Pregabalin Synthesis via Enzymatic Resolution and Racemization
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Solution Overview
Problem
Current methods for synthesizing Pregabalin face challenges such as low yield, high reagent consumption, environmental impact, and inefficiencies in recycling byproducts, making them economically and environmentally unsustainable for large-scale commercial production.
Innovation Solution
A genetically modified nitrilase enzyme is used to catalyze the conversion of 2-isobutylsuccinonitrile to racemic 3-cyano-5-methyl-hexanoic acid, followed by enzymatic enantioselective hydrolysis to produce (S)-Pregabalin, reducing waste and enabling recyclable byproducts, thus enhancing yield and chiral purity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If resolution through diastereomeric salt formation is used, then chiral purity can be achieved, but yield is reduced due to loss of R-enantiomer and part of S-isomer
Solution Approach 1:
The patent applies kinetic resolution where the unwanted R-enantiomer is converted into the desired S-enantiomer through racemization using base treatment. This transforms the harmful loss of R-enantiomer during resolution into a beneficial process where R-enantiomer is recycled back to S-enantiomer, achieving both high chiral purity and high yield by making the resolution process reversible and recyclable.
2Manufacturing precision
If multiple resolution steps are used, then chiral purity can be improved, but process complexity and number of steps increase
Solution Approach 1:
The patent combines the resolution step with a racemization step in a single integrated process sequence. Instead of separate resolution followed by separate racemization steps, the process merges these operations where the resolution intermediate is directly treated with base to effect both resolution and racemization in one operational sequence, reducing process complexity while maintaining high chiral purity.
3Ease of manufacture
If conventional reagents are used, then synthesis can be performed, but environmental impact and reagent consumption increase
Solution Approach 1:
The patent changes the chemical parameters of the process by using base-mediated racemization instead of traditional acid-mediated resolution methods. This parameter change from acid to base conditions allows for milder, more environmentally friendly conditions, reduces harmful waste generation, and enables better recyclability of byproducts, thereby reducing environmental impact while maintaining synthesis feasibility.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This process significantly improves the yield and chiral purity of Pregabalin while minimizing the use of reagents and organic solvents, making it more economically viable and environmentally friendly for commercial-scale production.
Implementation Method 1
A genetically modified nitrilase enzyme is used to catalyze the conversion of 2-isobutylsuccinonitrile to racemic 3-cyano-5-methyl-hexanoic acid
Implementation Method 2
conversion of 2-isobutylsuccinonitrile to racemic 3-cyano-5-methyl-hexanoic acid, followed by enzymatic enantioselective hydrolysis
Implementation Method 3
followed by enzymatic enantioselective hydrolysis to produce (S)-Pregabalin
Implementation Method 4
enzymatic enantioselective hydrolysis to produce (S)-Pregabalin
Data Source
AI summary
The present invention provides an improved process for the preparation of a compound of formula (I), which comprises the steps of: formula (I), (a) reacting isovaleraldehyde of formula (II) and alkyl cyanoacetate of formula (III) optionally in presence of salts of weak acid and weak base or weak base in a suitable solvent to get 2-cyano-5-methyl-hex-2-enoic acid alkyl ester of formula (IV); (b) reacting 2-cyano-5-methyl-hex-2-enoic acid alkyl ester of formula (IV) with a suitable cyanide source in water or in an organic solvent or mixture thereof to get 2-isobutylsuccinonitrile of formula (V); (c) obtaining optionally 2-isobutylsuccinonitrile of formula (V) by reacting isovaleraldehyde of formula (II) and alkyl cyanoacetate of formula (III) in presence of suitable cyanide source in water or in an organic solvent or mixture thereof in single step; (d) converting 2-isobutylsuccinonitrile of formula (V) to racemic 3-cyano-5-methyl-hexanoic acid or salt thereof of formula (VI) with a genetically modified nitrilase enzyme (Nit 9N_56_2) in water or optionally with an organic co-solvent at appropriate pH and temperature; (e) converting racemic 3-cyano-5-methyl-hexanoic acid or salt thereof of formula (VI) to racemic alkyl 3-cyano-5-methyl-hexanoate of formula (VII) by treatment with alcohol (R3OH) and acidic catalyst or alkyl halide (R3X) in presence of a base in a suitable solvent or a mixture of solvents thereof; (f) obtaining (S)-alkyl 3-cyano-5-methyl-hexanoate of formula (VIII) and (R)-3-cyano-5-methyl-hexanoic acid or salt thereof of formula (X) by enzymatic enantioselective hydrolysis in water or organic solvent or a mixture thereof from racemic alkyl 3-cyano-5-methyl-hexanoate of formula (VII); (g) obtaining optionally the compound of formula (VII) by racemizing unwanted (R)-3-cyano-5-methyl-hexanoic acid or salt thereof of formula (X) or substantially enriched (R)-3-cyano-5-methyl-hexanoic acid salt thereof of formula (X) in presence of a base in organic solvent or a mixture thereof; (h) converting (S)-alkyl 3-cyano-5-methyl-hexanoate of formula (VIII) to pregabalin of formula (I) by hydrolyzing ester group with suitable alkali or alkaline earth metal base followed by hydrogenation optionally in one pot in a solvent selected from water or other organic solvents or a mixture thereof in presence of a suitable hydrogenation catalyst.