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A kind of preparation technology of dasatinib

A technology of dasatinib and its preparation process, which is applied in the field of drug synthesis and can solve the problems of easy polymerization, increased cost, and reduced yield.

Active Publication Date: 2020-07-07
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

[0041] Embodiment 1: Preparation of 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide

[0042] 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, add 60mL of 78mmol Copper bromide in tetrahydrofuran, heated to reflux for 1h, filtered while hot, kept the filtrate, added 39mmol thiourea, 2.4mmol (NH 4 ) 3 [PMo 12 o 40 ], stirred and reacted at 20-25°C for 15 minutes, and monitored the reaction by TLC (following the reaction until the disappearance of the raw materials). After drying, 6.58 g of 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide was obtained, with a yield of 90.94% and a purity of 99.88%.

Embodiment 2

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

[0044] 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 over, add 60mL of 84mmol Copper bromide in tetrahydrofuran, heat to reflux for 1h, filter while hot, keep the filtrate, add 42mmol thiourea, 2.4mmolH to the filtrate 18 N 3 o 43 PW 12 , stirred and reacted at 20-25°C for 15 minutes, TLC monitored the reaction (followed the reaction until the disappearance of the raw materials), after the reaction, filtered the catalyst, evaporated the filtrate to remove the solvent under reduced pressure, added 50 mL of ether, stirred and crystallized for 20 minutes, suction filtered and dried Finally, 6.59 g of 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide was obtained, with a yield of 91.07% and a purity ...

Embodiment 3

[0045] Example 3: Preparation of 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide

[0046] Dissolve 30mmol of ethyl 3-oxopropionate and 30mmol 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 45min, after the reaction, add 60mL of 60mmol Copper bromide in tetrahydrofuran, heat to reflux for 1h, filter while hot, keep the filtrate, add 30mmol thiourea, 1.5mmol (NH 4 ) 3 [PMo 12 o 40 ], stirred and reacted at 20-25°C for 15 minutes, and monitored the reaction by TLC (following the reaction until the disappearance of the raw materials). After drying, 5.50 g of 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-carboxamide was obtained, with a yield of 85.31% and a purity of 99.69%.

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Abstract

The invention relates to a process for preparing dasatinib. The process includes steps of carrying out heating reflux on 3-oxo-propionic acid ethyl ester and 2-chlorine-6-methylaniline under alkalineconditions, adding cupric bromide, carrying out temperature-rise reflux, adding thiourea and a catalyst heteropoly acid salt, and carrying out room-temperature stirring reaction to obtain 2-amine-N-(2-chlorine-6-methyl phenyl)thiazole-5-formamide; carrying out 'one-pot reaction' on the 2-amine-N-(2-chlorine-6-methyl phenyl)thiazole-5-formamide, 4, 6-dichloro-2-methylpyrimidine and N-hydroxyethyl piperazine under the effects of catalysts to obtain the dasatinib. The process has the advantages of mild condition, simple step, environmental friendliness, high yield and applicability to industrialproduction.

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
CPCC07D417/12
Inventor 高红军吕鹏杨建柱
Owner SHANDONG LUOXIN PHARMA GRP CO LTD
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