2-amino-N-(2-chloro-6-methyl phenyl)thiazole-5-carboxamide synthesis method

Abstract

The invention relates to a 2-amino-N-(2-chloro-6-methyl phenyl)thiazole-5-carboxamide synthesis method, wherein the compound 2-amino-N-(2-chloro-6-methyl phenyl)thiazole-5-carboxamide is a key intermediate for synthesizing dasatinib. The synthesis method comprises that: 1) trichloroacetyl chloride and ethyl vinyl ether are subjected to a nucleophilic substitution and hydrolysis reaction one-pot method to synthesize 3-ethoxyacrylic acid; 2) 3-ethoxyacrylic acid is subjected to an acyl chlorination and amidation reaction one-pot method to synthesize N-(2-chloro-6-methyl phenyl)-3-ethoxy acrylamide; and 3) N-(2-chloro-6-methyl phenyl)-3-ethoxy acrylamide, NBS and thiourea are subjected to a reaction to obtain 2-amino-N-(2-chloro-6-methyl phenyl)thiazole-5-carboxamide. The synthesis method has characteristics of yield increase, cost reduction, operation simplifying, and high implementation value.

Description

technical field [0001] The present invention relates to a synthetic method of a pharmaceutical intermediate, especially a synthetic method of 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide, which is a synthetic method of dasatinib a key intermediate. Background technique [0002] Dasatinib (Dasatinib, trade name Sprycel) is an oral tyrosine kinase inhibitor developed by Bristol-Myers Squibb, its chemical name is N-(2-chloro-6-methylphenyl )-2-[6-[4-(2-Hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino-5-thiazolecarboxamide monohydrate. The drug was approved by the FDA in June 2006 for the treatment of patients with chronic myeloid leukemia who are resistant or intolerant to imatinib; at the same time, it is also used to treat patients with chronic myeloid leukemia who are resistant or intolerant to other therapies. Adult patients with chromosomally positive acute lymphoblastic leukemia. The drug achieved sales of 130 million US dollars in 2009, which sho...

AI Technical Summary

Problems solved by technology

[0018] The synthesis route of this method is relatively short, and it is a kind of well-suited synthetic train of thought, but this method has the following disadvantages: the second step needs to be degraded and decarboxylated at high temperature, and under this condition, the second step product 3-ethoxypropene Acyl chlorides are easy to polymerize, resulting in reduced yield and impure intermediate products, which require vacuum distillation and purification, and the energy consumption has higher requirements on equipment; in addition, the third and fourth steps use solvent tetrahydrofuran and dioxane respectively, and the cost The cost is also high

[0022] In summary, none of the methods reported in the literature is the best synthetic process for scale-up production

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