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Synthetic method for preparing roxatidine acetate hydrochloride with high purity

A technology for roxatidine acetate and hydrochloride, which is applied in the field of synthesis and preparation of high-purity roxatidine acetate hydrochloride, can solve the problem of low product conversion rate and difficulty in obtaining high-purity roxatidine acetate , the synthesis method is complicated to operate, etc., to achieve the effect of high product purity, conducive to industrial development and application, simple and safe synthesis process

Inactive Publication Date: 2013-03-27
哈药集团人民同泰医药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Regarding the synthesis of roxatidine acetate hydrochloride, many literatures and patent reports generally use m-hydroxybenzaldehyde as the starting material, undergoing ammonolysis reduction, Gabriel condensation, hydrazine hydrolysis, amidation, esterification and other processes. The synthesis of this product, but the synthesis method is cumbersome to operate, the synthesis process uses harmful substances to the human body, and the product conversion rate is low
Roxatidine acetate hydrochloride is easily degraded to generate roxatidine acetate in the preparation and refining process, therefore, it is difficult to obtain high-purity roxatidine acetate

Method used

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  • Synthetic method for preparing roxatidine acetate hydrochloride with high purity
  • Synthetic method for preparing roxatidine acetate hydrochloride with high purity

Examples

Experimental program
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Effect test

Embodiment 1

[0027] Synthesis of 3-(1-piperidinylmethyl)phenol

[0028] Place a 1000ml three-necked bottle in a low-temperature reaction tank, install and stir, add 70g of m-hydroxybenzaldehyde into the three-necked bottle while stirring, add 500ml of absolute ethanol after the addition, dissolve slowly under stirring, lower the temperature to 5°C, and slowly add six Hydropyridine 127ml, the solution becomes light yellow, and there is exothermic phenomenon, continue to stir for 30min to make it completely dissolved; control the temperature below 15°C and slowly add 23.8g of sodium borohydride in 6 times, there is exotherm during the addition, accompanied by Gas was generated. After the feeding was completed, the low-temperature reaction tank was closed, and the stirring reaction was continued for 5 hours at room temperature. (TLC monitors until complete, developer: dichloromethane / methanol=5:1) After the reaction is completed, concentrate under reduced pressure and distill off the reagent;...

Embodiment 2

[0030] Synthesis of 3-(3-(1-piperidinylmethyl)phenoxy)propylamine

[0031] Add 60g of the product intermediate a of the previous step and 350ml of anhydrous DMF into a 1000ml three-necked bottle, dissolve them all under stirring, slowly add 5.8g of sodium hydride and 170g of sodium hydroxide, and gas is generated; add 51g of 3-chloropropylamine hydrochloride under stirring, Introduce nitrogen, under the protection of nitrogen, heat up to 90-95°C and react for 2 hours. After the reaction, cool to room temperature, filter to remove the solid, collect the filtrate, wash the filter cake with DMF for 3 times, and concentrate the filtrate under reduced pressure to remove the reagent, leaving a reddish-brown liquid Add 400ml of ice water to the mixture, adjust the pH to 5 with glacial acetic acid, add 150ml of dichloromethane to extract and wash, add concentrated ammonia water to adjust the pH to 9, and generate white turbidity, extract with 150ml of dichloromethane×2 times, discard ...

Embodiment 3

[0033] Synthesis of 2-chloro-N-[3-[3-(piperidin-1-ylmethyl)phenoxy]propyl]acetamide

[0034] Dissolve 50g of the product intermediate (b) from the previous step in 200ml of dichloromethane, add 48.4g of anhydrous potassium carbonate while stirring, open the low-temperature reaction tank to control the internal temperature below 3°C, slowly add 28.4g of chloroacetyl chloride dropwise, drop After the addition, keep the internal temperature at 0-5°C and react for 3 hours at a low temperature. After the reaction, add 120ml of ice water, extract and separate the layers, discard the water layer; add 100ml of saturated saline to wash twice, anhydrous sulfuric acid Sodium was dried and filtered, and the filtrate was concentrated by distillation under reduced pressure to obtain a white oily product (c), weighing 61g.

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Abstract

The invention discloses a synthetic method for preparing roxatidine acetate hydrochloride with high purity. According to the invention, a starting material hydroxybenzaldehyde is subjected to condensation with piperidine to prepare 3-(1-piperidine methyl) phenol; an intermediate and 3-chloro amine hydrochloride are subjected to a backflow etherification reaction in a DMF at high temperature to obtain 3-(3-(1-piperidyl methyl) phenoxy) propylamine; the 3-(3-(1-piperidyl methyl) phenoxy) propylamine, chloroacetyl chloride and potassium acetate are subjected to a heating reflux reaction in a tetrahydrofuran solvent; and a HCl / THF solution is introduced to prepare a final product roxatidine acetate hydrochloride, with a total yield of 68%. The synthesis process has advantages of simpleness, low cost and high yield, can provide purity of the target product, and is in favor of industrial mass production of the product.

Description

technical field [0001] The invention relates to a preparation method of medicine. Specifically, it is a synthetic preparation method of high-purity roxatidine acetate hydrochloride. Background technique [0002] Roxatidine acetate (see formula below) is a new generation of histamine H developed by Imperial Organ Corporation of Japan 2 Receptor antagonists were first approved by the Japanese Ministry of Health and Welfare in 1986, and launched in Germany in September 1989. [0003] [0004] It is mainly used to prevent and treat digestive system diseases caused by hypersecretion of gastric acid. Peptic ulcer is a common disease that seriously threatens human health. According to reports, peptic ulcer patients account for about one-tenth of the world's population, mainly gastric ulcer and duodenal ulcer. The most common complication of peptic ulcer is upper gastrointestinal bleeding. About 20-30% of patients with peptic ulcer have a history of bleeding. Among them, duode...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D295/096
Inventor 刘占滨刘春凤秦雅英范宁王敬伟金连玉
Owner 哈药集团人民同泰医药股份有限公司
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