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Method for preparing RRRS and SSSR type nebivolol intermediate mixture

A technology of mixtures and intermediates, applied in the field of preparation of isomer mixtures, can solve the problems of low separation efficiency and inconvenient operation, and achieve the effect of high separation efficiency and easy operation

Active Publication Date: 2009-06-24
SHANGHAI SHYNDEC PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] The technical problem to be solved by this invention is to overcome the inconvenient operation and low separation efficiency of the key step of separating the intermediate mixture of RRRS, SSSR, RRSR and SSRS type in the method of existing nebivolol of synthetic RRRS and SSSR type defects, and provide a simple and high separation efficiency method to prepare RRRS and SSSR type nebivolol intermediate mixture

Method used

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  • Method for preparing RRRS and SSSR type nebivolol intermediate mixture
  • Method for preparing RRRS and SSSR type nebivolol intermediate mixture
  • Method for preparing RRRS and SSSR type nebivolol intermediate mixture

Examples

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Embodiment 1

[0039] Example 1 Preparation of RRRS and SSSR type nebivolol intermediate (formula I, X=H) mixture

[0040] In the solution prepared in Reference Example 1, add 250ml of n-hexane, heat to 30°C, then cool to 10-15°C, keep warm for crystallization for 4 hours, filter to obtain 67g (±)[R*[S*[S* (S*)]]]αα'-[phenylmethyliminobis(methylene)]bis-[6-fluoro-3,4-dihydro-2H-chromene-2-methanol]( Mixture of formula V and formula VI) (HPLC purity 99.2%).

Embodiment 2

[0041] Example 2 Preparation of RRRS and SSSR type nebivolol intermediate (formula I, X=H) mixture

[0042] Recover ethanol from the solution prepared in Reference Example 1 under reduced pressure to obtain 160 g of the mixture (Formula IV), add 160 g of ethanol: isopropyl ether = 1:4 mixed solution, heat to reflux, then cool to 10-15 ° C, and keep warm for crystallization After 18 hours, filter to obtain 68g (±)[R*[S*[S*(S*)]]]α α'-[phenylmethyliminobis(methylene)]bis-[6-fluoro -3,4-Dihydro-2H-chromene-2-methanol] (mixture of Formula V and VI) (HPLC purity 99.6%).

Embodiment 3

[0043] Example 3 Preparation of RRRS and SSSR type nebivolol intermediate (formula I, X=H) mixture

[0044] In the solution prepared in reference example 1, add 1000ml of n-hexane, heat to reflux, cool to 10~15°C, keep warm for crystallization for 4 hours, filter to obtain 67g (±)[R*[S*[S*(S *)]]]αα'-[phenylmethyliminobis(methylene)]bis-[6-fluoro-3,4-dihydro-2H-chromene-2-methanol] (formula V and formula VI) (HPLC purity 99.2%).

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Abstract

The invention discloses a method for preparing a mixture of a RRRS nebivolol intermediate and a SSSR nebivolol intermediate respectively shown in formula II and formula III. The method is characterized by optionally adopting one of the following two manners: (1) adding a precipitation solvent to an alcohol solvent of the mixture containing RRRS, SSSR, RRSR and SSRS nebivolol intermediates as shown in formula I, heating, cooling to separate out crystal, and filtering; and (2) adding the mixture of the RRRS, SSSR, RRSR and SSRS nebivolol intermediates of the formula I to a mixed solvent of the alcohol solvent and the precipitation solvent, heating to dissolve, cooling to separate out crystal, and filtering, wherein, X is H, or C1-C6 alkyl or C1-C6 alkoxyl, and n is 1-5. The method has the advantages of simple and convenient operation, and high separation efficiency, and is available for industrialized production.

Description

technical field [0001] The invention relates to a method for preparing an isomer mixture of a compound, in particular to a method for preparing a mixture of RRRS and SSSR type nebivolol intermediates. Background technique [0002] Nebivolol is shown in the following formula. There are 4 chiral carbon atoms in its structure, and theoretically there are 16 stereoisomers. Considering the symmetry factor, only 10 stereoisomers exist. [0003] [0004] Among them, d-nebivolol (RRRS) and 1-nebivolol (SSSR) are β-receptor blockers with antihypertensive effect. [0005] [0006] Patents EP145067 and EP334429 describe the preparation method of nebivolol and related compounds, and the synthetic route is as follows: [0007] [0008] [0009] In this patent, except for 1a, 2a, 3a, 4a and 5a, there are no examples to specifically describe the preparation process, nor the separation and purification process of 7a and 7a, but they can be prepared according to similar methods....

Claims

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Application Information

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IPC IPC(8): C07D311/20C07B57/00
CPCC07D311/58
Inventor 王国平陈旭东侯建
Owner SHANGHAI SHYNDEC PHARMA CO LTD
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