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A kind of synthetic method of 2-amino-n-(2-chloro-6-methylphenyl) thiazole-5-carboxamide

A technology of methyl phenyl and synthesis method, which is applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of short synthesis route, high cost, and not amplified production synthesis process, and achieve short synthesis route, low equipment requirements and large implementation value effect

Active Publication Date: 2016-01-27
ZHEJIANG LUOXING IND CO LTD
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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 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
[0021] This method improves the synthesis of 3-ethoxyacryloyl chloride, overcomes the problems of method 3), but the synthetic route becomes longer and the operation is cumbersome
[0022] In summary, none of the methods reported in the literature is the best synthetic process for scale-up production

Method used

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  • A kind of synthetic method of 2-amino-n-(2-chloro-6-methylphenyl) thiazole-5-carboxamide
  • A kind of synthetic method of 2-amino-n-(2-chloro-6-methylphenyl) thiazole-5-carboxamide
  • A kind of synthetic method of 2-amino-n-(2-chloro-6-methylphenyl) thiazole-5-carboxamide

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Embodiment 1

[0036] 1) Synthesis of 3-ethoxyacrylic acid by one-pot method of alkali hydrolysis after nucleophilic substitution of trichloroacetyl chloride and vinyl ether, the specific method is:

[0037] Add 2kg of trichloroacetyl chloride into a 3L reaction bottle, cool with ice salt to below -5°C under stirring, then add 1kg of vinyl ether dropwise, and control the internal temperature <0°C. After the dropwise addition, keep the temperature < 0°C and react for 24 hours, then naturally return to temperature and stir for about 24 hours. GC detects that there is no trichloroacetyl chloride. Water pump vacuum distillation, the temperature of the reaction solution is gradually raised to 100°C, and the reaction solution is distilled until no gas is produced. Cool down to obtain a black liquid crude product, which is directly used in the next step.

[0038] Into a 10L reaction flask, add 500g of sodium hydroxide and 4L of water, stir to dissolve, and then cool down to room temperature. The ...

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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...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D277/56
CPCC07D277/56
Inventor 孙科炎蓝玉明李佶辉常东亮
Owner ZHEJIANG LUOXING IND CO LTD
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