Synthetic method of 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester

Abstract

The invention relates to a synthetic method of 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester. The synthetic method comprises the following steps of: carrying out bromination reaction on propionaldehyde and bromine at the temperature of 0-50 DEG C to obtain 2-bromopropanal, wherein the adopted solvent is a non-proton solvent; and carrying out ring-closure reaction on 2-bromopropanal, ethyl acetoacetate and ammonia water to obtain 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester. The synthetic method of 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester has the advantages of mild reaction conditions, available raw materials, high conversion rate, simple operation steps and easy realization of large-scale industrialized production; the defects of too high cost and pollution of sodium nitrite to the environment and disadvantages on large-scale industrial production, which are caused by adoption of tert-butyl acetoacetate, can be avoided; available ethyl acetoacetate and ammonia water are adopted as raw materials, operation is easy, aftertreatment is simple, and large-scale industrial production is easy to realize; and the defects of unmanageable reaction process, high product impurity content and low yield during hydrolysis, which are caused as tert-butyl acetoacetate is adopted as a closed-loop reagent, can be avoided.

Description

technical field [0001] The invention relates to a method for synthesizing ethyl 2,4-dimethyl-3-pyrrolecarboxylate, and relates to the field of medicinal chemistry. Background technique [0002] 2,4-dimethyl-3-pyrrole carboxylic acid ethyl ester, its structural formula is as follows: [0003] [0004] Ethyl 2,4-dimethyl-3-pyrrolecarboxylate is an important intermediate in the synthesis of sunitinib malate. Sunitinib, chemical name N-[2-(diethylamino)ethyl]-5-[(Z)-5-fluoro-1,2-dihydro-2-oxoindole- 3-enmethyl]-2,4-dimethyl-1H-pyrrole carboxamide, an oral multi-target receptor tyrosine kinase inhibitor launched in 2006, is clinically used for malignant gastrointestinal stromal tumors and metastasis treatment of renal cell carcinoma. Sunitinib has dual effects of anti-tumor growth and inhibition of angiogenesis. On January 26, 2006, it was approved by the US FDA for the treatment of ARCC and GIST. [0005] The existing synthetic routes of 2,4-dimethyl-3-pyrrolecarboxylic ...

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Problems solved by technology

[0008] The method mainly has the following disadvantages: a, long synthetic route, poor economy; b, adopting sodium nitrite and zinc as reaction reagents, which easily pollutes the environment; c, difficult to control the reaction during hydrolysis, resulting in product purity and yield Low; d. The operation steps are cumbersome, the post-processing is complicated, and the industrial productivity is not good

[0011] This method mainly has the following deficiencies: a, the raw materials are relatively rare, and the price is relatively high; b, the hydrolysis process is difficult to control, and the post-treatment is complicated

[0014] This method mainly has the following disadvantages: 1) The reagents 2-hydroxypropylamine and triphenylpalladium phosphide are relatively expensive, resulting in high production costs; 2) The reaction conditions are harsh, post-processing is troublesome, and it is not easy for large-scale industrial production

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