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Preparation method of imatinib impurity

A technology of imatinib and impurities, which is applied in the field of preparation of impurities, can solve the problems of compound synthesis methods that have not been reported in literature, and achieve the effects of improving drug safety, simple preparation methods, and high yields

Active Publication Date: 2015-11-04
山东安信制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Through literature review, it is found that there is no specific synthetic method of this compound reported in the literature

Method used

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  • Preparation method of imatinib impurity
  • Preparation method of imatinib impurity
  • Preparation method of imatinib impurity

Examples

Experimental program
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Effect test

Embodiment 1

[0020] Dissolve 26.0 g of methyl p-chloromethylbenzoate in 400 ml of dichloromethane, add 55 g of triethylamine with stirring at room temperature, slowly add 6.1 g of piperazine after the addition, and slowly raise the temperature to reflux for 4 hours after the addition. The temperature was lowered, the system was washed three times with 200ml of purified water, dried over anhydrous sodium sulfate and then spin-dried to obtain 24g of intermediate 3. Dissolve 25.2g of sodium hydroxide in 480ml of water, add 24g of intermediate 3, raise the temperature to 60°C and stir the reaction until the system is dissolved, adjust the pH=2~3 to precipitate a white solid, filter and dry to obtain 19.2g of compound 4, according to the purity of 100 % carry out the next step reaction.

Embodiment 2

[0022] Add 9.6g of compound 4 and 150ml of dimethyl sulfoxide into a round bottom flask, add 6.6g of 1-hydroxybenzotriazole, 7.0g of N,N-diisopropylcarbodiimide, add N, 10.5g of N-diisopropylethylamine, heated up to 60°C, stirred until completely dissolved, then added 15.8g of imaamine and stirred at constant temperature until the reaction did not change. After cooling down to room temperature, the reaction solution was poured into ice water, A yellow solid precipitated out and was filtered with suction to obtain a yellow solid. Disperse the obtained solid in water, add hydrochloric acid to adjust the pH to 3-5, filter with suction and dry. 18.2 g of impurity E was obtained by beating with methanol, with a molar yield of 76.8% and a purity of 96.4%.

Embodiment 3

[0024] Add 9.6g of compound 4 and 150ml of dimethyl sulfoxide into a round bottom flask, add 4.8g of 1-hydroxybenzotriazole, 5.3g of N,N-diisopropylcarbodiimide, add N, 8.6g of N-diisopropylethylamine, heated up to 60°C, stirred until completely dissolved, then added 17.8g of imamamine and stirred at constant temperature until no change, lowered to room temperature, poured the reaction solution into ice water, and precipitated A yellow solid was obtained by suction filtration to obtain a yellow solid. Disperse the obtained solid in water, add hydrochloric acid to adjust the pH to 3-5, filter with suction and dry. 17.2 g of impurity E was obtained by beating with methanol, with a molar yield of 72.6% and a purity of 96.1%.

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Abstract

The invention discloses a preparation method of an imatinib impurity. The preparation method comprises: using 1,4-bi(4-carboxybenzyl)piperazine as a raw material, and at presence of N,N- diisopropylcarbodiimide, 1-hydroxy benzotriazole and N,N-diisopropylethylamine, reacting with imaamine to obtain the imatinib impurity 1,4-bi[4-[4-methyl-3-[[4-(pyridine-3-group)pyrimidyl-2group]amino]phenyl]carbamoyl radical]benzyl piperazine. The preparation method provided by the invention is simple, low in requirement on reaction conditions, high in product purity, high in yield, and suitable for industrial production. The synthesized impurity can be used for qualitative and quantitative analysis of the impurity, thus improving drug safety of the imatinib.

Description

technical field [0001] The invention belongs to the technical field of medicine, and more specifically relates to a method for preparing impurities produced in the preparation process of imatinib. Background technique [0002] Imatinib (Imatinib) is known as "Gleevec" in China. It is an oral drug developed and marketed by Swiss Novartis for the treatment of chronic myelogenous leukemia, gastrointestinal stromal tumors and other cancers. The drug was approved by the U.S. Food and Drug Administration (FDA) in 2001, and by 2011, the drug was FDA-approved to treat 10 different cancers. Imatinib has increased the 10-year survival rate of patients with chronic granular cell leukemia from less than 50% in the past to about 90% now, and the vast majority of patients can work and live normally, so it has a good market prospect. In order to ensure the safety and quality of imatinib, it is necessary to conduct rigorous research on related impurities and control the impurities within s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14
CPCC07D401/14
Inventor 周学文杨庆坤杨波勇李保勇吴柯张兆珍董廷华张雷雷周先国江海平高大龙赵雪宁
Owner 山东安信制药有限公司
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