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Arotinolol hydrochloride preparation method

A technology of alololol hydrochloride and molar ratio, which is applied in the field of pharmaceutical chemical industry and pharmaceutical chemistry, can solve the problems of difficult industrialization, cumbersome operation, and low yield, and achieve the effects of low cost, low reaction temperature, and high yield

Active Publication Date: 2021-12-21
CHENGDU EASTON BIOPHARMACEUTICALS CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route is catalyzed by Lewis acid, which has high cost, low yield, cumbersome operation and great difficulty in industrialization

Method used

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  • Arotinolol hydrochloride preparation method
  • Arotinolol hydrochloride preparation method
  • Arotinolol hydrochloride preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Example 1: Preparation of Alololol Hydrochloride

[0036] (a) Preparation of Intermediate I:

[0037] At room temperature, 10.0 g (41.27 mmol) of starting material I was suspended in 200 ml of water, 5.2 g (61.90 mmol) of sodium bicarbonate was added, and 3.82 g (41.29 mmol) of epichlorohydrin was added dropwise with stirring. After dropping, the temperature was raised to 45-50°C and stirred for 2h. After filtering, the filter cake was rinsed with 10 ml of water, and dried under reduced pressure at 50° C. to obtain 13.6 g (40.62 mmol) of a light yellow solid, yield 98.43%, HPLC purity: 99.57%.

[0038] ESI: [M+H] + = 335.0.

[0039] 1 H-NMR (DMSO-d6, δTMS0): 3.31~3.36ppm (1H, m), 3.51~3.55ppm (1H, m), 3.66~3.76ppm (2H, m), 4.04~4.07ppm (1H, m) , 5.80~5.81ppm (1H, d, J=4.0), 7.44 ppm (1H, br), 7.55~7.56ppm (1H, d, J=4.0), 7.72~7.73ppm (1H, d, J=4.0) , 7.99ppm (2H, br).

[0040] (b) Preparation of Alololol Hydrochloride:

[0041] Add 13.0g (38.82mmol) of intermedi...

Embodiment 2

[0044] Embodiment 2: Preparation of Alololol Hydrochloride

[0045] (a) Preparation of Intermediate I:

[0046]At room temperature, 10.0 g (41.27 mmol) of starting material I was suspended in 50 ml of water, 4.96 g (49.52 mmol) of potassium bicarbonate was added, and 11.46 g (123.87 mmol) of epichlorohydrin was added dropwise with stirring. After dropping, the temperature was raised to 25-30°C and stirred for 5h. After filtering, the filter cake was rinsed with 10 ml of purified water, and dried under reduced pressure at 50° C. to obtain 13.5 g (40.32 mmol) of a light yellow solid with a yield of 97.70% and an HPLC purity of 99.36%.

[0047] (b) Preparation of Alololol Hydrochloride:

[0048] Add 13.0g (38.82mmol) of intermediate I to 42.6g (582.44mmol) of tert-butylamine, cool down to 5°C, and add 65.0ml of ethanol dropwise. After dropping, replace with nitrogen, heat up to 55-60°C and keep stirring for 5 hours. TLC monitors, after the reaction is complete, cool down to 0...

Embodiment 3

[0049] Example 3: Preparation of Alololol Hydrochloride

[0050] (a) Preparation of Intermediate I:

[0051] At room temperature, 10.0 g (41.27 mmol) of starting material I was suspended in 400 ml of water, 8.74 g (82.50 mmol) of sodium carbonate was added, and 5.73 g (61.93 mmol) of epichlorohydrin was added dropwise with stirring. After dropping, the temperature was raised to 25-35°C and stirred for 3h. After filtering, the filter cake was rinsed with 10 ml of water, and dried under reduced pressure at 50° C. to obtain 13.3 g (39.72 mmol) of a light yellow solid, yield 96.24%, HPLC purity: 99.15%.

[0052] (b) Preparation of Alololol Hydrochloride:

[0053] Add 13.0g (38.82mmol) of intermediate I to 14.2g (194.10mmol) of tert-butylamine, cool down to 5°C, and drop in 39.0ml of isopropanol. After dropping, replace with nitrogen, heat up to 60-65°C and keep stirring for 4 hours. TLC monitors, after the reaction is complete, cool down to 0°C, slowly add 1N hydrochloric acid...

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Abstract

The invention relates to a novel arotinolol hydrochloride preparation method, which comprises: (1) carrying out a reaction on 5-(2-mercapto-4-thiazolyl)-2-thiophenecarboxamide and epoxy chloropropane in water under the catalysis of an alkali to obtain an intermediate; and (2) reacting the obtained intermediate with tert-butylamine, cooling, and adding hydrochloric acid to adjust the pH value, thereby obtaining arotinolol hydrochloride. The method has the advantages of mild reaction conditions in each step, cheap and easily available raw materials, high atom utilization rate, simplicity and controllability in operation, high yield and purity, less discharge of three wastes, environmental friendliness and suitability for large-scale industrial production.

Description

technical field [0001] The invention relates to the technical fields of medicinal chemistry and pharmaceutical chemical industry, in particular 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] The chemical structural formula of Alololol hydrochlo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/04
CPCC07D417/04Y02P20/55
Inventor 刘建林松王颖
Owner CHENGDU EASTON BIOPHARMACEUTICALS CO LTD
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