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A kind of preparation technology of dasatinib

A dasatinib and preparation technology, applied in the field of drug synthesis, can solve the problems of large environmental pollution, cumbersome operation, and reduced yield, and achieve the effects of reducing production costs, simple reaction steps, and fast reaction speed

Active Publication Date: 2022-05-10
SHANDONG LUOXIN PHARMA GRP 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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  • A kind of preparation technology of dasatinib
  • A kind of preparation technology of dasatinib
  • A kind of preparation technology of dasatinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Embodiment 1: the synthesis of compound 3

[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 1h, after the reaction is completed, cool to room temperature, The reaction solution was concentrated to remove tetrahydrofuran, and the residue was poured into 100 mL of ice water. The pH was adjusted to 6-7 with 3N hydrochloric acid, and a solid precipitated out. After filtering, the filter cake was washed with ice water and dried to obtain 5.56 g of compound 3, with a yield of 97.30%. , 99.94% purity.

Embodiment 2

[0045] Embodiment 2: the synthesis of compound 3

[0046] Dissolve 30mmol of ethyl 3-oxopropionate and 39mmol of sodium methoxide in 80mL of tetrahydrofuran, stir at room temperature for 10min, add 30mmol of 2-chloro-6-methylaniline, heat up and reflux for 1h, after the reaction is completed, cool to room temperature, and react The solution was concentrated to remove tetrahydrofuran, the residue was poured into 100 mL of ice water, and the pH was adjusted to 6-7 with 3N hydrochloric acid, then a solid precipitated out, filtered, the filter cake was washed with ice water, and dried to obtain 6.09 g of compound 3 with a yield of 95.83%. 99.92% pure.

Embodiment 3

[0047] Embodiment 3: the synthesis of compound 3

[0048] Dissolve 30mmol of ethyl 3-oxopropionate and 36mmol of sodium methoxide in 80mL of tetrahydrofuran, stir at room temperature for 10min, add 24mmol of 2-chloro-6-methylaniline, heat up and reflux for 1h, after the reaction is completed, cool to room temperature, and react The solution was concentrated to remove tetrahydrofuran, the residue was poured into 100 mL of ice water, and the pH was adjusted to 6-7 with 3N hydrochloric acid, then a solid precipitated out, filtered, the filter cake was washed with ice water, and dried to obtain 4.80 g of compound 3 with a yield of 94.48%. 99.90% pure.

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Abstract

The present invention relates to a preparation process of dasatinib, which comprises the steps of: reacting ethyl 3-oxopropionate with 2-chloro-6-methylaniline under alkaline conditions to obtain compound 3; compound 3 , copper bromide and thiourea are under the effect of hydroxyethyl-β-cyclodextrin, and the heating reaction obtains 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide; 4,6-dichloro-2-methylpyrimidine is successively mixed with N-hydroxyethylpiperazine, 2-amino-N-(2-chloro-6-methylbenzene) under conditions of alkali, catalytic system and organic solvent Base) thiazole-5-carboxamide is reacted to obtain compound 1, i.e. dasatinib. The invention has mild conditions, simple steps, environmental friendliness and high yield, and is suitable for industrialized production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation process 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-m...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D417/12
Inventor 刘振腾朱绪辉谢有翠
Owner SHANDONG LUOXIN PHARMA GRP CO LTD
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