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Method for preparing nebivolol hydrochloride epoxy intermediate 6-fluoro-2-epoxy ethyl chroman

A technology of nebivolol hydrochloride epoxy and epoxyethyl chroman, applied in the field of preparation of nebivolol hydrochloride intermediate 6-fluoro-2-oxiranyl chroman, which can solve the active nature of nitrogen salts and potential safety hazards , not suitable for long-term storage and other problems, to achieve the effect of simple operation, high product purity and high yield

Inactive Publication Date: 2016-04-20
广安凯特制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the sodium nitrite reagent is highly toxic and should not be stored in large quantities for a long time. In addition, the intermediate heavy nitrogen salt produced is active in nature and easily decomposed to produce a large amount of nitrogen. Industrial production has a great potential safety hazard

Method used

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  • Method for preparing nebivolol hydrochloride epoxy intermediate 6-fluoro-2-epoxy ethyl chroman
  • Method for preparing nebivolol hydrochloride epoxy intermediate 6-fluoro-2-epoxy ethyl chroman
  • Method for preparing nebivolol hydrochloride epoxy intermediate 6-fluoro-2-epoxy ethyl chroman

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] (1) Add 32g of potassium dihydrogen phosphate and 2kg of water into a 3L reaction flask and stir to dissolve, adjust the pH value to 7.0-7.4 with 2mol / L NaOH solution, then add 40g of zinc chloride, 40g of ammonium formate, and 200g of aldose reductase in sequence , NADPH 20g, (S)-2-chloro-1-(6-fluorochroman-2-yl)ethanone 100g, use 2mol / L sodium hydroxide solution to adjust the pH value to 7.0-7.4, at 55℃±2℃ React for about 12 hours, filter with suction, wash the filter cake with 200ml ethyl acetate, separate the layers, take the water phase and wash it with 200ml ethyl acetate × 3, combine the organic phases and evaporate to dryness under reduced pressure to obtain (S,S)-2-chloro -1-(6-fluorochroman-2-yl)ethanol 95.6g, yield 94.8%, ee%>99.5%;

[0042] (2) Take 90 g of (S, S)-2-chloro-1-(6-fluorochroman-2-yl) ethanol obtained in step (1), 220 g of ethanol, and 16.2 g of sodium hydroxide, and add them into a dry reaction bottle, Raise the temperature to reflux for 4 hou...

Embodiment 2

[0044](1) Add 53g of sodium dihydrogen phosphate and 4kg of water into a 3L reaction flask and stir to dissolve, adjust the pH value to 6.8-7.8 with 2mol / L NaOH solution, then add 78g of zinc chloride, 80g of ammonium formate, and 400g of aldose reductase in sequence , NADPH42g, (S)-2-chloro-1-(6-fluorochroman-2-yl)ethanone 100g, use 2mol / L sodium hydroxide solution to adjust the pH value to 6.8-7.8, at 55℃±2℃ React for about 12 hours, filter with suction, wash the filter cake with 400ml of ethyl acetate, separate layers, take the water phase and wash with 400ml of ethyl acetate × 3, combine the organic phases and evaporate to dryness under reduced pressure to obtain (S,S)-2-chloro -1-(6-fluorochroman-2-yl)ethanol 93.8g, yield 93%, ee%>99.5%;

[0045] (2) Take 90 g of (S, S)-2-chloro-1-(6-fluorochroman-2-yl)ethanol obtained in step (1), 230 g of methanol, and 22.7 g of potassium hydroxide, and add them into a dry reaction flask, Raise the temperature to reflux for 4 hours, fi...

Embodiment 3

[0047] (1) Add 60g of potassium dihydrogen phosphate and 4kg of water into a 3L reaction flask and stir to dissolve, adjust the pH value to 6.8-7.8 with 2mol / L NaOH solution, then add 78g of zinc chloride, 80g of ammonium formate, and 400g of aldose reductase in sequence , NADPH42g, (R)-2-chloro-1-(6-fluorochroman-2-yl)ethanone 100g, use 2mol / L sodium hydroxide solution to adjust the pH value to 6.0-8.0, at 55℃±2℃ React for 12-14 hours, filter with suction, wash the filter cake with 400ml of ethyl acetate, separate layers, take the water phase and wash with 400ml of ethyl acetate×3, combine the organic phases and evaporate to dryness under reduced pressure to obtain (R,R)-2- Chloro-1-(6-fluorochroman-2-yl)ethanol 92g, yield 91.2%, ee%>99.5%;

[0048] (2) Take 90g of (R,R)-2-chloro-1-(6-fluorochroman-2-yl)ethanol obtained in step (1), 240g of isopropanol, and 22.7g of potassium hydroxide, and add to dry reaction bottle, heated to reflux for 4 hours, filtered, evaporated the mo...

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Abstract

The invention discloses a method for preparing a nebivolol hydrochloride epoxy intermediate 6-fluoro-2-epoxy ethyl chroman. The method includes the following steps that firstly, under the conditions that water, phosphate, inorganic alkali B1, zinc chloride, a hydrogen source, aldose reductase and NADPH exist, the temperature is 30-70 DEG C and the pH value is 6.0-8.0, a reduction reaction happens to 2-chloro-1-(6-fluorochromane-2-yl)-ethanon, and 2-chloro-1-(6-fluorochromane-2-yl)-alcohol is obtained; secondly, 2-chloro-1-(6-fluorochromane-2-yl)-alcohol is heated in a C1-C6 alkanol solvent and inorganic alkali B2 for a reflux reaction, an organic ester solvent is added dropwise for crystallization after the reaction ends, and 6-fluoro-2-epoxy ethyl chroman is obtained. The preparation method is mild in reaction condition, raw materials and solvents are easy to obtain, and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and specifically relates to a preparation method of nebivolol hydrochloride intermediate 6-fluoro-2-oxiranyl chroman. Background technique [0002] Nebivolol hydrochloride, developed by U.S. Johnson&Johnson company, is used for the treatment of the medicine of essential hypertension, and the cardioselective beta-receptor blocker of vasodilating effect concurrently, has the advantages such as remarkable curative effect, taking convenience, its The chemical structural formula is as follows: [0003] [0004] 6-Fluoro-2-oxirane chroman is a key intermediate in the preparation process of nebivolol. At present, reports on its synthesis process include: [0005] European patent EP0145067 discloses a method for preparing 6-fluoro-2-oxirane chroman, which uses 6-fluorochroman-2-carboxylic acid as a raw material, which is first reduced to the corresponding alcohol, and then oxidized to obt...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D407/04
CPCC07D407/04
Inventor 谭超周旭东王廷圣邹鑫向世川张稳稳
Owner 广安凯特制药有限公司
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