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Preparation method of medicine of itopride hydrochloride for promoting gastrointestinal motility

A technology of itopride hydrochloride and gastrointestinal motility, applied in the field of medicine, can solve the problems of poor selectivity, low yield, long route, etc., and achieve the effect of novel route, high purity and easy process

Inactive Publication Date: 2017-05-31
IANGSU COLLEGE OF ENG & TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The synthetic route of existing Itobi hydrochloride mainly contains following two kinds: a kind of scheme is that benzoyl chloride and amide react first, then etherification, but this method yield is lower, and selectivity is poor
Such as patent US2009177008, WO200774386; Another method is to etherify first, then synthesize benzylamine, and finally react with benzoyl chloride. This method is currently the main method for preparation, but the route is longer and the yield is lower. Such as patent WO2006051079, CN1706815, CN201210549091.5

Method used

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  • Preparation method of medicine of itopride hydrochloride for promoting gastrointestinal motility
  • Preparation method of medicine of itopride hydrochloride for promoting gastrointestinal motility
  • Preparation method of medicine of itopride hydrochloride for promoting gastrointestinal motility

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preparation example Construction

[0035] A summary is as follows: a preparation method for promoting gastrointestinal motility drug itopride hydrochloride, comprising the following steps: the first step: the synthesis of 4-(2-dimethylaminoethoxy) benzyl bromide:

[0036] Synthesize 4-(2-dimethylaminoethoxy)benzaldehyde with 2-(dimethylamino)ethyl chloride hydrochloride and p-hydroxytoluene in an inert solvent in the presence of a base, and then undergo free radical bromination Reaction synthetic target product; Concrete reaction formula is as follows:

[0037]

[0038] The second step: the synthesis of 3,4-dimethoxybenzonitrile:

[0039] Use 3,4-dimethoxybenzaldehyde as raw material to react with hydroxylamine hydrochloride, and then use thionyl chloride to dehydrate in a non-polar solvent to synthesize nitrile; the specific reaction formula is as follows:

[0040]

[0041] The third step: the synthesis of itopride:

[0042] Under solvent-free conditions, 4-(2-dimethylaminoethoxy)benzyl bromide and 3,4...

Embodiment 1、4

[0053] The preparation of embodiment 1,4-[2-(dimethylamino) ethoxy] toluene

[0054] Take 108g (1mol) of p-hydroxytoluene, 150g (1.1mol) of potassium carbonate, add 500mL of DMF and 50mL of isopropyl ether and stir, then add 158g (1.1mol) of 2-(dimethylamino) ethyl chloride hydrochloride and dissolve it in 200ml of DMF , add a solution of 210g of triethylamine, and stir the reaction at 80°C for 2h. After the reaction, remove the insoluble matter by filtration, recover most of the solvent from the filtrate under reduced pressure, and use 2mol·L -1 Acidify with sulfuric acid to pH to 2, add 500 mL of chloroform to extract twice, neutralize the aqueous phase with sodium hydroxide solution (w=20%) under ice water cooling, until the pH reaches 10, then extract with 500 mL of ethyl acetate, anhydrous Dry over sodium sulfate, recover ethyl acetate under reduced pressure, and distill under reduced pressure to obtain 159.3 g of colorless oil, yield: 89%.

Embodiment 2、4

[0055]The preparation of embodiment 2,4-[2-(dimethylamino) ethoxy] toluene

[0056] Take 108g (1mol) of p-hydroxytoluene, 61.7g (1.1mol) of potassium hydroxide, add 200mL of DMF and 20mL of isopropyl ether and stir, then add 158.7g (1.1mol) of (2-(dimethylamino) ethyl chloride hydrochloride Dissolve in 250DMF, add a solution of 110g of triethylamine, stir and react at 80°C for 2 hours, after the reaction, remove insoluble matter by filtration, recover most of the solvent from the filtrate under reduced pressure, and use 2mol L -1 Acidify with sulfuric acid to pH to 2, add 500 mL of chloroform to extract twice, neutralize the aqueous phase with sodium hydroxide solution (w=20%) under ice water cooling, until the pH reaches 10, then extract with 500 mL of ethyl acetate, anhydrous Dry over sodium sulfate, recover ethyl acetate under reduced pressure, and distill under reduced pressure to obtain 162.8 g of colorless oil, yield: 91%.

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Abstract

The invention discloses a preparation method of medicine of itopride hydrochloride for promoting gastrointestinal motility. The method comprises the following steps that p-hydroxy methylbenzene is used as a raw material to take a reaction with dimethylaminoethyl chloride hydrochloride; then, 4-(2-dimethylamino oxethyl) benzyl bromide is synthesized through bromination; next, the 4-(2-dimethylamino oxethyl) benzyl bromide and 3,4-dimethoxybenzonitrile take a reaction to obtain a product of itopride under the solvent-free condition through copper trifluoromethanesulfonate catalysis. The preparation method has the advantages a bran-new synthesis route is provided; the itopride is synthesized through Ritter reaction under the solvent-free condition; the advantage of green and environment-friendly effects is realized; meanwhile, the used raw material resources are wide and sufficient; the price is low; the reaction conditions are mild.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a preparation method of itopride hydrochloride, a drug for promoting gastrointestinal motility. Background technique [0002] Itopride hydrochloride is a new type of gastrointestinal motility drug developed by Hokuriku Pharmaceutical Co., Ltd., which antagonizes dopamine D 2 Receptors and anticholine enzymes exert curative effects, and are suitable for various symptoms caused by functional dyspepsia, such as: postprandial bloating, loss of appetite, nausea, and vomiting. Compared with cisapride, there is no peripheral neurotoxicity. [0003] The synthetic route of existing Itobi hydrochloride mainly contains following two kinds: a kind of scheme is first reaction of benzoyl chloride and amide, and then etherification, but this method yield is low, and selectivity is poor. Such as patent US2009177008, WO200774386; Another method is to etherify first, then synthesize benzylami...

Claims

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Application Information

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IPC IPC(8): C07C231/12C07C235/48A61P1/14
CPCC07C231/12C07C213/00C07C213/08C07C231/06C07C249/08C07C253/00C07C235/48C07C255/54C07C251/48C07C217/54
Inventor 冯成亮尹桂波严宾
Owner IANGSU COLLEGE OF ENG & TECH
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