Racemization recovery method for by-products in split mother liquor of Vernakalant intermediates

A vernakalant intermediate and racemization technology, applied in the field of racemization recovery, can solve the problems of difficult storage and transportation, long reaction time, etc., and achieve the effect of simple operation, short reaction time and less by-products

Active Publication Date: 2014-01-29
ZHEJIANG UNIV OF TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Only WO2006075778 reports that the mother liquor after the resolution of racemic 2-((R)-3-(arylmethoxy)-1-pyrrolidinyl)cyclohexanol 5 is recovered and treated, and methanesulfonyl chloride is used as the reaction reagent , carry out racemization treatment to obtain diastereomers, the disadvantage is that methanesulfonyl chloride is a strong irritant liquid, storage and transportation are difficult, and the reaction time is long (3~4 days)

Method used

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  • Racemization recovery method for by-products in split mother liquor of Vernakalant intermediates
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  • Racemization recovery method for by-products in split mother liquor of Vernakalant intermediates

Examples

Experimental program
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Effect test

Embodiment 1

[0030] Get 25g R-3-hydroxypyrrolidine, according to the method of WO2004099137 example 1, obtain the racemic vernakalant intermediate, then according to the resolution method of WO2006088525 example 1, add 4gL-tartaric acid for resolution, collect the resolved Filtrate, get wherein 90mL liquid (chiral HPLC detection wherein contains (1S, 2S)-2-((R)-3-(benzyloxy)-1-pyrrolidinyl)cyclohexanol-L-tartrate 13.75 g), wash once with 50mL 1mol / L sodium hydroxide, wash twice with 50mL water, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain 8.55g of dark yellow oily liquid with ee value of 73.8%, HPLC The purity is 97.6%, and the recovery rate is 95.2%.

Embodiment 2

[0032]Get 25g R-3-hydroxypyrrolidine, according to the method of WO2004099137 example 1, obtain the racemic vernakalant intermediate, then according to the resolution method of WO2006088525 example 1, add 5g of L-di-p-toluoyl tartaric acid for resolution , collect the split filtrate, get 130mL of the liquid (chiral HPLC detection wherein contains (1S, 2S)-2-((R)-3-(benzyloxy)-1-pyrrolidinyl) cyclohexanol -L-di-p-toluoyl tartrate 21.37g), washed once with 15mL 10mol / L sodium hydroxide, washed twice with 50mL water, combined organic phase, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain dark yellow oil The liquid is 8.62g, the ee value is 76.8%, the HPLC purity is 98.2%, and the recovery rate is 96.9%.

Embodiment 3

[0034] Get 25g R-3-hydroxypyrrolidine, according to the method of WO2004099137 example 1, obtain the racemic vernakalant intermediate, then according to the resolution method of WO2006088525 example 1, add 5g of L-di-p-toluoyl tartaric acid for resolution , collect the split filtrate, get 130mL of the liquid (chiral HPLC detects that it contains (1S,2S)-2-((R)-3-(4-methoxybenzyloxy)-1-pyrrolidine Base) cyclohexanol-L-di-p-toluoyl tartrate 22.37g), washed once with 50mL1mol / L sodium hydroxide, washed twice with 50mL water, combined organic phase, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure 8.92 g of dark yellow oily liquid was obtained, the ee value was 75.2%, the HPLC purity was 98.1%, and the recovery rate was 96.5%.

[0035] The second part: (1S,2S)-2-((R)-3-(arylmethoxy)-1-pyrrolidinyl) cyclohexanol epirotization treatment

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Abstract

The invention discloses a racemization recovery method for by-products in split mother liquor of Vernakalant intermediates, wherein the racemized Vernakalant intermediates that are 2-((R)-3-(aromatic methoxyl)-1-pyrrolidyl)cyclohexanol are processed through chemical resolution for preparing mother liquor with RRR configurations, and the mother liquor with RRR configurations is purified; SSR configurations that are obtained through recovery are taken as reaction substrates, react with dichloro triaryl phosphines in alkaline substances for 1 to 5 hours under the temperature ranging from 40 to 100 DEG C; then water is added, and the reaction along with stirring is performed for 1 to 5 hours under the temperature ranging from 40 to 100 DEG C; then liquid reactant is processed through pH adjustment to obtain racemized products that contain the RRR configurations and the SSR configurations and are formed by a pair of diastereoisomers, and triaryl phosphine oxides are obtained through recovery at the same time; and in addition, the diastereoisomers are repeatedly split and salified so as to prepare final chiral products. By adopting the racemization recovery method, waste mother liquor is converted to the products, waste is changed into valuable, yield coefficient is improved greatly, the triaryl phosphine oxides can be recycled, the manufacturing cost is lowered, the environmental protection problem of treatment of split mother liquor can be solved, and the economical benefits and the social benefits are obvious.

Description

(1) Technical field [0001] The invention relates to a method for recovering racemization of by-products in the split mother liquor of an antiarrhythmic drug vernakalant intermediate. (2) Background technology [0002] The new antiarrhythmic drug Vernakalant (English name: Vernakalant) is jointly developed by Cardionme Pharmaceutical Company of Canada and Astellas Pharmaceutical Company of the United States. In September 2010, the product was approved for marketing in the European Union, Iceland and Norway in the form of intravenous injection "Brinavess", and the US FDA is still in the approval review stage. [0003] [0004] Vernakalant is a selective blocker of atrial sodium and potassium (I kur ) ion channel dual inhibitors. The mechanism of action is to selectively block atrial sodium and potassium ion channels during the onset of atrial fibrillation, inhibit I kur The current can prolong the action potential duration of the atrium and reduce the risk of arrhythmia....

Claims

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Application Information

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Patent Type & AuthorityPatents(China)
IPC IPC(8): C07D207/12C07F9/53
Inventor俞传明叶海伟钟为慧苏为科何人宝王莺妹
OwnerZHEJIANG UNIV OF TECH