Preparation method of itopride hydrochloride

A technology of itopride hydrochloride and formic acid, which is applied in the field of medicine, can solve problems such as increasing the reaction and post-treatment process, increasing the difficulty of removing impurities, and affecting product yield, so as to achieve environmental protection of the reaction, reduce solvent consumption, and save The effect of equipment costs

Active Publication Date: 2015-04-29
迪嘉药业集团股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The deficiencies of this route: the one, 3,4-dimethoxybenzoyl chloride (I) and p-hydroxybenzylamine (II) when reacting in alkaline conditions, produce a large amount of ester group by-products while generating amide product, affect this The yield of the first step product, and the existence of a large amount of ester-based by-products increases the difficulty of removing impurities; the second is the raw material N used in the second step, N-dimethylaminoethyl chloride hydrochloride (IV) and p-hydroxybenzyl Amines are expensive and not readily available
This method reaction still needs to use expensive raw material N, N-dimethylaminoethyl chloride hydrochloride (IV), causes cost to be difficult to reduce
Reductive ammoniation to the intermediate (IX) needs to be divided into two steps, and the catalytic hydrogenation process needs to use high-pressure hydrogenation equipment, which has not only increased the reaction and post-treatment process, but also reduced the overall 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
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Embodiment 1

[0031] The preparation of embodiment 1, 4-(2-dimethylaminoethoxy) benzaldehyde.

[0032] N, N-dimethylethanolamine 89g (1mol), add 800mlDMF, then add 44g60%NaH (1.1mol), stir until no bubbles are generated, then add p-fluorobenzaldehyde 124g, gradually heat up to 60 ° C for 4 hours, After the reaction was detected by TLC, the solvent was recovered under reduced pressure, 1000ml of ice water was added, the pH was adjusted to about 3 with hydrochloric acid, extracted once with toluene, the aqueous layer was adjusted to about 10 with liquid caustic soda, and extracted twice with 400ml of dichloromethane. combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 165 g of light yellow oil with a yield of 85.6%.

Embodiment 2

[0033] The preparation of embodiment 2, 4-(2-dimethylaminoethoxy) benzaldehyde.

[0034] Add 200g of N,N-dimethylethanolamine, add 1200ml of DMA, then add 277g of potassium tert-butoxide, stir for 1 hour, then add 293g of p-fluorobenzaldehyde, gradually raise the temperature to 80°C and react for 4 hours, TLC detects that the reaction is complete, and then depressurize Recover the solvent, add 2500ml of ice water, adjust the pH to about 3 with hydrochloric acid, extract once with toluene, adjust the pH of the water layer to about 10 with liquid caustic soda, extract twice with 800ml of chloroform, wash once with saturated saline after combining, and then It was dried over anhydrous sodium sulfate, filtered and concentrated to obtain 398 g of a light yellow oily substance with a yield of 91.7%.

Embodiment 3

[0035] Preparation of embodiment 3, 4-(2-dimethylaminoethoxy)benzylamine.

[0036] 125g of 4-(2-dimethylaminoethoxy)benzaldehyde and 45g of hydroxylamine hydrochloride were added to methanol for reflux reaction for 1 hour, and the reaction in the TLC spot plate was complete. After cooling to room temperature and under the protection of nitrogen, 122g of ammonium formate and 5g of ammonium formate were added. %Pd / C, the catalyst was recovered by filtration after 6 hours of reaction, the solvent was evaporated under reduced pressure, dichloromethane and water were added for extraction, and the organic layer was concentrated to obtain 103 g of oily 4-(2-dimethylaminoethoxy) benzylamine. The yield was 82.4%. After HPLC detection, the HPLC detection purity was 96.7%. The product was directly used in the next reaction without purification.

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Abstract

The invention relates to a preparation method of gastrointestinal crude drug itopride hydrochloride, and belongs to the field of medicines. The invention discloses a method for preparing itopride hydrochloride, which comprises the following steps of: taking cheap N,N-dimethylaminoethanol as an initial raw material; implementing an etherification reaction to obtain an intermediate product (VII) and implementing one-step reduction ammoniation to obtain a benzylamine product (IX); and reacting with 3,4-dimethoxy benzoyl chloride to generate hydrochloride. The preparation method of the itopride hydrochloride is cheap in raw material, moderate in reacting condition, and low in preparation cost of the itopride hydrochloride.

Description

Technical field: [0001] The invention relates to a preparation method of itopride hydrochloride, a raw material drug for gastrointestinal motility, and belongs to the technical field of medicine. Background technique: [0002] Itopride hydrochloride is a gastrointestinal prokinetic drug, suitable for various symptoms caused by functional dyspepsia, such as: upper abdominal discomfort, postprandial fullness, loss of appetite, nausea, vomiting, etc. Compared with the previous generation cisapride, there is no peripheral neurotoxicity. It is a drug widely used clinically. The drug was first developed by Hokuriku Pharmaceutical Co., Ltd. of Japan. The synthetic route of existing itopride hydrochloride has following two kinds of methods: [0003] (1) Amide method: US patent application US2009177008 and international patent application WO200774386 disclose this method. [0004] The specific route is as follows: [0005] [0006] This method is with 3,4-dimethoxybenzoyl chl...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C231/02C07C235/48C07C215/50C07C213/02
Inventor 吴荣贵姜凯石龙云张丽丽
Owner 迪嘉药业集团股份有限公司
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