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Preparation method of imidic acid or hydrochloride thereof

A technology of imaric acid hydrochloride and imaic acid, applied in the field of preparation of imaric acid or its hydrochloride, can solve the problems of unsuitability for industrial production, large amount of N-methylpiperazine, complicated refining process and the like , to achieve the effect of low cost, high conversion rate and high product purity

Active Publication Date: 2021-02-05
江苏八巨药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The main problem of this synthetic route is that the carboxyl group and N-methylpiperazine in the raw material can form a salt, so that the amount of N-methylpiperazine used is particularly large, and polymerization occurs after the salt formation, resulting in a large amount of impurities. The process is complicated, the overall yield is low, and it is not suitable for industrial production

Method used

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  • Preparation method of imidic acid or hydrochloride thereof
  • Preparation method of imidic acid or hydrochloride thereof
  • Preparation method of imidic acid or hydrochloride thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] In a clean reaction flask, add 16.85 g of 4-chloromethyl acetophenone, add 200 mL of ethanol, stir and mix evenly, then add 11 g of N-methylpiperazine and 60 mL of 10% aqueous sodium hydroxide solution in Stir the reaction at 20-30°C for 5 hours, and carry out central control. The HPLC detection purity reaches 99.1%, and the residual 4-chloromethyl acetophenone is 0.15%. After the reaction is completed, the reaction solution is cooled to 0-5°C , slowly drop 300mL of 10% sodium hypochlorite aqueous solution directly into the reaction solution, and control the temperature at 0-5°C for dropwise addition. After the dropwise addition, raise the temperature to 45-55°C for insulation reaction for 3h, central control HPLC The purity of the product was detected to be 99.1%, and the residual intermediate was 0.12%. The temperature was lowered to room temperature, and the solvent was directly removed to obtain the corresponding imaic acid product;

[0044] If you need to synthesiz...

Embodiment 2

[0046] In a clean reaction flask, add 21.3 g of 4-bromomethyl acetophenone, add THF 200 ml, stir and mix evenly, then add 12 g of N-methylpiperazine and 60 ml of 10% aqueous sodium hydroxide solution in After stirring and reacting at 20-30°C for 5 hours, the central control, the HPLC detection purity reached 99.4%, and the residual 4-bromomethylacetophenone was 0.11%. After the reaction, the reaction solution was cooled to 0-5°C, and directly Slowly add 300ml of sodium hypochlorite aqueous solution with a mass percentage of 10% to the reaction solution dropwise, and control the temperature at 0-5°C for dropwise addition. After the dropwise addition, raise the temperature to 45-55°C for insulation reaction for 3 hours, and the central control HPLC detects 99.2 %, the residual intermediate is 0.08%, the temperature is lowered to room temperature, and the solvent is directly removed to obtain the corresponding imaic acid product.

[0047] If you need to synthesize ima hydrochlori...

Embodiment 3

[0049] In a clean reaction flask, add 21.3 g of 4-bromomethyl acetophenone, add 200 ml of methanol, stir and mix evenly, then add 13 g of N-methylpiperazine and 60 ml of 10% aqueous sodium hydroxide solution by mass percentage, After stirring and reacting at 20-30°C for 5 hours, the central control, the HPLC detection purity reached 99.6%, and the residual 4-bromomethyl acetophenone was 0.05%. After the reaction, the reaction solution was cooled to 0-5°C. Slowly add 300ml of sodium hypochlorite aqueous solution with a mass percentage of 10% directly to the reaction solution, and control the temperature at 0-5°C for dropwise addition. After the dropwise addition, raise the temperature to 45-55°C for insulation reaction for 3 hours, and central control HPLC detection 99.7%, intermediate residual 0.04%, cooled to room temperature, directly distilled off the solvent to obtain the corresponding imaic acid product.

[0050] If you need to synthesize ima hydrochloride, you can add co...

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Abstract

The invention relates to a preparation method of imidic acid or hydrochloride thereof, which belongs to the technical field of medicine synthesis. In order to solve the problems of easy salification and low yield in the prior art, the invention provides a preparation method of imidic acid or hydrochloride thereof, which comprises the following steps of in the presence of an acid application agent,reacting 4-halogenated methyl acetophenone with N-methylpiperazine to obtain a corresponding intermediate, under the action of pypocholoride, enabling the intermediate to be subjected to an oxidationreaction to obtain corresponding imidic acid, when the imidic acid hydrochloride is synthesized, after the oxidation reaction is finished, adjusting the pH value to be strongly acidic, so that the corresponding imidic acid hydrochloride is formed. According to the method, the reaction has the effect of high conversion rate during condensation, byproducts of salifying reaction products are effectively avoided, raw material residues can be effectively controlled to be less than 0.2%, and the method has the effect of high product yield.

Description

technical field [0001] The invention relates to a preparation method of imatic acid or its hydrochloride, which belongs to the technical field of medicine synthesis. Background technique [0002] Imalic acid [chemical name: 4-(4-methylpiperazine-1-methyl)benzoic acid hydrochloride] can be used to synthesize antineoplastic drugs, mainly for the synthesis of imatinib mesylate; The structural formula of imatic acid or its hydrochloride is as follows: [0003] [0004] At present, the synthetic methods of reported about imatic acid mainly contain the following methods: [0005] 1. Use N-methylpiperazine and p-cyanobenzyl bromide to condense and then hydrolyze to prepare imatic acid. The chemical reaction equation of this reaction is as follows: [0006] [0007] Although the route of this reaction is relatively short, when we repeated the reaction route, we found that the cyano group had a hydrolysis phenomenon during the first condensation reaction, and then formed a sa...

Claims

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Application Information

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IPC IPC(8): C07D295/155
CPCC07D295/155
Inventor 胡建涛程加铭陈恬程祖福王建军汪东海
Owner 江苏八巨药业有限公司
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