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Preparation method for 6-fluorine-3,4-dihydro-2H-1-benzopyran-2-ethyl formate

A technology of benzopyran and ethyl formate, which is applied in the field of preparing nebivolol intermediates, can solve the problems of low yield of starting materials, difficult to obtain, etc., and achieves easy preparation, little environmental pollution, and high yield Effect

Active Publication Date: 2011-09-14
ZHEJIANG HUAHAI PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the yield was low (79%) and the starting material (6-fluoro-3,4-dihydro-2H-1-chromene-2-carboxylic acid) was not readily available

Method used

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  • Preparation method for 6-fluorine-3,4-dihydro-2H-1-benzopyran-2-ethyl formate

Examples

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Effect test

Embodiment 1

[0020] Example 1: Using ethanol as a solvent to prepare nebivolol intermediate (6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid ethyl ester)

[0021] In a 500ml hydrogenation kettle, 20g (0.085mol) of nebivolol intermediate (6-fluoro-4-oxo-4H-1-benzopyran-2-carboxylic acid ethyl ester), palladium carbon (7% Pd / C, water content 65%) 6.8g, add in 180ml ethanol solvent. Under the condition of 4.5MPa hydrogen and 62°C, the reaction was mechanically stirred for 24 hours. The reaction solution was filtered to recover palladium carbon, and the ethanol solvent in the filtrate was evaporated under reduced pressure. The distillation residue was dissolved in dichloromethane and neutralized to pH=6-7 with saturated sodium bicarbonate solution. The aqueous phase was back extracted once with dichloromethane, and the dichloromethane phases were combined. The dichloromethane was distilled off under reduced pressure to obtain an oily substance, and after vacuum drying for 24 hours, ...

Embodiment 2

[0022] Example 2: Using ethanol as a solvent to prepare nebivolol intermediate (6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid ethyl ester)

[0023] In a 1200L hydrogenation kettle, 84.5Kg (0.085mol) of nebivolol intermediate (6-fluoro-4-oxo-4H-1-benzopyran-2-carboxylic acid ethyl ester), palladium carbon (7% Pd / C, water content 65%) 44Kg, add in 800L ethanol solvent. Under the condition of 4.2MPa hydrogen and 62°C, the reaction was carried out with mechanical stirring for 96 hours. The reaction solution was filtered to recover palladium carbon, and the ethanol solvent in the filtrate was evaporated under reduced pressure. The distillation residue was dissolved in dichloromethane and neutralized to pH=6-7 with saturated sodium bicarbonate solution. The aqueous phase was back extracted once with dichloromethane, and the dichloromethane phases were combined. Dichloromethane was distilled off under reduced pressure to obtain an oily substance, and after vacuum drying f...

Embodiment 3

[0024] Example 3: Preparation of nebivolol intermediate (6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid ethyl ester) using a mixed solvent of ethanol and acetic acid

[0025] In a 500ml hydrogenation kettle, 30g (0.127mol) of nebivolol intermediate (6-fluoro-4-oxo-4H-1-benzopyran-2-carboxylic acid ethyl ester), palladium carbon (7% Pd / C, water content 65%) 10.2g, add in the mixed solvent of ethanol and acetic acid (ethanol 180ml, acetic acid 1.8ml). Under the condition of 4.5MPa hydrogen and 62°C, the reaction was mechanically stirred for 24 hours. The reaction solution was filtered to recover palladium carbon, and the ethanol solvent in the filtrate was evaporated under reduced pressure. The distillation residue was dissolved in dichloromethane and neutralized to pH=6-7 with saturated sodium bicarbonate solution. The aqueous phase was back extracted once with dichloromethane, and the dichloromethane phases were combined. Dichloromethane was distilled off under red...

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Abstract

The invention discloses a preparation method for a Nebivolol intermediate of (6-fluorine-3,4-dihydro-2H-1-benzopyran-2-ethyl formate). In the preparation method, the Nebivolol intermediate is prepared from a Nebivolol intermediate of (6-fluorine-4-oxo-4H-1-benzopyran-2-ethyl formate) serving as a raw material in the presence of a palladium carbon catalyst (Pd / C) and a dehydrating agent in an alcohol solvent or a mixed solvent of alcohol and acid under the conditions of hydrogen pressure of 4 to 4.5 MPa and the temperature of between 55 and 65 DEG C. In the preparation method, a starting material is easy to prepare; the yield is high; a treatment method after the reaction is simple and efficient; and waste liquid treatment burden and environmental pollution are light, so the preparation method is a simple and green process method for preparing the Nebivolol intermediate and is suitable for large-scale production.

Description

technical field [0001] The invention relates to a high-yield and environment-friendly method for preparing a nebivolol intermediate (6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid ethyl ester). Background technique [0002] The antihypertensive drug Nebivolol hydrochloride (also known as: Nebivolol, CAS: 99200-09-6), is a highly selective and potent third-generation β1 receptor blocker without endogenous sympathetic nerve Active, has the effect of lowering blood pressure and peripheral vascular resistance, and can improve left ventricular function. As a third-generation beta-receptor antagonist, it combines a highly selective beta-receptor antagonist with nitric oxide-mediated vasodilation and is well tolerated in patients with hypertension and heart failure. With its protective effect on the heart, good antihypertensive effect, good tolerance, less adverse reactions, low dose and good curative effect, nebivolol has broad market prospects and great potential. [00...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/66
Inventor 姜桥汪伟谢永
Owner ZHEJIANG HUAHAI PHARMA CO LTD
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