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Synthetic method of nebivolol

A synthesis method and mixture technology, applied in the field of chemical synthesis of drugs, can solve the problems of difficult batch production, low yield, long synthesis route, etc.

Active Publication Date: 2014-06-04
BEIJING NORMAL UNIVERSITY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] The multiple nebivolol synthetic methods described above generally have long synthetic routes, low yield, relatively harsh conditions for reaction requirements, and shortcomings such as difficult control of the reaction, so it is difficult to realize industrialized batch production

Method used

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  • Synthetic method of nebivolol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Starting from a mixture of racemic diastereomer A and racemic diastereomer B

[0048] (1) Preparation of racemic diastereomer A and racemic diastereomer B

[0049] 2-Amino-1-(-6-fluoro-2-chromanyl)ethanol diastereomeric mixture (2 g) was recrystallized from ethanol to give crystals (0.6 g, 30%) as pure diastereomer A , The solvent was removed by rotary evaporation of the mother liquor, and the obtained solid was recrystallized several times to obtain diastereomer B.

[0050] Diastereomer A 1 HNMR (CDCl 3 , 400MHz): δ6.78-6.73(m,3H),3.97(ddd,J=10.1Hz,4.6Hz,3.0Hz,1H),3.66(dt,J=7.2Hz,4.5Hz,1H),2.97- 2.73(m,4H),1.98-1.91(m,2H).

[0051] (2) Preparation of Bromide (IIb)

[0052]Mix and stir 2-amino-1-(-6-fluoro-2-chromanyl)ethanol diastereomer B (0.85g) with sulfuric acid (1.25M, 85ml), then add potassium bromide (5.1g) and Diethyl ether (60ml). With cooling and stirring in an ice-water bath, drop NaNO 2 solution (0.45g dissolved in 10ml water). After the dropwise a...

Embodiment 2

[0059] (S,R) and (S,S)-2-amino-1-(-6-fluoro-2-chromanyl)ethanol diastereomeric mixture and (R,S) and (R,R)- 2-Amino-1-(-6-fluoro-2-chromanyl)ethanol diastereomeric mixture as starting material

[0060] (1) Preparation of diastereomer S-A and diastereomer S-B

[0061] (S,R) and (S,S)-2-Amino-1-(-6-fluoro-2-chromanyl)ethanol diastereomeric mixture (2 g) was recrystallized from ethanol to give crystals (0.6 g ) is the pure diastereomer S-A, the mother liquor is rotatably evaporated to remove the solvent, and the obtained solid is recrystallized several times to obtain the diastereomer S-B.

[0062] Diastereomer S-A 1 HNMR (CDCl 3 , 400MHz): δ6.78-6.73(m,3H),3.97(ddd,J=10.1Hz,4.6Hz,3.0Hz,1H),3.66(dt,J=7.2Hz,4.5Hz,1H),2.97- 2.73(m,4H),1.98-1.91(m,2H).

[0063] (2) Preparation of diastereomer R-A and diastereomer R-B.

[0064] The (R,S) and (R,R)-2-amino-1-(-6-fluoro-2-chromanyl)ethanol diastereomeric mixture (2 g) was recrystallized from ethanol to give crystals (0.6 g ) is ...

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Abstract

The invention discloses a synthetic method of nebivolol. The synthetic method comprises the following steps: by taking a 2-amino-1-(-6-fluoro-2-chromanyl) ethanol diastereomer mixture as an initial raw material, firstly, recrystallizing and separating the 2-amino-1-(-6-fluoro-2-chromanyl) ethanol diastereomer mixture to respectively obtain corresponding diastereomers A and B; carrying out reactions such as diazotization, halogenation and cyclization on the diastereomer B to synthesize an epoxy compound; and then, carrying out a reaction on the obtained epoxy compound and the diastereomer A to obtain nebivolol. The method disclosed by the invention is mild in reaction condition, simple and convenient to operate and short in synthetic line, and is suitable for industrialized batch production of nebivolol.

Description

Technical field [0001] The invention relates to the technical field of chemically synthesized medicines, in particular to a method for synthesizing nebivolol. Background technique [0002] Nebivolol is a novel, highly effective, selective action on β 1 Antihypertensive drugs for adrenergic receptors, the molecular structural formula is as follows: [0003] [0004] There are four chiral carbon atoms in the structural formula. Due to the symmetry of the molecule, there can be 10 isomers, among which the isomers in the (S, R, R, R) configuration are: [0005] have a good beta 1 Receptor blocking properties, the isomers of its enantiomer (R,S,S,S) configuration are: [0006] It has the ability to control the release of NO, so the commercially available drugs are the hydrochloride salts of their racemates. [0007] Nebivolol molecule has symmetry. According to retrosynthesis analysis, Nebivolol can be divided into two fragments, one is amino alcohol fragment, and the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/58
CPCC07D311/58
Inventor 张站斌杨维芳周欣王学斌唐志刚张俊波关淑贞
Owner BEIJING NORMAL UNIVERSITY