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A kind of preparation method of dasatinib

A technology of dasatinib and compound, applied in the field of preparation of dasatinib, can solve the problems of low product purity and yield, large amount of three wastes, poor operation safety, etc., and achieves high purity and yield and low cost , the effect of less side effects

Active Publication Date: 2020-08-18
XINFA PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0023] The raw material 2-aminothiazole-5-carboxylic acid methyl ester used in the above synthetic route 5 is easy to self-polymerize, and in addition, it is unavoidable to produce the disubstituted side reaction impurity of 4,6-dichloro-2-methylpyrimidine
[0024] In summary, in the prior art, the preparation method of dasatinib has disadvantages such as many steps, cumbersome operation, poor operation safety, large amount of three wastes, high cost, many side reactions, low product purity and yield, etc. It is of great significance to design a synthetic route of dasatinib with simple steps, safe and convenient operation, green environmental protection, low cost, easy realization, high selectivity, high yield and high purity

Method used

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  • A kind of preparation method of dasatinib
  • A kind of preparation method of dasatinib
  • A kind of preparation method of dasatinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] Example 1: 2-[[6-[4-(2-Acetoxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxylic acid (Ⅵ) preparation of

[0075] In a 1000 ml four-necked flask connected with a stirring, thermometer, and vacuum distillation device, add 500 g of N,N-dimethylformamide, 41.6 g (0.2 moles) of 2-bromothiazole-5-carboxylic acid (II), 100.0 grams (0.73 moles) of potassium carbonate, 29.0 grams (0.2 moles) of 2-methyl-4-amino-6-chloropyrimidine (Ⅲ), heating, stirring at 90 to 95 ° C for 4 hours, while slightly reducing pressure to collect low boiling (aqueous solvent), cooled to 70-75°C, added 37.8 grams (0.22 moles) of 4-(2-acetoxy)ethylpiperazine (Ⅴ), stirred and reacted at 100 to 105°C for 4 hours, while collecting low boiling (aqueous solvent), the solvent is recovered by distillation under reduced pressure, cooled to 30-50 ° C, added 300 grams of water, 30% hydrochloric acid to neutralize the pH value of the system to 2.0, filtered, the filter cake was washed twice...

Embodiment 2

[0076] Example 2: 2-[[6-[4-(2-Acetoxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxylic acid (Ⅵ) preparation of

[0077] In a 1000 ml four-necked flask connected with a stirring, thermometer, and vacuum distillation device, add 500 g of N,N-dimethylformamide, 41.6 g (0.2 moles) of 2-bromothiazole-5-carboxylic acid (II), 57.6 grams (0.8 moles) lithium carbonate, 29.0 grams (0.2 moles) 2-methyl-4-amino-6-chloropyrimidine (Ⅲ), 80 to 85 ℃ stirring reaction for 5 hours, while slightly reducing pressure to collect low boilers ( water-containing solvent), cooled to 70-75°C, added 37.8 grams (0.22 moles) of 4-(2-acetoxy)ethylpiperazine (Ⅴ), stirred and reacted at 90 to 95°C for 5 hours, while collecting low boilers ( water-containing solvent), the solvent is recovered by distillation under reduced pressure, cooled to 30-50 ° C, 300 grams of water is added, and the pH value of the neutralization system with 30% hydrochloric acid is 2.0, filtered, the filter cake ...

Embodiment 3

[0078] Example 3: N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-acetoxyethyl)-1-piperazinyl]-2-methyl- Preparation of 4-pyrimidinyl]amino]-5-thiazole carboxamide (Ⅶ)

[0079] In the 500 milliliter four-necked flask that is connected with agitator, thermometer, reflux condenser and connected with 35% sodium hydroxide aqueous solution absorption device, add 350 grams of 1,2-ethylene dichloride, 40.6 grams (0.1 moles) implement Example 1 method gained 2-[[6-[4-(2-acetoxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxylic acid (Ⅵ) , 23.8 grams (0.2 moles) of thionyl chloride, stirred and reacted at 55-60° C. for 4 hours. Cool to 30°C, change to a vacuum distillation device, and recover 1,2-dichloroethane and excess thionyl chloride by vacuum distillation (for the next batch reaction after analyzing the content), after the distillation is completed, cool to 20- At 25°C, the resulting residue (intermediate product) was dissolved in 150 g of 1,2-dichloroethane, and t...

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Abstract

The invention provides a preparation method of Dasatinib. 2-Bromothiazole-5-formic acid and 2-methyl-4-amino-6-cloro pyridine are adopted as raw materials, a first-time substitution reaction is performed, the raw materials and 4-(2-acetyl oxyl) Ethylpiperazine are subjected to a second-time substitution reaction to prepare 2-[[6-[4-(2-acetyloxy ethyl)-1-piperazinyl]-2-methl-4-pyrimidyl]amino]-5-Febuxostat; then, the product and an acylating chlorination reagent are subjected to an acylating chlorination reaction and subjected to an amidation reaction with 2-cholo-6-methylaniline, and finally ahydrolysis reaction is performed to remove acetyl to prepare dasatinib. The raw materials are cheap and easy to obtain and low in cost; the technological process is simple, operation is safe and easy, technological wastewater generation amount is small, and the method is environmentally friendly; raw materials and intermediate products stability is suitable, the reaction activity and selectivityare high, reaction conditions are easy to obtain, side reactions are few, the manufactured dasatinib contains few impurities, the purity and yield are high, and industrial production of dasatinib is facilitated.

Description

technical field [0001] The invention relates to a preparation method of dasatinib, which belongs to the technical field of medicinal chemistry. 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-thiazolecarboxamide (monohydrate), trade name sprycel, is an oral tyrosine kinase inhibitor developed by Bristol-Myers Squibb. Dasatinib was granted priority approval by the US FDA in June 2006, and is clinically applicable to the treatment of chronic myelogenous leukemia and acute lymphoblastic leukemia with benign Philadelphia chromosomes. The structural formula of Dasatinib is as follows: [0003] [0004] The main preparation methods of Dasatinib are as follows: [0005] 1. The document J.Med.Chem.2004,47(27),6658-6661 uses 2-chlorothiazole as the starting material, and reacts with 2-chloro-6-methylphenylisocyanate under the action of n-butyllithium to obtain 2-Ch...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D417/12
CPCC07D417/12
Inventor 王德银戚聿新朱成臣
Owner XINFA PHARMA
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