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A kind of synthetic method of dasatinib intermediate

A technology for dasatinib and its intermediates, which is applied in the field of synthesis of N--2-[amino]-5-thiazolecarboxamide, the intermediate of dasatinib Product quality impact and other issues

Active Publication Date: 2017-06-23
SHANDONG NEWTIME PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the maximum impurity content of the obtained product is high, and the impurity is easily introduced into the next reaction to form more by-products, which has a great impact on the quality of the final product of dasatinib

Method used

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  • A kind of synthetic method of dasatinib intermediate
  • A kind of synthetic method of dasatinib intermediate

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Embodiment 1

[0027] Add 8.73g of potassium hydride (30% content, 65.38mmol) to 80ml of tetrahydrofuran cooled to -25°C; after addition, stir for 10min; slowly add 5.00g of 2-amino-N-(2-chloro-6-methyl Phenyl)thiazole-5-carboxamide, add the process to control the temperature -25°C; add the tetrahydrofuran (7ml) solution containing 3.65g of 2-methyl-4,6-dichloropyrimidine prepared in advance to the reaction system at one time After stabilization, heat up, stir and react at -10°C for 4h; then slowly add 1mol / L hydrochloric acid dropwise to quench the reaction, adjust the pH to 6, control the temperature at 0-5°C, crystallize for 2h, centrifuge, wash with THF, and dry to obtain the crude product 7.27g. The yield is 98.7%, the purity is 99.95% (HPLC), and the maximum simple impurity content is 0.03%.

Embodiment 2

[0029] Add 2.84g of sodium hydride (60% content, 70.98mmol) to 70ml of tetrahydrofuran cooled to -30°C; after addition, stir for 10min; slowly add 5.00g of 2-amino-N-(2-chloro-6-methyl Phenyl)thiazole-5-carboxamide, add the process to control the temperature -30°C; add the tetrahydrofuran (10ml) solution containing 3.65g of 2-methyl-4,6-dichloropyrimidine prepared in advance to the reaction system at one time After stabilization, heat up, stir and react at -8°C for 6h; then slowly add 1mol / L hydrochloric acid dropwise to quench the reaction, adjust the pH to 6, control the temperature at 0-5°C, crystallize for 2h, centrifuge, wash with THF, and dry to obtain the crude product 7.15g. The yield is 97.1%, the purity is 99.90% (HPLC), and the maximum simple impurity content is 0.04%.

Embodiment 3

[0031]Add 2.19g of sodium amide to 70ml of tetrahydrofuran cooled to -20°C; after addition, stir for 10min; slowly add 5.00g of 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-methanol Amide, add process temperature control -20 ° C; add the tetrahydrofuran (10ml) solution containing 3.35g of 2-methyl-4,6-dichloropyrimidine prepared in advance to the reaction system at one time, and heat up after stabilization, -10 Stir the reaction at ℃ for 2 h; then slowly drop 1 mol / L hydrochloric acid to quench the reaction, adjust the pH to 5, control the temperature at 0-5 °C, crystallize for 3 h, centrifuge, wash with THF, and dry to obtain 7.13 g of crude product. The yield is 96.8%, the purity is 99.82% (HPLC), and the maximum simple impurity content is 0.06%.

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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a Dasatinib intermediate N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methyl-4-pyrimidinyl)amino]-5-thiazolecarboxamide. The method comprises the following steps: adding organic base, 2-amino-N-(2-chloro-6-methylphenyl)-thiazole-5-formamide, and 2-methyl-4,6-dichloropyrimidine into an aprotic solvent in sequence; raising the temperature for reaction, so as to prepare N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methyl-4-pyrimidinyl)amino]-5-thiazolecarboxamide. Compared with the prior art, the synthesis method has the advantages that the yield is higher; the maximum single impurity content is lower; suitability for industrialized production is realized.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to a dasatinib intermediate N-(2-chloro-6-methylphenyl)-2-[(6-chloro-2-methyl-4-pyrimidinyl) The synthetic method of amino]-5-thiazole carboxamide. Background technique [0002] Dasatinib (I), chemical name: N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]- 2-Methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide monohydrate, English name: N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl )-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide, monohydrate, molecular formula: C 22 h 26 ClN 7 o 2 S·H 2 O, is an oral tyrosine kinase inhibitor developed by Bristol-Myers Squibb, which was approved by the US FDA in June 2006. Celloid leukemia (CML) can also be used to treat adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (ph+ALL) who are resistant or intolerant to other therapies. [0003] [0004] At present, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D417/12
CPCC07D417/12
Inventor 张贵民张现利林建伟
Owner SHANDONG NEWTIME PHARMA
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