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Preparation method of arotinolol hydrochloride

A technology of alololol hydrochloride and molar ratio, which is applied in the field of preparation of arololol hydrochloride, can solve the problems that the specific process of arololol hydrochloride is not announced, the product purity is not enough, and the process cycle is long, etc., to achieve easy post-processing Simple operation and post-processing, and the effect of improving product purity and yield

Active Publication Date: 2015-02-25
SHIJIAZHUANG GERUI PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Patents EP0021840 and US4130566 all relate to the preparation of arololol hydrochloride, but with 5-(2-mercapto-4-thiazolyl)-2-thiophenecarboxamide The specific process for obtaining alololol hydrochloride as a raw material has not been announced
The CN103626750 patent report published in 2014 uses 5-(2-mercapto-4-thiazolyl)-2-thiophene carboxamide as raw material, and the post-treatment in one step of epoxidation condensation makes the process cycle longer, and the crude product of alololol is directly In one step of salt formation, the yield is very low due to the solubilizing effect of residual tert-butylamine after ammonolysis; this patent uses hydrogen chloride gas to form salt, which requires high equipment
Domestic literature reports use 5-(2-mercapto-4-thiazolyl)-2-thiophenecarboxamide as a raw material, undergo three steps of epoxidation condensation, amination, and salt formation, and in the first step, ethyl acetate extracts and recovers Solvent, the process is cumbersome, and the yield is low; the third step uses ethyl acetate for recrystallization, which requires a large amount of solvent and is not suitable for industrial scale-up. On the other hand, the yield is low, and the product purity is not enough (see literature: Liu Hongbin, Tang Hui, Ji Qinggang, et al. Synthesis of Alolol Hydrochloride[J]. China Journal of Pharmaceutical Industry, 2011,42(9):641-644.)

Method used

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  • Preparation method of arotinolol hydrochloride
  • Preparation method of arotinolol hydrochloride
  • Preparation method of arotinolol hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Prepare arolol hydrochloride as follows:

[0046] (1) Synthesis of 2-[2,3-epoxypropyl-4-(5-carbamoyl-2-thienyl)]thiazole

[0047]Dissolve sodium bicarbonate (3.36g, 0.04mol) into 290mL distilled water, add 5-(2-mercapto-4-thiazolyl)-2-thiophenecarboxamide (9.69g, 0.04mol) in batches, stir for 30 min, Add epichlorohydrin (3.70g, 0.04mol), react at 20°C for 4h, monitor the completion of the reaction with TCL, filter with suction, and filter the crude product with 71mL of methyl tert-butyl ether to obtain a pale yellow solid, which is dried to obtain 2-[2 , 3-epoxypropyl-4-(5-carbamoyl-2-thienyl)]thiazole (10.38 g, yield 87%).

[0048] (2) Synthesis of Alololol

[0049] Dissolve 2-[2,3-epoxypropyl-4-(5-carbamoyl-2-thienyl)]thiazole (11.94 g, 0.04 mol) and tert-butylamine (8.78 g, 0.12 mol) in absolute ethanol After reflux at 70~75°C for 14 hours, the reaction liquid was concentrated to remove absolute ethanol, the residue was added to 89 mL of toluene and slurried for 2...

Embodiment 2

[0053] Prepare arolol hydrochloride as follows:

[0054] (1) Synthesis of 2-[2,3-epoxypropyl-4-(5-carbamoyl-2-thienyl)]thiazole

[0055] Dissolve sodium bicarbonate (6.72g, 0.08mol) into 290mL distilled water, add 5-(2-mercapto-4-thiazolyl)-2-thiophenecarboxamide (9.69g, 0.04mol) in batches, stir for 30 min, Add epichlorohydrin (3.70g, 0.04mol), react at 20°C for 4h, monitor the completion of the reaction with TCL, filter with suction, and filter the crude product with 71mL of methyl tert-butyl ether to obtain a pale yellow solid, which is dried to obtain 2-[2 , 3-epoxypropyl-4-(5-carbamoyl-2-thienyl)]thiazole (10.74 g, yield 90%).

[0056] (2) Synthesis of Alololol

[0057] Dissolve 2-[2,3-epoxypropyl-4-(5-carbamoyl-2-thienyl)]thiazole (11.94 g, 0.04 mol) and tert-butylamine (14.63 g, 0.20 mol) in absolute ethanol After reflux at 70-75°C for 14 hours, the reaction solution was concentrated to remove absolute ethanol, the residue was added to 89 mL of toluene to make a slur...

Embodiment 3

[0061] Prepare arolol hydrochloride as follows:

[0062] (1) Synthesis of 2-[2,3-epoxypropyl-4-(5-carbamoyl-2-thienyl)]thiazole

[0063] Dissolve sodium bicarbonate (6.72g, 0.08mol) into 290mL distilled water, add 5-(2-mercapto-4-thiazolyl)-2-thiophenecarboxamide (9.69g, 0.04mol) in batches, stir for 30 min, Add epichlorohydrin (3.70g, 0.04mol), react at 40°C for 4h, monitor the completion of the reaction with TCL, filter with suction, and filter the crude product with 71mL of methyl tert-butyl ether to obtain a light yellow solid, which is dried to obtain 2-[2 , 3-epoxypropyl-4-(5-carbamoyl-2-thienyl)]thiazole (11.22 g, yield 94%).

[0064] (2) Synthesis of Alololol

[0065] Dissolve 2-[2,3-epoxypropyl-4-(5-carbamoyl-2-thienyl)]thiazole (11.94 g, 0.04 mol) and tert-butylamine (14.63 g, 0.20 mol) in absolute ethanol After reflux at 75-80°C for 20 h, the reaction solution was concentrated to remove absolute ethanol, the residue was added to 89 mL of toluene and slurried for ...

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Abstract

The invention relates to a preparation method of arotinolol hydrochloride. The preparation method comprises the following steps: (1) preparing 2-[2,3-glycidyl-4-(5-carbamyl-2-thienyl)] thiazole; (2) dissolving 2-[2,3-glycidyl-4-(5-carbamyl-2-thienyl)] thiazole in absolute ethyl alcohol, adding tert-butylamine and performing a reflux reaction to obtain arotinolol; and (3) dissolving arotinolol in dimethyl sulfoxide and then adding concentrated hydrochloric acid to generate the arotinolol hydrochloride. The preparation method disclosed by the invention is short in production period, simple in process, high in yield, safe and reliable, and the arotinolol hydrochloride prepared by the method disclosed by the invention is high in purity.

Description

technical field [0001] The invention belongs to the field of preparation of drugs for treating hypertension and angina pectoris, and in particular relates to a preparation method of arololol hydrochloride. Background technique [0002] Alolol hydrochloride was developed by Japan's Sumitomo Pharmaceutical Co., Ltd. and was first launched in Japan in 1985. Alolol hydrochloride is known as the fourth-generation beta-blocker and is the first-line drug for beta-blockers. Clinically, it is mainly used for the treatment of mild to moderate essential hypertension and angina pectoris. This product is a selective β1-adrenergic receptor antagonist with weak α1-adrenoceptor blocking effect, which can inhibit the excitation of α-adrenergic receptors and reduce the tension of sympathetic nerve while lowering blood pressure. The antihypertensive effect is more ideal, and it is more suitable for the treatment of adolescent hypertension. [0003] Patents EP0021840 and US4130566 all involv...

Claims

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Application Information

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IPC IPC(8): C07D417/04
CPCC07D417/04C07D417/14
Inventor 蔡红颖耿佳赵雪卫
Owner SHIJIAZHUANG GERUI PHARMA CO LTD
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