 3.5 hours. After the reaction was completed, it was cooled to 10° C., allowed to stand for stratification, and the lower water layer was removed to obtain the upper oil layer as crude product, weighing 92.6 g, yield: 98%.

Embodiment 2

[0037] Synthesis of diethyl isonitrosomalonate (I):

[0038]Add acetic acid: 150ml, diethyl malonate: 80g into a 500ml four-necked bottle, stir and cool to below 10 degrees, slowly add 40% sodium nitrite aqueous solution: 300g, keep the temperature at 5-10 degrees during the dropping After the dropwise addition is completed, slowly raise the temperature to 30-35°C and keep it warm for 5 hours. After the reaction is completed, cool to 10°C, let it stand for stratification, remove the lower water layer, and obtain the upper oil layer which is diethyl isonitrosomalonate Ⅰ. Crude product, weighing 90.4g, yield: 95%.

Embodiment 3

[0040] Synthesis of diethyl formylaminomalonate (Ⅱ):

[0041] Add crude diethyl isonitrosomalonate I: 92.6g, formic acid: 260g into a 1000ml four-necked bottle, add 90g of zinc powder in batches under stirring, during the addition, control the temperature at 30-32°C, and raise the temperature after the addition After 6 hours of reflux reaction, after the reaction is over, cool down to room temperature, add 200 g of water to recover formic acid under reduced pressure, a large amount of solids precipitate out after recovery, cool down to 10 degrees and filter to obtain a white solid, and dry to obtain the product formylaminomalonic acid di Ethyl ester II: 93.8 g, yield: 95%.

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Abstract

The invention relates to a method for preparing 2-amino-4,6-dichloro-5-formamido pyrimidine. The method comprises the following steps of: performing nitrosation on malonic acid diethyl ester and acetic acid serving as raw materials and sodium nitrite at first; then, performing reduction and formylation with formic acid in the presence of zinc powder to form formyl amino malonic acid diethyl ester; finally, performing condensation and cyclization with guanidine hydrochloride to produce 2-amino-4,6-dichloro-5-formamido pyrimidine; performing chlorination by using quaternary ammonium salt as a catalyst; fractionally performing hydrolysis under an alkali action to obtain a product. The method has easily-available raw materials, and is short in reaction time, simple in aftertreatment and high in hydrolysis selectivity; the cost is obviously reduced; the total yield is up to 74 percent and the purity of the product is up to 99.0 percent.

Description

technical field [0001] The invention relates to a preparation method of an intermediate 2-amino-4,6-dichloro-5-carboxamidopyrimidine of the anti-AIDS drug abacavir, belonging to the technical field of chemical pharmacy. Background technique [0002] AIDS is a clinical syndrome that is prone to opportunistic infections and tumors due to deficiencies in human defense skills caused by human immunodeficiency virus infection. The number of AIDS patients in the world is increasing at an average annual rate of 20%, which seriously threatens human health. Among the many AIDS treatment programs, "cocktail therapy" is by far the most effective method for treating AIDS, and abacavir is an indispensable drug component in "cocktail therapy". Abacavir (abacavir,) was produced by Glaxo Wellcome in the UK and was launched in July 1999. Its chemical name is (1S, 4R)-cis-4-(2-amino-6-cyclopropylamino-9 -H-purin-9-yl)-2-cyclopentene-1-methanol belongs to nucleoside reverse transcriptase inhi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/48
CPCC07D239/48
Inventor 曾淼徐剑锋蒋长生孙思
Owner SUZHOU KAIYUAN MINSHENG SCI & TECH CORP
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