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Preparation process of arotinolol hydrochloride intermediate

A preparation technology of alololol hydrochloride, which is applied in the field of medicinal chemical preparation, can solve the problems of high-temperature reaction, large equipment corrosion, and many impurities, and achieve the effect of less synthesis steps, high atom utilization rate, and high purity

Pending Publication Date: 2022-07-22
北京鑫诺康桥药物研究有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Among them, for the synthesis of intermediate II in the route, the literature "Synthesis and β-adrenergic blocking action of a new thiazolylthiopropanolamine derivative, Journal of Pharmaceutical Sciences, 1878, 67(9), 1334)", the literature "Synthesis of Alololol Hydrochloride, China Impurities in Pharmaceutical Industry. 2011, 42(9), 641", literature "Improvement of Arololol Hydrochloride Synthesis Process, Progress in Pharmacy, 2013, 37(3), 137" and related preparation methods reported in patent CN104447731A, all use As a bromine source, bromine has disadvantages such as high toxicity, high temperature reaction, many impurities, low yield, and great corrosion to equipment.

Method used

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  • Preparation process of arotinolol hydrochloride intermediate
  • Preparation process of arotinolol hydrochloride intermediate
  • Preparation process of arotinolol hydrochloride intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Example 1: Preparation of 5-(2-bromoacetyl)thiophene-2-carboxamide

[0043] (a) Preparation of Intermediate I:

[0044] Suspend 11.5kg of 5-acetyl-thiophene-2-carboxylic acid in 152.4kg of dichloromethane, add 230g of N,N-dimethylformamide, replace with nitrogen, stir and cool down to 0°C, and slowly add 11.15kg of oxalyl chloride. After the addition was completed, the temperature was slowly raised to 15-25°C and stirred. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure. 152.4 kg of dichloromethane was added to the residue, and after stirring and dissolving completely, it was used for later use. 23L of concentrated ammonia water was added to the reaction kettle, cooled to -5~5°C, and the dichloromethane solution of the above-mentioned intermediate state—acyl chloride was slowly added. After the addition is completed, centrifugation, and the filter cake is rinsed with water. After drying under reduced pressure...

Embodiment 2

[0049] Example 2: Preparation of 5-(2-bromoacetyl)thiophene-2-carboxamide

[0050] (a) Preparation of Intermediate I:

[0051]115g of 5-acetyl-thiophene-2-carboxylic acid was suspended in 1524g of acetonitrile, 2.3g of N,N-dimethylformamide was added, and after nitrogen replacement, the temperature was lowered to 0°C with stirring, and 128.9g of oxalyl chloride was slowly added. After the addition was completed, the temperature was slowly raised to 30-40°C and stirred. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure. 1524 g of acetonitrile was added to the residue, and after stirring to dissolve completely, it was used for later use. 1.15L of concentrated ammonia water was added to the reaction kettle, the temperature was lowered to 15-25°C, and the acetonitrile solution of the above-mentioned intermediate state-acyl chloride was slowly added. After adding, filter and rinse the filter cake with water. After drying ...

Embodiment 3

[0054] Example 3: Preparation of 5-(2-bromoacetyl)thiophene-2-carboxamide

[0055] (a) Preparation of Intermediate I:

[0056] 115g of 5-acetyl-thiophene-2-carboxylic acid was suspended in 1524g of tetrahydrofuran, 2.3g of N,N-dimethylformamide was added, and after nitrogen replacement, the temperature was lowered to 0°C with stirring, and 94.4g of oxalyl chloride was slowly added. After the addition was completed, the temperature was slowly raised to 10-15°C and stirred. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure. 1524 g of tetrahydrofuran was added to the residue, and the mixture was stirred and dissolved, and it was used for later use. 172.5ml of concentrated ammonia water was added to the reaction kettle, the temperature was lowered to -10~0°C, and the tetrahydrofuran solution of the above-mentioned intermediate state-acyl chloride was slowly added. After adding, filter and rinse the filter cake with water....

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Abstract

The invention discloses a preparation method of an arotinolol hydrochloride intermediate, and particularly, the preparation method comprises the following steps: firstly carrying out acylating chlorination reaction on 5-acetyl-thiophene-2-carboxylic acid to prepare intermediate acyl chloride, then carrying out ammonolysis reaction to prepare an intermediate I, and finally reacting the intermediate I with a bromination reagent. The method has the beneficial effects that the reaction conditions of each step are mild, the reaction steps are short, the atom utilization rate is high, the operation is simple and controllable, the reaction yield is high, the product purity is high, a high-toxicity reagent is not used, environmental protection and labor protection are utilized, and the method is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry preparation, in particular to a preparation method of arolol hydrochloride intermediate. Background technique [0002] Arololol hydrochloride was developed by Japan's Sumitomo Pharmaceutical Co., Ltd. and was first listed in Japan in 1985. Arolol hydrochloride is known as a 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, which has weak α1-adrenoceptor blocking effect. The antihypertensive effect is more ideal, and it is more suitable for the treatment of adolescent hypertension. [0003] The chemical structural formula of arolol hydrochloride is as follows: [0004] [0005] There are many documents about the preparation method of arolol hydrochloride at present, and the mainstream synthe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/38
CPCC07D333/38
Inventor 刘建林松张涛乔智涛刘涛陈洪王颖
Owner 北京鑫诺康桥药物研究有限公司
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