Method for preparing nebivolol midbody

A technology of nebivolol and intermediates, which is applied in the field of drug synthesis, can solve the problems of unfavorable industrial production, high process requirements, and short routes, and achieve the effects of being beneficial to industrial applications, high chiral purity, and reducing production costs

Active Publication Date: 2014-04-09
江苏八巨药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Although this method has a short route, the cost of raw materials such as n-butyllithium used is relatively high, and the process requirements are high, and the reaction needs to be carried out at -70°C, which is not conducive to industrial production.

Method used

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  • Method for preparing nebivolol midbody
  • Method for preparing nebivolol midbody
  • Method for preparing nebivolol midbody

Examples

Experimental program
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Effect test

Embodiment 1

[0042] Add 20g of (S)-6-fluorochroman-2-carboxylic acid into the reactor, then add 300mL of organic solvent diethyl ether, then stir and cool down to -10°C, add 20.6g of acid agent triethylamine dropwise, and keep warm for 0.5h , then lower the temperature to -20°C, add 22g of ethyl chloroformate dropwise, after the dropwise addition, control the temperature at -20°C and keep it warm for 1h, after the reaction, directly dropwise add 8.6g of diazomethane to the reaction liquid Diethyl ether solution, control the temperature at -25°C for heat preservation reaction for 2.5 hours, after the reaction, directly pass a sufficient amount of HCl into the reaction solution, and control the temperature at 0°C for halogenation reaction for 3 hours, the halogenation reaction is over Finally, add 60mL of deionized water to the reaction solution and stir until the solid dissolves, then let it stand for stratification, collect the organic layer, concentrate and remove the solvent to obtain 33g...

Embodiment 2

[0044] Take 20g of (R)-6-fluorochroman-2-carboxylic acid and add it into the reactor, then add 300mL of organic solvent diethyl ether, then, stir and cool down to -10°C, add 20.6g of acid agent triethylamine dropwise, keep warm for 0.5h , then lower the temperature to -30°C, add 22g of ethyl chloroformate dropwise, after the dropwise addition, control the temperature at -30°C to keep warm for 1h, after the reaction is over, directly dropwise add 8.6g of diazomethane tetrasodium diazomethane into the reaction solution Carbon chloride solution, keep the temperature at -30°C for 2.5 hours, add a sufficient amount of HBr after the reaction, and control the temperature at 0°C to keep the halogenation reaction for 3 hours. After the halogenation reaction, add Add 60mL of deionized water and stir until the solid dissolves, then let stand to separate layers, collect the organic layer, concentrate and remove the solvent to obtain 39.5g of crude oily product, add 50mL of ethanol, stir an...

Embodiment 3

[0046] Take 20g of (S)-6-fluorochroman-2-carboxylic acid, add 300mL of organic solvent tetrahydrofuran, then stir and cool down to -15°C, add 20.6g of triethylamine dropwise, keep warm for 0.5h, then cool down to -30°C, Add 22g of ethyl chloroformate dropwise. After the dropwise addition, keep the temperature at -30°C for 1 hour. After the reaction, add 8.6g of diazomethane-containing ether solution directly to the reaction solution, and control the temperature at -30°C. ℃ for 2.5 hours, after the reaction, add enough HCl directly to the reaction solution, and control the temperature at -10 ℃ for halogenation reaction for 3 hours, after the halogenation reaction, directly concentrate to remove the organic solvent, and then add dichloro Stir 200mL of methane and 60mL of water until the solid is dissolved, let stand to separate layers, collect the organic layer, and then concentrate to remove the solvent to obtain 34g of crude oil, add 50mL of isopropanol, stir and cool to -5°C f...

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Abstract

The invention relates to a method for preparing a nebivolol midbody, which belongs to the technical field of medicament synthesis, for solving the problems that the conventional raw material is high in cost, long in route and low in yield. The method comprises the following steps: enabling 6-fluorine chroman-2-formic acid as a raw material to react with chloro-carbonic ester with the presence of a deacid reagent, then adding diazomethane after the reaction is accomplished, so as to enable the midbody to react with the diazomethane to generate a reaction liquid of an intermediate product, and then adding a hydrogen halide gas or a hydrogen halide solution into the reaction liquid to perform halogenating reaction so as to obtain a compound of formula IV, namely, (6-(fluorine-3,4-dihydro-2H-benzopyran-2-methanol-2-yl) ethanone halogenate. The method provided by the invention has the advantages that the reaction route is short, the yield is high, and the used material is low in price and easy to purchase.

Description

technical field [0001] The invention relates to a preparation method of a nebivolol intermediate, which belongs to the technical field of medicine synthesis. Background technique [0002] Nebivolol was first developed by Johnson & Johnson Company of the United States, and was approved for marketing by Menarim Company in Italy; it was first launched in Germany and the Netherlands in 1997 for the treatment of essential hypertension, and it was launched in more than 30 countries including the United Kingdom in May 1999 . Nebivolol hydrochloride is a β1 receptor blocker, which can gently slow down the heart rate and lower blood pressure, and is mainly used for the treatment of essential hypertension and chronic heart failure. Nebivolol hydrochloride has the advantages of significant curative effect, convenient administration, and few adverse reactions. One of the "Ten Blockbusters" with good market prospects. [0003] And (6-fluoro-3,4-dihydro-2H-benzopyran-2-methanol-2-yl)et...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/58
CPCC07D311/58
Inventor 王玉钢虞盛舟徐斌孙振宇程祖福
Owner 江苏八巨药业有限公司
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