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Preparation process of dasatinib

A preparation process and technology of dasatinib, applied in the field of preparation technology of dasatinib, can solve the problems of large environmental pollution, complicated operation, high cost and high cost, achieve high yield and purity, avoid high volatility, reduce The effect of production costs

Active Publication Date: 2019-04-26
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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  • Preparation process of dasatinib
  • Preparation process of dasatinib
  • Preparation process of dasatinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Embodiment 1: the preparation of compound 3

[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 1h, after the reaction is completed, cool to room temperature, add 60mL tetrahydrofuran dissolved with 78mmol copper bromide, heated to reflux for 2h, filtered while hot, the filter cake was washed with 50mL of hot tetrahydrofuran, the filtrate was combined with the washing liquid, washed with water until neutral, the solvent was distilled off under reduced pressure, and the residue was poured into 50mL Stir in ice water for 0.5 h, filter under reduced pressure, wash the filter cake with ice water, and dry to obtain 7.19 g of compound 3 with a yield of 91.60% and a purity of 99.92%.

Embodiment 2

[0047] Embodiment 2: the preparation of compound 3

[0048] Dissolve 30mmol of ethyl 3-oxopropionate and 39mmol of sodium carbonate 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, cool to room temperature, add 60mL tetrahydrofuran dissolved with 84mmol copper bromide, heated to reflux for 2h, filtered while hot, the filter cake was washed with 50mL of hot tetrahydrofuran, the filtrate was combined with the washing liquid, washed with water until neutral, the solvent was distilled off under reduced pressure, and the residue was poured into 50mL Stir in ice water for 0.5 h, filter under reduced pressure, wash the filter cake with ice water, and dry to obtain 7.10 g of compound 3 with a yield of 90.43% and a purity of 99.90%.

Embodiment 3

[0049] Embodiment 3: the preparation of compound 3

[0050] Dissolve 30mmol of ethyl 3-oxopropionate and 30mmol of sodium bicarbonate 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, cool to room temperature, Add 60mL tetrahydrofuran dissolved with 60mmol copper bromide, heat to reflux for 2h, filter while hot, wash the filter cake with 50mL hot tetrahydrofuran, combine the filtrate and washing liquid, wash with water until neutral, remove the solvent by distillation under reduced pressure, and pour the residue into Stir in 50 mL of ice water for 0.5 h, filter under reduced pressure, wash the filter cake with ice water, and dry to obtain 5.99 g of compound 3 with a yield of 85.72% and a purity of 99.82%.

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Abstract

The invention relates to a preparation process of dasatinib. The method comprises the following steps: enabling 3-oxopropionic acid ethyl ester to react firstly with 2-chlo-6-methylaniline under an alkaline condition, then adding a solvent dissolved with cupric bromide, and reacting to obtain a compound 3; cyclizing the compound 3 and thiourea in solvent water to obtain 2-amino-N-(2-chlo-6-methylphenyl)thiazole-5-formamide; and then synthesizing dasatinib from 4,6-dichloro-2-methyl pyrimidine, N-ethoxyl piperazine, and 2-amino-N-(2-chlo-6-methyl phenyl)thiazole-5-formamide through a one-pot method under the actions of an alkali K3PO4 and a catalyst 1-butyl-3-methylimidazole glycinate. The conditions are mild, the steps are simple, and the preparation process is environmentally-friendly, high in yield and suitable for industrial 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 Applications(China)
IPC IPC(8): C07D417/12
CPCC07D417/12
Inventor 李明杰李呈龙李成
Owner SHANDONG LUOXIN PHARMA GRP CO LTD
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