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Resolution method for preparing optically pure metoprolol

A pure and optical technology, applied in the field of splitting racemic metoprolol to prepare its S- and -R--metoprolol isomers, can solve the problem of low optical purity and achieve small loss of resolving agent , high splitting efficiency, and the effect of saving production costs

Active Publication Date: 2011-05-25
HEBEI UNIVERSITY OF SCIENCE AND TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The asymmetric synthesis of photoactive metoprolol is also characterized by low optical purity due to partial racemization in the synthesis process

Method used

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  • Resolution method for preparing optically pure metoprolol
  • Resolution method for preparing optically pure metoprolol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] (1) Add 267.37g (1mol) of racemic metoprolol and 242.35g (1mol) of (-)-4-phenyl-2-hydroxy-5,5-dimethyl in 2L of methyl tert-butyl ether base-2-oxo-1,3,2-dioxaphosphorinane, heated to reflux and stirred until the solution was clear, continued to stir for 1h, crystals gradually precipitated, filtered, and washed the filter cake with 200mL methyl tert-butyl ether , to obtain filter cake 244.5g after drying;

[0024] (2) Dissolve the above filter cake into 500mL water, adjust the pH=8 with 10% NaOH solution, stir at room temperature for 1h, extract three times with ethyl acetate, each time 100mL, dry the organic layer, and evaporate the organic solvent to obtain S -(-)-Metoprolol 120.33g, the yield is 90.2%, 96% e.e. . The pH of the water layer is adjusted to strong acidity, and solids are gradually precipitated, filtered, and the cyclic phosphoric acid resolving agent is recovered;

[0025] (3) Combine the filtrate and washing liquid in step (1), evaporate the organic ...

Embodiment 2

[0028] (1) Add 267.37g (1mol) racemic metoprolol and 276.5g (1mol) (+)-4-(2-chlorophenyl) in 2L ether / ethanol solution (volume ratio 9:1) -2-Hydroxy-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane, heated to reflux and stirred until the solution was clear, continued to stir for 1h, crystals gradually precipitated, filtered, The filter cake was washed with 200 mL of ether, and 250.5 g of the filter cake was obtained after drying;

[0029] (2) Dissolve the above filter cake in 500mL of water, adjust the pH=8 with 10% KOH solution, stir at room temperature for 1h, extract three times with ethyl acetate, 100mL each time, dry the organic layer, and evaporate the organic solvent to obtain R-(+)-metoprolol 122.33g, the yield is 91.5%, 96.4% e.e. . The pH of the water layer is adjusted to strong acidity, and solids are gradually precipitated, filtered, and the cyclic phosphoric acid resolving agent is recovered;

[0030] (3) Combine the filtrate and lotion in step (1), distill off the...

Embodiment 3

[0033] (1) Add 267.37g (1mol) of racemic metoprolol and 275.4g (1mol) of combined cyclic phosphoric acid resolving agent into 2L ether / methanol solution (volume ratio: 9:1), heat and reflux and stir until the solution is clear , continue to stir for 1h, crystals gradually precipitate out, filter, wash the filter cake with 200mL ether, and obtain 257.82g of the filter cake after drying;

[0034] The combined cyclic phosphoric acid resolving agent is 98% (-)-4-(2-chlorophenyl)-2-hydroxyl-5,5-dimethyl-2-oxo-1,3,2-di Oxaphosphorinane and 2% of (-)-4-(2-methoxyphenyl)-2-hydroxy-5,5-dimethyl-2-oxo-1,3,2- Dioxaphosphine, the molar ratio of the two is 98: 2;

[0035] (2) Dissolve the above filter cake in 500mL of water, add 10% ammonia solution to adjust pH = 8, stir at room temperature for 1h, extract three times with ethyl acetate, 100mL each time, dry the organic layer, evaporate the organic solvent to obtain S- (-)-metoprolol 126.33g, the pH of the water layer was adjusted to st...

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Abstract

The invention discloses a resolution method for preparing optically pure metoprolol, which belongs to the field of racemic compound resolution. Chiral cyclic phosphoric acid is taken as a resolving agent for preparing the optically pure metoprolol, and the chiral cyclic phosphoric acid resolving agent can be used independently or in a mixed mode. The method comprises the following steps that: racemic metoprolol and the chiral cyclic phosphoric acid resolving agent form diastereoisomer salt in a solvent, the diastereoisomer salt with low solubility is filtered, and a filter cake is dissociated to obtain the optically pure metoprolol; and filtrate is dissociated to obtain another diastereoisomer of the metoprolol. The method is characterized in that: the optically active metoprolol has high optical purity and yield, the resolving agent can be recycled, and the method is easy to operate and suitable for industrialized amplification.

Description

technical field [0001] The present invention relates to a resolution method for racemic compounds, in particular to a new method for preparing its S-(-) and -R-(+)-metoprolol isomers by separating racemic metoprolol . Background technique [0002] In order to be able to use drugs safely and accurately, the demand for chiral drugs has become increasingly urgent. β-blockers are an important class of drugs that are widely used clinically to treat hypertension and angina pectoris. Most β-blockers are currently on the market in the form of racemates. The β-blocker metoprolol has two optical isomers: R-(+)-metoprolol and S-(-)-metoprolol, which exhibit pharmacokinetic and pharmacodynamic Great difference in learning. Studies have shown that the S-enantiomer of metoprolol has a β-receptor affinity 25 times that of its R-enantiomer, and in isolated hearts, its S-enantiomer blocks isoproterenol-activated adenosine The cyclase activity is 33 times that of its enantiomer, and there...

Claims

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Application Information

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IPC IPC(8): C07C217/32C07C213/10
Inventor 孙凤霞王德彬张炳烛
Owner HEBEI UNIVERSITY OF SCIENCE AND TECHNOLOGY
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