Synthesis method of dasatinib key intermediate

A synthesis method and technology of dasatinib, which are applied in the field of synthesis of key intermediates of dasatinib, can solve the problems affecting reaction selectivity, final yield, harsh conditions, and increased cost, and achieve the improvement of atom utilization, The effect of improving the reaction yield and reducing the workload

Inactive Publication Date: 2018-07-20
安庆奇创药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] In the above method, a large amount of NBS is used for the formation of the thiazole ring, which greatly increases the cost, and the NBS reaction must be carried out at low temperature, and the conditions are harsh, which increases the workload of post-processing. In addition, the synthesis of the thiazole ring will have an impact on by-products Reaction selectivity and final yield

Method used

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  • Synthesis method of dasatinib key intermediate
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  • Synthesis method of dasatinib key intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0040] (1) Preparation of N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (Compound 2)

[0041] At room temperature, 14.1g (100mmol) of 2-chloro-6-methylaniline and 14.7g (110mmol) of NCS were added to the flask, stirred and mixed in 80ml of acetonitrile, and reacted for 1.5h; then the temperature was raised to 60°C and the 5-methylthiazole 14.9g (150mmol), catalyst ferric chloride 1.6g (10mmol), oxidizer 60wt% tert-butyl hydroperoxide aqueous solution 27g (300mmol) and additive tetrabutylammonium iodide 3.7g (10mmol) were added to the mixture obtained by mixing The medium contact reaction for 5h, cool to room temperature, extract with dichloromethane, concentrate the organic phase, wash with water, then recrystallize from ethanol and dry to obtain N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (compound 2 ) 22.9g, the yield is 91%, and the HPLC purity is 99.72%.

Embodiment 2

[0043] Preparation of N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (Compound 2)

[0044] At room temperature, 14.1g (100mmol) of 2-chloro-6-methylaniline and 14.7g (110mmol) of NCS were added to the flask, stirred and mixed in 80ml of acetonitrile, and reacted for 1.5h; then the temperature was raised to 80°C and the 5-methylthiazole 14.9g (150mmol), catalyst ferric chloride 1.6g (10mmol), oxidizer 60wt% tert-butyl hydroperoxide aqueous solution 27g (300mmol) and additive tetrabutylammonium iodide 3.7g (10mmol) were added to the mixture obtained by mixing The medium contact reaction for 5h, cool to room temperature, extract with dichloromethane, concentrate the organic phase, wash with water, then recrystallize from ethanol and dry to obtain N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (Compound 2 ) 23.9g, the yield is 95%, and the HPLC purity is 99.65%.

Embodiment 3

[0046] Preparation of N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (Compound 2)

[0047] At room temperature, 14.1g (100mmol) of 2-chloro-6-methylaniline and 14.7g (110mmol) of NCS were added to the flask, stirred and mixed in 80ml of acetonitrile, and reacted for 1.5h; then the temperature was raised to 90°C and the 5-methylthiazole 14.9g (150mmol), catalyst ferric chloride 1.6g (10mmol), oxidizer 60wt% tert-butyl hydroperoxide aqueous solution 27g (300mmol) and additive tetrabutylammonium iodide 3.7g (10mmol) were added to the mixture obtained by mixing The medium contact reaction for 5h, cool to room temperature, extract with dichloromethane, concentrate the organic phase, wash with water, then recrystallize from ethanol and dry to obtain N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide (Compound 2 ) 23.68g, the yield is 94%, and the HPLC purity is 99.76%.

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Abstract

The invention discloses a synthesis method of a dasatinib key intermediate. The synthesis method comprises the step of carrying out dehydration condensation reaction on a compound 2 and a compound 3 to generate a compound 4, i.e., the dasatinib key intermediate. By adopting the synthesis method of the dasatinib key intermediate, disclosed by the invention, the occurrence of side reaction is greatly reduced, the selectivity of the reaction is improved, and the final yield of dasatinib is improved; the synthesis method is suitable for industrial production. A formula is shown in the description.

Description

Technical field [0001] The invention belongs to the field of medicine and chemical industry, and specifically relates to a method for synthesizing a key intermediate of dasatinib. Background technique [0002] Dasatinib, the chemical name is N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxy)-1-piperazinyl]-2- Methyl-4-pyrimidinyl]amino]-5-thiazolcarboxamide is an oral multiple tyrosine kinase inhibitor developed by Bristol-Myers Squibb. The inhibitors inhibited include Bcr-Abl and Src kinase family (including Fgr , Fyn, Hck, Lck, Lyn and Yes), c-Kit and PDGFR-β etc. Its monohydrate was approved by the US FDA in 2006. It is clinically used to treat chronic myelogenous leukemia, and it can also treat Philadelphia chromosome-positive acute lymphoblastic leukemia. This product has an inhibitory effect on a variety of mutants of Bcr-Ab1 kinase, and the inhibitory strength is greatly improved compared with Imatinib, and no drug resistance has been found. The specific structure is as f...

Claims

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Application Information

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IPC IPC(8): C07D417/12
CPCC07D417/12
Inventor 吴学平时珠勇
Owner 安庆奇创药业有限公司
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