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Preparation method of imatinib intermediate

A technology of intermediates and compounds, applied in the field of chemical synthesis

Inactive Publication Date: 2012-07-25
成都格蓝洋生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] Chinese patent CN201010283894.1 discloses a new imatinib synthesis method, with N—(5-amino-2-methylphenyl)—4 —(3-pyridyl)-2-aminopyrimidine and compound 4-(-methylpiperazine methyl) benzoic acid are used as raw materials to prepare imatinib, but phosphite compounds are used in the reaction, which is toxic. Strong irritant, so not suitable for industrial production
[0013] Chinese patent CN200810033189.9 discloses a synthetic method of imatinib, using N—(4-methyl-3-3 aminophenyl)—4 —(4-methyl-piperazinyl-1-methyl)-benzamide is raw material, under the effect of polypeptide condensing agent and organic base and 4-methyl-(3-pyridyl)-2-pyrimidinone reaction to obtain imatinib, the catalyst in this route is expensive, and there are many impurities after the reaction, which are not easy to remove
[0018] (1) The process is complicated, and toxic reagents are used in the reaction, which is not suitable for industrial production
[0019] (2) After the reaction, there are many impurities, which are easy to introduce in the preparation of imatinib

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0043] Synthesis of Methanesulfonyl-4-(3-pyridyl)-pyrimidine

[0044] (1) Synthesis of compound Ⅰ

[0045] Measure 11ML of 3-acetylpyridine into a 250ML single-mouth bottle, then add 27ML of DMF-DMA and mix well, add 35ML of reaction solvent o-xylene, heat to X—Y℃ for reflux reaction; react in reflux state for 13h, cool down to room temperature, add 20ML of n-hexane Placed in the reaction solution, a large amount of light yellow precipitate precipitated out. The solid was collected by filtration to obtain 10.94 g of compound I as a solid product, with a yield of 62.2%.

[0046] ES—MS m / z 177[M+1]

[0047] Melting point: 83.8~84.5℃

[0048] (2) Synthesis of compound Ⅱ

[0049] Weigh 17.6g of solid compound I and 9.13g (0.12mol) of thiourea into a 500ML flask, then add 4g of solid sodium hydroxide and 200ML of n-butanol, and the reaction is carried out under reflux. After reacting for about 1.5 hours, the solvent was evaporated to dryness to obtain 16.2 g of compound II; yi...

Embodiment 2

[0070] Synthesis of Ethyl-4-(3-pyridyl)-pyrimidine

[0071] (1) The synthesis method of compound I and II is the same as in Example 1.

[0072] (2) Synthesis of compound Ⅲ

[0073] Weigh 18.9 g of compound II, dissolve it in 120 mL of sodium hydroxide solution with a concentration of 1 mol / L, add 8 mL of iodoethane, react for about 1 hour, a large amount of precipitation precipitates out, filter, wash with distilled water, and dry to obtain solid compound III. 15.5g, yield 71.4%.

[0074] (3) Synthesis of intermediate IV, namely ethylsulfonyl-4-(3-pyridyl)-pyrimidine

[0075] Weigh 21.5g of solid compound III, dissolve it in 100ML acetone, add 30ML hydrogen peroxide, react at 40°C for 2 hours, evaporate the reaction solution to dryness, dissolve it in dichloromethane, add saturated sodium bisulfite solution, wash three times, and distilled water , the organic phase was dried by adding anhydrous sodium sulfate, and the solvent was evaporated to dryness to obtain 21.8 g of pr...

Embodiment 3

[0084] Synthesis of propanesulfonyl-4-(3-pyridyl)-pyrimidine

[0085] (1) The synthesis method of intermediates I and II is the same as in Example 1.

[0086] (2) Synthesis of compound Ⅲ

[0087] Weigh 18.9 g of compound II, dissolve it in 120 mL of 1 mol / L sodium hydroxide solution, add 8 mL of iodopropane, react for about 1 hour, a large amount of precipitation precipitates out, filter, wash with distilled water, and dry to obtain a solid III compound 17.8 g, yield 77.05%.

[0088] (3) Synthesis of intermediate IV, i.e. propanesulfonyl-4-(3-pyridyl)-pyrimidine

[0089] Weigh 22.7g of solid compound III, dissolve it in 100ML acetone, add 30ML hydrogen peroxide, react at 40°C for 2 hours, evaporate the reaction solution to dryness, dissolve it in dichloromethane, add saturated sodium bisulfite solution, wash three times, and distilled water , the organic phase was dried by adding anhydrous sodium sulfate, and the solvent was evaporated to obtain 23.2 g of product intermedia...

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Abstract

The invention relates to a preparation method of an imatinib intermediate, which solves the problems of complex preparation technique, multiple impurities and influence on imatinib purity in the existing imatinib intermediate. The preparation method comprises the following steps: by using 3-acetylpyridine and N,N-dimethylformamidodimethylacetal as the initial raw materials, carrying out condensation reaction, thiocarbamide cyclization reaction and iodomethane substitution reaction, and oxidizing with oxydol to obtain the imatinib intermediate. The inventiom mainly aims to synthesize the medicine for treating chronic myelogenous leukemia, imatinib methanesulfonate. The invention has the advantages of simple technique, cheap and accessible raw materials, high yield and short reaction time, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and relates to a preparation method of imatinib mesylate intermediate sulfonyl-4-(3-pyridyl)-pyrimidine. technical background [0002] Imatinib mesylate is a small molecule tyrosine kinase (Pmfein-fyrosihe Kinase) inhibitor. Clinically, it is mainly used for the treatment of chronic myelogenous leukemia ((Chronic mye21oid leukelllia, CML) in blast phase, accelerated phase or chronic phase after failure of alpha-interferon therapy, and for the treatment of unresectable and metastatic malignant gastrointestinal stromal tumors ( GIST) in adult patients. [0003] Imatinib is a new drug first developed by Novartis in Switzerland. Its trade name is Gleevec. It is the first molecular targeted therapy drug designed and developed rationally for the cause of cancer. It will affect normal cells and create an era of tumor molecular targeted therapy, which is hailed as a milestone discovery. In ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04
Inventor 陈书峰陈少武张效实胡杨洋
Owner 成都格蓝洋生物医药科技有限公司
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