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Novel process method for preparing arotinolol hydrochloride

A technology of alololol hydrochloride and thiophenecarboxamide, which is applied in the field of medicine, can solve the problems of high cost of industrial scale-up, poor sample color, troublesome operation, etc., and achieve the effect of low cost, small impurities and easy control

Active Publication Date: 2015-04-22
JIANGXI BAISHEN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The preparation method of arololol hydrochloride reported in literature and patents has a long cycle, troublesome operation, poor color of the obtained sample, low purity, more and larger impurities, and a large solvent system used for refining, which leads to industrial scale-up Disadvantages such as higher cost

Method used

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  • Novel process method for preparing arotinolol hydrochloride
  • Novel process method for preparing arotinolol hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0031] Example 1: Preparation of 5-[2-[(3-chloro-2-hydroxypropyl)thio]-4-thiazolyl]-2-thiophenecarboxamide

[0032] In a 250ml three-necked reaction flask, add 10g (41.26mmol) of 5-(2-mercapto-4-thiazolyl)-2-thiophene carboxamide (compound II), 4.1g (44.32mmol) of epichlorohydrin, anhydrous chlorine Zinc chloride 1.5g, anhydrous methanol 200ml, under stirring conditions, heat up to 65±3°C, control the temperature and react for about 3 hours, monitor with TLC spot plate, until the reaction is complete, cool down to room temperature naturally, filter, and concentrate the filtrate under reduced pressure To dryness, the intermediate compound 5-[2-[(3-chloro-2-hydroxypropyl)sulfanyl]-4-thiazolyl]-2-thiophenecarboxamide 11.23g was obtained, the yield was 81.27%, and the purity was checked by HPLC is 99.07%.

Embodiment 2

[0033] Example 2: Preparation of 5-[2-[(3-chloro-2-hydroxypropyl)thio]-4-thiazolyl]-2-thiophenecarboxamide

[0034] In a 250ml three-necked reaction flask, add 5-(2-mercapto-4-thiazolyl)-2-thiophene carboxamide (compound II) 10g (41.26mmol), epichlorohydrin 3.8g (41.26mmol), anhydrous chlorine Zinc chloride 2.0g, anhydrous methanol 180ml, under stirring conditions, heat up to 65±3°C, control the temperature and react for about 3 hours, monitor with TLC spot plate, until the reaction is complete, cool down to room temperature naturally, filter, and concentrate the filtrate under reduced pressure To dryness, the intermediate compound 5-[2-[(3-chloro-2-hydroxypropyl)sulfanyl]-4-thiazolyl]-2-thiophenecarboxamide 10.82g was obtained, the yield was 78.23%, and the purity was checked by HPLC is 99.15%.

Embodiment 3

[0035] Example 3: 5-[2-[[[3-(1,1-dimethylethyl)amino]-2-hydroxypropyl]thio]-4-thiazolyl]-2-thiophene carboxamide salt salt (alololol hydrochloride) is prepared

[0036] In a 250ml three-necked reaction flask, add the intermediate compound 5-[2-[(3-chloro-2-hydroxypropyl)sulfanyl]-4-thiazolyl]-2-thiophenecarboxamide 10g (29.86mmol), acetonitrile 150ml, stir at a medium speed, add 22.92g (298.60mmol) of tert-butylamine dropwise at room temperature, the dropwise addition is completed in about 30 minutes, then heat up to 60°C, control the temperature at 60±3°C for 10 hours, monitor with TLC spotting until the reaction is complete , naturally cool down to room temperature, adjust the pH of the system to 1~2 with 15% HCl, then use an ice-water bath to control the temperature T=0~5°C, stir and crystallize for 3 hours, filter with suction, wash the filter cake with 20ml of methanol, and dry it, 50 ℃ vacuum drying to obtain 10.2 g of the crude product of arrolol hydrochloride as a dry...

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Abstract

The invention belongs to the technical field of medicines and particularly relates to a simple and efficient method for preparing selective beta 1 adrenoceptor antagonists 5-[2-[[[3-(1,1-dimethylethyl)amino]-2-hydroxypropyl]thio]-4-thiazolyl]-2-thiophene carboxamide hydrochloride. The method comprises the following steps: firstly, reacting 5-(2-mercapto-4-thiazolyl)-2-thiophenecarboxamide and epoxy chloropropane in the presence of Lewis acid as a catalyst in an organic solvent, after the reaction is completed by the monitoring of TLC, filtering and carrying out pressure reduced concentration to dryness to obtain an intermediate; and secondly, reacting the intermediate and t-butylamine in an organic solvent, cooling to room temperature, adding hydrochloric acid to adjust the pH, carrying out reflux reaction, naturally cooling and crystallizing to obtain arotinolol hydrochloride.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a simple and efficient method for preparing a selective β1 adrenal receptor antagonist 5-[2-[[[3-(1,1-dimethylethyl)amino]-2- Hydroxypropyl]thio]-4-thiazolyl]-2-thiophenecarboxamide hydrochloride (Arotinolol hydrochloride) method. [0002] The structural formula of arolol hydrochloride is: [0003] technical background [0004] Arololol hydrochloride, the chemical name is 5-[2-[[[3-(1,1-dimethylethyl)amino]-2-hydroxypropyl]thio]-4-thiazolyl]-2 - Thiophene carboxamide hydrochloride (structural formula shown in above I), mainly used in the treatment of mild to moderate essential hypertension, angina pectoris, tachyarrhythmia and essential tremor etc. clinically, and for the treatment of obesity Hypertension does not cause weight gain in patients. The drug is a selective β1 adrenoceptor inhibitor with weak α1-adrenoceptor antagonism. It can inhibit α-adrenergic rec...

Claims

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Application Information

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IPC IPC(8): C07D417/04
CPCC07D417/04
Inventor 李怀玉谭灵芝
Owner JIANGXI BAISHEN PHARMA
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