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Racemization method of optically pure isobutyl butanedinitrile

A technology of pure isobutylsuccinonitrile and isobutylsuccinonitrile, applied in chemical instruments and methods, chemical recovery, organic chemistry, etc., can solve the problems of difficult catalyst recovery, a large amount of waste acid, waste water, etc., and achieve the goal of eliminating Fast rotation speed and simple post-processing effects

Pending Publication Date: 2021-11-16
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are many shortcomings in the homogeneous catalytic racemization method: catalyst recovery is difficult, and isobutylsuccinonitrile needs to be separated and purified through multiple steps such as extraction, pickling, filtration, and concentration after racemization, resulting in a large amount of waste acid and waste water.

Method used

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  • Racemization method of optically pure isobutyl butanedinitrile
  • Racemization method of optically pure isobutyl butanedinitrile
  • Racemization method of optically pure isobutyl butanedinitrile

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] In a 25mL reactor, add 0.5g (R)-isobutylsuccinonitrile (ee value 89.01%, see HPLC figure 1 ) and 10mL ethanol, after incubation for 30min, add 0.5g solid base catalyst HND-63, react at 35°C and 150rpm for 1h, centrifuge the reaction solution at 8000rpm for 10min, and wash the centrifuged HND-63 with ethanol. Combine the supernatant and washing liquid after centrifugation, and rotate at 70°C for 2h to obtain 0.45g racemic isobutylsuccinonitrile (ee value 1.78%, yield 90%, see HPLC figure 2 ).

[0025] The gas chromatographic column model is BGB-174, and the chromatographic conditions are: the injection volume is 1.0 μL, the temperature of the injection port and the detector is 250 °C, the column temperature is 120 °C, keep for 15 min, and then raise the temperature to 170 °C at 10 °C / min. The flow rate was 1.0 mL / min.

[0026] The enantiomeric excess value (ee value) is calculated with reference to the calculation method of Rakels et al. (Enzyme & Microbial Technology...

Embodiment 2

[0028] Add 0.5g (R)-isobutylsuccinonitrile (ee value 89.01%) and 10mL ethanol into a 25mL reactor, keep warm for 30min, add 0.5g solid base catalyst HND-63, and react at 40°C and 150rpm After 10 hours, the reaction solution was centrifuged at 8000rpm for 10 minutes, the HND-63 obtained by centrifugation was washed with ethanol, the supernatant and washing solution after centrifugation were combined, and rotary steamed at 70°C for 2 hours to obtain 0.45 g of racemic isobutylbutyl Dinitrile (ee value 1.08%, yield 90%).

Embodiment 3

[0030] In a 25mL reactor, add 0.5g (R)-isobutylsuccinonitrile (ee value 89.01%) and 10mL ethanol, after 30min of heat preservation, add 0.5g solid base catalyst HND-63, at 20°C, 150rpm After reacting for 1.5h, the reaction solution was centrifuged at 8000rpm for 10min, the HND-63 obtained by centrifugation was washed with ethanol, the supernatant after centrifugation was combined with the washing solution, and the solution was rotary evaporated at 70°C for 2h to obtain 0.47g of racemic isobutyl Succinonitrile (ee value 0.68%, yield 94%).

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Abstract

The invention relates to a racemization method of optical pure isobutyl butanedinitrile. The method comprises the steps of: mixing (S)-isobutyl butanedinitrile or (R)-isobutyl butanedinitrile with an organic solvent, adding a solid base catalyst, stirring for reaction for 1-10 hours at 20-50 DEG C, obtaining a reaction mixed solution after the reaction is finished, centrifuging, washing, recycling the solid base catalyst, combining centrifuged supernate and a washing solution, and recycling the organic solvent, the residual liquid being racemic isobutyl butanedinitrile. According to the method, the solid base catalyst is adopted for racemization in the organic solvent, the racemization speed is high, and the racemization yield reaches 90% or above. The racemic isobutyl butanedinitrile obtained by the method can be further used for enzyme catalysis reaction, the racemic catalyst is easy to separate and reusable, and the post-treatment is simple and environment-friendly. The method is simple, convenient and easy to operate, and can be applied to a large-scale racemizing and recycling process of optically pure isobutyl butanedinitrile in a process for synthesizing pregabalin by a nitrilase method.

Description

(1) Technical field [0001] The invention relates to a racemization method of optically pure isobutylsuccinonitrile. (2) Background technology [0002] Pregabalin, whose chemical name is (S)-3-aminomethyl-5-methylhexanoic acid, is a structural analogue of γ-aminobutyric acid developed by Pfizer. Pregabalin is one of the best-selling prescription drugs in the world and is widely used to treat post-herpetic neuralgia, epilepsy, anxiety disorders and other diseases. [0003] The process route of enzymatic splitting by nitrilase is one of the most competitive routes for the synthesis of pregabalin, which has the advantages of easy availability of raw materials, high atom economy, and less discharge of "three wastes" (ZL201810136409.4). When different selective nitrilase splits isobutylsuccinonitrile to synthesize optically pure 3-cyano-5-methylhexanoic acid, (R)- or (S)-isobutylsuccinonitrile can be obtained, wherein Pregabalin can be synthesized from (S)-3-cyano-5-methylhexano...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C255/04C07C253/30
CPCC07C253/30C07C255/04Y02P20/584
Inventor 郑仁朝林超平徐晨辉吴哲明郑裕国
Owner ZHEJIANG UNIV OF TECH
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