Cardiovascular drug acebutolol intermediate 2- acetyl-4-n-butyramidophenol synthesis method

A technique for the synthesis of acebutolol, which is applied in the field of medicinal chemistry, can solve the problems of high cost, complex reaction operation, toxicity and pollution of reagents used, and achieve the effects of low cost, low dosage and low toxicity

Inactive Publication Date: 2007-05-30
TECHNICAL INST OF PHYSICS & CHEMISTRY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The purpose of the present invention is to provide a green and environmentally friendly synthetic method to synthesize the cardiovascular drug acebutolol in order to overcome the problems of relatively high toxicity and pollution of reagents used in the prior art, high cost, and complicated reaction operations. (Acebutolol) intermediate

Method used

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  • Cardiovascular drug acebutolol intermediate 2- acetyl-4-n-butyramidophenol synthesis method
  • Cardiovascular drug acebutolol intermediate 2- acetyl-4-n-butyramidophenol synthesis method

Examples

Experimental program
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Effect test

Embodiment 1

[0021] (1) Put 2400g of n-butyric acid, 1000g of p-aminophenol, and 3400g of toluene into the reaction bottle, heat up and reflux for dehydration. Reflux for about 8 hours, (moisture content is about 145g) carry out atmospheric distillation and reclaim toluene. After recovering about 80% of the amount of toluene, carry out vacuum distillation to evaporate the toluene. Cool to T<35°C, add 1000g of water, stir and add 6000g of 30% aqueous sodium hydroxide solution dropwise, and then add dropwise 2200g of acetic anhydride. Stir for 2.5 hours. Cool to T<35°C and filter. Recrystallize from toluene:ethanol. Activated carbon decolorization, hot filtration. The crystalline product was dried until it had no toluene smell. Yield 65%.

[0022] (2) Put 1400g of aluminum trichloride into the reaction bottle, stir and heat up until the internal temperature reaches 100-105°C. 800 g of 4-n-butyrylaminophenol was added in 10 times, and the temperature was raised to 110° C. for 4 hours. ...

Embodiment 2

[0024] (1) Put 2400g of n-butyric acid, 1000g of p-aminophenol, and 3400g of toluene into the reaction bottle, heat up and reflux for dehydration. Reflux for about 10 hours, (moisture content is about 146g) carry out atmospheric distillation and reclaim toluene. After recovering about 80% of the amount of toluene, carry out vacuum distillation to evaporate the toluene. Cool to T<35°C, add 1000g of water, stir and add 6000g of 30% sodium hydroxide dropwise, and then add dropwise 2200g of acetic anhydride. Stir for 2.5 hours. Cool to T<35°C and filter. Recrystallize from toluene:ethanol. Activated carbon decolorization, hot filtration. The crystalline product was dried until it had no toluene smell. Yield: 67%.

[0025] (2) Put 1400g of aluminum trichloride into the reaction flask, stir and raise the temperature until the internal temperature reaches 100-105°C. 800 g of 4-n-butyrylaminophenol was added in 10 times, and the temperature was raised to 120° C. for 4 hours. C...

Embodiment 3

[0027] (1) Put 2400g of n-butyric acid, 1000g of p-aminophenol, and 3400g of toluene into the reaction bottle, heat up and reflux for dehydration. Reflux for about 12 hours, (moisture content is about 145g) carry out atmospheric distillation and reclaim toluene. After recovering about 80% of the amount of toluene, carry out vacuum distillation to evaporate the toluene. Cool to T<35°C, add 1000g of water, stir and add 6000g of 30% sodium hydroxide dropwise, and then add dropwise 2200g of acetic anhydride. Stir for 2.5 hours. Cool to T<35°C and filter. Recrystallize from toluene:ethanol. Activated carbon decolorization, hot filtration. The crystalline product was dried until it had no toluene smell. Yield 68%.

[0028] (2) Put 1400g of aluminum trichloride into the reaction bottle, stir and raise the temperature until the internal temperature reaches 100---105°C. 800 g of 4-n-butyrylaminophenol was added in 10 times, and the temperature was raised to 140° C. for 4 hours. ...

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Abstract

The invention discloses a synthesizing method of 2-acetyl-4-butanamide phenol as cardiovascular drug acetate butyrate intermediate in the drug chemical domain, which comprises the following steps: blending p-aminophenol and n-butyrate; reacting through tank agent; distilling to remove tank agent; cooling reacting product; adding water as dispersant; adding liquid alkaline to react to generate phenolate; dripping acid anhydride; stirring to generate ester; recrystallizing the first-step product; adopting non-solvent solid-phase rearranging reaction; blending aluminium chloride and the first-step product; feeding batch by batch; heating to rearrange; adding water to decompose after reacting; filtering to obtain rough product; recrystallizing to obtain the product.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a green synthesis method of an intermediate of cardiovascular drug Acebutolol, which is an atom-economical synthesis method. Background technique [0002] Cardiovascular drug Acebutolol (Acebutolol) is a β1-adrenergic receptor selective β-receptor blocker, which can be used to treat hypertension, and can also be used to treat arrhythmia, myocardial infarction and other diseases, 2 -Acetyl-4-n-butyrylphenol is an important intermediate in the synthesis of the cardiovascular drug Acebutolol. [0003] About the synthesis of acebutolol (Acebutolol) intermediate 2-acetyl-4-n-butyrylaminophenol, the method of U.S. Patent No. 3,726,919 is to use 4-butyrylaminophenol and acetyl chloride to heat and reflux in benzene, and then The final product is obtained by rearranging the product of the first step with aluminum trichloride in a solvent of 1,1,2,2-tetrachloroethane. The toxicity and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/02C07C233/33A61P9/00
Inventor 王乃兴盛瑞隆
Owner TECHNICAL INST OF PHYSICS & CHEMISTRY - CHINESE ACAD OF SCI
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