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Preparation method of itopride hydrochloride

A technology of itopride hydrochloride and ethyl acetate, which is applied in the field of preparation of itopride hydrochloride, can solve the problems of strict residue requirements, increased purification step loss, and high cost, and achieve improved solvent capacity, excellent stability, and The effect of increasing the yield

Active Publication Date: 2014-12-24
珠海保税区丽珠合成制药有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Some organic solvents such as toluene can bring certain adverse effects, such as toxicity, high cost, poor solubility of raw materials, strict residue requirements, great harm to workshop operators, and not conducive to environmental protection, etc., and in hydrochloric acid or hydrochloric acid alcohol solution Salt formation causes water to be introduced, thus increasing losses in salt formation and subsequent purification steps, reducing yield

Method used

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  • Preparation method of itopride hydrochloride
  • Preparation method of itopride hydrochloride
  • Preparation method of itopride hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Embodiment 1: Take dichloromethane as solvent

[0047] Dissolve 0.738 kg of N, N-dimethylaminoethoxybenzylamine in 4.3 liters of dichloromethane, then add 8.6 liters of dichloromethane solution containing 0.969 kg of 3,4-dimethoxybenzoyl chloride, and control the temperature After reacting for 3 hours, add 3.5 liters of 1.8% dilute hydrochloric acid and stir for 30 minutes before separating the liquids;

[0048] Take the upper water phase and filter, use 20% sodium hydroxide aqueous solution to adjust the pH of the filtrate to about 8, mix slightly, stop adding lye for 1 hour, and gradually adjust to pH = 10-11 (total consumption of 20% sodium hydroxide aqueous solution is about 1L) , filtered, washed with water, and dried to obtain the prototype of itopride;

[0049] Heat and dissolve the itopride prototype in 5 liters of ethanol, add 0.62 liters of 30% isopropanol hydrochloride solution to form a salt, gradually precipitate crystals, and filter to obtain the crude ...

Embodiment 2

[0070] The itopride hydrochloride prepared in Example 1 was analyzed by HPLC. The same retention time and peak area of ​​the reference substance and the test substance S100903001 are shown in Table 1 below.

[0071] Table 1

[0072]

[0073] Calculation method of relative retention time: set the peak elution time of the main peak of the product as 1, divide the peak elution time of a certain peak by the peak elution time of the main peak to obtain the relative retention time of the peak, because the use of multiple tests is different Due to instrument errors and changes in chromatographic columns and mobile phases, the eluting time of the main peak and impurity peaks cannot be the same, so the relative retention time is proposed as a unified comparison.

[0074] According to the data of the relative retention time in Table 1, it can be considered that all HPLC peaks of the S100903001 sample correspond to the control sample without new impurity production and one-to-one co...

Embodiment 3

[0076] Contrastive analysis of itopride hydrochloride obtained by using ethyl acetate and itopride hydrochloride obtained by not using ethyl acetate. The results are shown in Table 2 below.

[0077] Table 2

[0078]

[0079] As can be seen from Table 2, the product main peak area of ​​the inventive method accounts for a percentage greater than the product main peak of the reference sample, indicating that the product purity obtained is better than that of the reference sample, and that the use of ethyl acetate crystallization can effectively remove Certain impurities improve product quality.

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Abstract

The invention provides a preparation method of itopride hydrochloride. The method comprises a step that N,N-dimethylamino ethoxy aniline and 3,4-dimethoxy benzoyl chloride are subjected to an amidation reaction in dichloromethane. The method provided by the invention also comprises a step that a hydrogen chloride isopropyl alcohol solution and an itopride prototype material are subjected to a reaction, such that a salt is produced. According to the itopride hydrochloride preparation method provided by the invention, dichloromethane is used for replacing toluene, such that the harm brought by toluene is avoided. Also, no water is introduced during the salt formation process, such that loss can be reduced, product yield can be improved, and impurities are further removed. Therefore, the quality of a finished product is improved.

Description

technical field [0001] The invention belongs to the technical field of pharmacy, in particular, the invention relates to a preparation method of Itopride Hydrochloride. Background technique [0002] Itopride Hydrochloride is a methoxybenzamide drug, which is N-[4-[2-(dimethylamino)ethoxy]benzyl]-3,4-dimethoxybenzene The hydrochloride of formamide has the following structural formula: [0003] [0004] The raw material drug of itopride hydrochloride was developed by Hokuriku Pharmaceutical Co., Ltd., Japan, and has obtained patent rights in Japan and Europe. From a pharmacological point of view, itopride hydrochloride increases the release of acetylcholine through the antagonism of dopamine D2 receptors, and at the same time inhibits the decomposition of released acetylcholine through the inhibition of acetylcholinease, thereby enhancing the motility of the stomach and duodenum. Therefore, it is currently mainly used for various symptoms caused by functional dyspepsia, s...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C235/48C07C231/02C07C231/12C07C231/24
Inventor 王逸英刘智慧向以东肖鸿
Owner 珠海保税区丽珠合成制药有限公司
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