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
CN105503842AInactive Publication Date: 2016-04-20广安凯特制药有限公司
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Patent Information

Authority / Receiving Office
CN · China
Patent Type
Applications(China)
Current Assignee / Owner
广安凯特制药有限公司
Publication Date
2016-04-20
Estimated Expiration
Not applicable · inactive patent

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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.
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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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