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High-purity arotinolol hydrochloride and preparation method thereof

A high-purity technology for arololol hydrochloride, which is applied in the field of medicine and can solve the problems of lack of purity of arololol hydrochloride, large solvent system, and low yield

Inactive Publication Date: 2014-03-12
北京博爱旺康医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The researchers of the present invention have found through a large number of tests that the solubility of arololol hydrochloride in methanol, water, ethyl acetate, and acetone is not large. If these solvents are used for recrystallization, the solvent system is very large on the one hand and is not suitable for industrial scale-up. On the one hand, after the recrystallization step is repeated twice, not only the yield is low, but also the product purity is not high. HPLC shows that there are two impurities exceeding the standard at t=13.8min and t=15.3min
Due to the poor stability of alololol in the solvent state, if arololol is first refined and then salted, it is also impossible to obtain arololol hydrochloride with good purity, and the yield is lower

Method used

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  • High-purity arotinolol hydrochloride and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Embodiment 1 Alololol hydrochloride syrup of the present invention

[0030] 1) Put [5-(2-mercapto-4-thiazolyl)-2-thiophenecarboxamide] and acetonitrile in a three-necked flask, reflux for 0.5h under stirring, keep warm, add epichlorohydrin, and continue the reflux reaction to HPLC After monitoring the completion of the reaction, the reaction solution was lowered to room temperature, filtered with suction, and stirred. A large amount of solids were precipitated. Stir overnight, and continued to stir in an ice-water bath for 3 hours. The solid was collected by suction filtration, rinsed with acetonitrile, and air-dried at 40°C to obtain a solid product;

[0031] 2) Put the solid product, methanol or ethanol or acetone, and tert-butylamine in a three-necked flask, and react under slight reflux for 10 hours. The reaction solution is concentrated to remove the solvent, and the residue is dissolved in methyl tert-butyl ether and methanol or ethanol or acetone, and then passed ...

Embodiment 2

[0034] Example 2 Arololol hydrochloride enteric-coated tablet of the present invention

[0035] 1) Put [5-(2-mercapto-4-thiazolyl)-2-thiophene carboxamide] and acetone in a three-necked flask, reflux for 1 hour under stirring, keep warm, add epichlorohydrin, and continue to reflux until HPLC monitoring After the reaction was completed, the reaction liquid was lowered to room temperature, filtered with suction, and stirred. A large amount of solids were precipitated. Stir overnight. Continue stirring in an ice-water bath for 5 hours. The solid was collected by suction filtration, rinsed with acetone, and air-dried at 60°C to obtain a solid product;

[0036] 2) Put the solid product, methanol or ethanol or acetone, and tert-butylamine in a three-necked flask, and react under slight reflux for 15 hours. The reaction solution is concentrated to remove the solvent, and the residue is dissolved in methyl tert-butyl ether and methanol or ethanol or acetone, and then passed into HCL T...

Embodiment 3

[0039] Example 3 Arololol hydrochloride injection of the present invention

[0040] 1) Put [5-(2-mercapto-4-thiazolyl)-2-thiophenecarboxamide] and ethyl acetate in a three-necked flask, reflux for 0.8h under stirring, keep warm, add epichlorohydrin, and continue the reflux reaction When the reaction is monitored by HPLC, lower the reaction solution to room temperature, filter it with suction, and stir it. A large amount of solids precipitate out. Stir overnight. Continue to stir in an ice-water bath for 3-5 hours. Dried to obtain a solid product;

[0041]2) Put the solid product, methanol or ethanol or acetone, and tert-butylamine in a three-necked flask, and react under slight reflux for 12 hours. The reaction solution is concentrated to remove the solvent, and the residue is dissolved in methyl tert-butyl ether and methanol or ethanol or acetone, and then passed into HCL The gas is saturated, and a solid is precipitated. The solid is collected by filtration and dried to obt...

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Abstract

The invention belongs to the medical technical field, and specifically discloses a high-purity arotinolol hydrochloride and a preparation method thereof. Through lots of research trials, the technicians of the invention find out the fact that the arotinolol hydrochloride having the purity of more than 99.95% can be obtained through the steps of combining two steps of reactions ammonolysis and salification and directly forming a hydrochloride, and then carrying out stirring and washing with absolute ethyl alcohol twice.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a high-purity arololol hydrochloride and a preparation method thereof. Background technique [0002] Arololol hydrochloride, chemical name 5-[2-[(3-tert-butylamino-2-hydroxypropyl)mercapto]-4-thiazolyl]-2-thiophene carboxamide hydrochloride, is a selective β1-adrenergic receptor inhibitors, with weak α1-adrenoceptor antagonistic effect, can inhibit α1-adrenergic receptor excitation while lowering blood pressure, reduce sympathetic tension, and reduce β-receptor blockade Adverse reactions, relieve diastolic blood pressure, and make the antihypertensive effect more ideal. Clinically, it is mainly used to treat mild to moderate essential hypertension, angina pectoris, tachyarrhythmia and essential tremor. [0003] Alolol hydrochloride was developed by Sumitomo Pharmaceutical Co., Ltd., Japan, and was first listed in Japan in 1985. J.Pharmaceutical Sciences, 67 (9), 197...

Claims

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Application Information

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IPC IPC(8): C07D417/04
CPCC07D417/04
Inventor 黄华
Owner 北京博爱旺康医药科技有限公司
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