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Method for preparing dasatinib tablets

A technology of dasatinib and quantitative ratio, which is applied in the field of drug synthesis, can solve the problems of long synthetic routes, impure intermediate products, and large environmental pollution, and achieve the effects of increased yield, short reaction time, and reduced pollution

Active Publication Date: 2019-03-22
SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0023] This synthetic route is shorter, is a kind of suitable synthetic train of thought, but there is following shortcoming in this method: the first step reaction uses the large vinyl ethyl ether of danger to make starting material and trichloroacetyl chloride reaction, synthetic ( E)-3-ethoxyacryloyl chloride is highly volatile and difficult to preserve; the second step is to decarboxylate at high temperature. Under this condition, the second step product 3-ethoxyacryloyl chloride is easy to polymerize, resulting in a reduction in yield 1. The intermediate product is impure and needs to be purified by vacuum distillation, and the energy consumption has higher requirements on the equipment; in addition, the third and fourth steps use solvent tetrahydrofuran and dioxane respectively, and the cost is also high, and the fourth step A large amount of NBS is used in the first step, the cost is greatly increased, and the NBS reaction must be carried out at low temperature, and the conditions are harsh. In addition, the workload of post-processing is also increased.
[0026] This method improves the synthesis of 3-ethoxyacryloyl chloride, but the synthesis route becomes longer, the operation is cumbersome, and chlorinated reagents that are volatile and pollute the environment are used in the reaction process

Method used

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  • Method for preparing dasatinib tablets
  • Method for preparing dasatinib tablets
  • Method for preparing dasatinib tablets

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Embodiment 1: Preparation of 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide

[0044] Dissolve 30mmol of ethyl 3-oxopropionate and 37.5mmol of sodium methoxide in 80mL of tetrahydrofuran, stir at room temperature for 10min, add 27mmol of 2-chloro-6-methylaniline, heat up and reflux for 45min, after the reaction, cool to room temperature, Add 60mL tetrahydrofuran dissolved with 81mmol copper bromide, heat to reflux for 1h, filter while it is hot, keep the filtrate, add 42mmol thiourea and 4.5mmol [Bmim]Br to the filtrate, stir and react at 20-25°C for 30min, monitor by TLC Reaction (follow the reaction until the raw materials disappear), after the reaction, pour into ice water, extract with dichloromethane, concentrate the organic phase, wash with water, add 50mL ether and stir for crystallization for 20min, filter and dry to obtain 2-amino-N-( 6.68 g of 2-chloro-6-methylphenyl)thiazole-5-carboxamide, yield 92.31%, purity 99.91%.

Embodiment 2

[0045] Example 2: Preparation of 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide

[0046] Dissolve 30mmol of ethyl 3-oxopropionate and 36mmol of sodium methoxide in 80mL of tetrahydrofuran, stir at room temperature for 10min, add 27mmol of 2-chloro-6-methylaniline, heat up and reflux for 45min, after the reaction, cool to room temperature, add 60mL tetrahydrofuran dissolved with 78mmol copper bromide was heated to reflux for 1h, filtered while it was hot, and the filtrate was collected, and 36mmol thiourea and 3mmol [Bmim]Br were added to the filtrate, and the reaction was stirred at 20-25°C for 30min, and the reaction was monitored by TLC ( Follow the reaction until the raw material disappears), after the reaction, pour into ice water, extract with dichloromethane, concentrate the organic phase, wash with water, add 50mL ether to stir and crystallize for 20min, suction filter and dry to obtain 2-amino-N-(2- Chloro-6-methylphenyl)thiazole-5-carboxamide 6.53g, yield 9...

Embodiment 3

[0047] Example 3: Preparation of 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide

[0048] Dissolve 30mmol of ethyl 3-oxopropionate and 39mmol of sodium methoxide in 80mL of tetrahydrofuran, stir at room temperature for 10min, add 27mmol of 2-chloro-6-methylaniline, heat up and reflux for 45min, after the reaction is completed, cool to room temperature, add 60mL tetrahydrofuran dissolved with 84mmol copper bromide was heated to reflux for 1h, filtered while it was hot, and the filtrate was retained, and 48mmol thiourea and 12mmol [Bmim]Br were added to the filtrate, and the reaction was stirred at 20-25°C for 30min, and the reaction was monitored by TLC ( Follow the reaction until the raw material disappears), after the reaction, pour into ice water, extract with dichloromethane, concentrate the organic phase, wash with water, add 50mL ether to stir and crystallize for 20min, suction filter and dry to obtain 2-amino-N-(2- Chloro-6-methylphenyl)thiazole-5-carboxamide 6...

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Abstract

The invention relates to a method for preparing dasatinib tablets. The method comprises the following steps: enabling 3-oxo-ethyl propionate to react with 2-chlorine-6-methylaniline under an alkali condition, further adding a solvent in which cupric bromide is dissolved to carry out a reaction, further adding thiourea, and cyclizing with a catalyst so as to obtain 2-amino-N-(2-chlorine-6-methyphenyl)thiazole-5-formamide; further synthesizing dasatinib tablets from 4,6-dichloro-2-methyl pyrimidine, N-ethoxy piperazine and 2-amino-N-(2-chlorine-6-methyphenyl)thiazole-5-formamide according to a one-pot method under the action of an alkali and an ionic liquid 1-butyl-3-methylimidazole glycinate. The method is mild in condition, simple in step, environmentally friendly, high in yield and applicable to industrial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of dasatinib. Background technique [0002] Dasatinib (Dasatinib, trade name Sprycel), chemical name N-(2-chloro-6-methylphenyl)-2-[6-[4-(2-hydroxyethyl)-1-piper Azinyl]-2-methyl-4-pyrimidinyl]amino-5-thiazole carboxamide is an oral tyrosine kinase inhibitor developed by Bristol-Myers Squibb. The drug was approved by the FDA in June 2006 for the treatment of chronic myelogenous leukemia and also for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia. This product has inhibitory effects on various mutants of Bcr-Ab1 kinase, and the inhibitory intensity is much higher than that of Imatinib, and no drug resistance has been found. Its structural formula is as follows: [0003] [0004] Regarding the synthesis of dasatinib, there are many domestic and foreign literature reports, most of which are intermediate 2-amino-N-(2-chloro-6-me...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12
CPCC07D417/12
Inventor 高红军张会任庆伟
Owner SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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