181289-16-7

Usage

Uses

Used in Pharmaceutical Industry:
Pregabalin Cyano Acid IMpurity is used as an intermediate compound for the synthesis of anticonvulsant medications. Its role in the development of these drugs is crucial, as it contributes to the overall effectiveness and potency of the final product.
Used in Research and Development:
In the field of research and development, Pregabalin Cyano Acid IMpurity serves as a valuable compound for studying the structure-activity relationships of GABA analogues. This helps scientists and researchers to better understand the mechanisms of action and potential therapeutic applications of these compounds in treating neurological disorders.
Used in Quality Control:
Pregabalin Cyano Acid IMpurity is also utilized in the quality control processes of pharmaceutical manufacturing. It is essential to monitor and control the presence of impurities in the final drug product to ensure safety, efficacy, and compliance with regulatory standards.

Upstream product

• 148553-50-8 pregabilin 
• 181289-37-2 3-(S)-cyano-5-methyl-hexanoic acid 
• 51615-30-6 diethyl 2-(3-methylbutylidene)malonate 
• 186038-82-4 2-ethoxycarbonyl-3-cyano-5-methylhexanoic acid ethyl ester 
• 590-86-3 isovaleraldehyde 
• 724773-54-0 2-cyano-5-methylhex-2-enoic acid methyl ester 
• 61312-86-5 2-isobutyl succinonitrile 
• 1415320-54-5 3-cyano-5-methylhexanoic acid n-butyl ester 
• 1415320-53-4 3-cyano-5-methylhexanoic acid n-propyl ester 
• 1374689-17-4 2-cyano-2-isobutylsuccinic acid 
• 1374689-15-2 4-ethyl 1-methyl 2-cyano-2-isobutylsuccinate 
• 1350373-50-0 diethyl 2-cyano-2-isobutylsuccinate 
• 181289-17-8 (R,S)-3-cyano-5-methylhexanoic acid ethyl ester 
• 7352-02-5 ethyl 2-cyano-4-methylpentanoate 

Downstream Products

• 959760-03-3 (3S)-cyano-5-methylhexanoic acid (S)-phenyl ethyl amine salt 
• 128013-69-4 (R,S)-3-iso-butyl-4-aminobutyric acid 
• 148553-50-8 pregabilin 

Relevant academic research and scientific papers

Enzymatic production of (S)-3-cyano-5-methylhexanoic acid ethyl ester with high substrate loading by immobilized Pseudomonas cepacia lipase

(S)-3-Cyano-5-methylhexanoic acid ethyl ester is a valuable synthetic intermediate for pregabalin. Immobilized lipase PS from Pseudomonas cepacia was screened and shown to be the best biocatalyst for the enantioselective hydrolysis of 3-cyano-5-methylhexanoic acid ethyl ester, a racemic mixture involving a β-stereocenter. The optimum temperature and pH for the biocatalytic process were 35 °C and 6.0, respectively. Lipase PS IM exhibited a strong tolerance toward high substrate concentrations of up to 2.0 M (366 g/l). In the scaled-up biotransformation, (S)-3-cyano-5-methylhexanoic acid ethyl ester was produced in 0.89 M (162.9 g/l), 99.2% ee, and 44.5% yield. These results indicated that lipase PS IM catalyzed the preparation of (S)-3-cyano-5-methylhexanoic acid ethyl ester and could be used as an efficient route for the large-scale production of pregabalin.

From pregabalin to rac-3-cyano-5-methylhexanoic acid: An easy conversion which valorizes waste pregabalin enantiomer

(S)-(+)-3-Aminomethyl-5-methylhexanoic acid (pregabalin) was converted in one-pot to (S)-(-)-3-cyano-5-methylhexanoic acid (pregabalin nitrile) by N-dichlorination and double dehydrochlorination. The (S) β-cyanoacid was racemized under mild conditions by

AN IMPROVED PROCESS FOR THE PREPARATION OF PREGABALIN

The present invention relates to an improved process for the preparation of Pregabalin (I), which is simple, economical, efficient, and environment friendly, commercially viable with chemical and chiral purity at least 99.95%.

GREENER AND ECONOMIC PROCESS FOR PREPARATION OF PREGABALIN

The present invention relates to an economical, enzyme catalyzed and commercially viable greener process for manufacturing Pregabalin of formula (I) in high yield with highchemical and chiral purity.

Method for synthesizing Pregabalin by taking isovaleraldehyde as raw material

The invention discloses a method for synthesizing Pregabalin by taking isovaleraldehyde as a raw material. The method comprises the steps: carrying out Knoevenagel condensation on isovaleraldehyde and diethyl malonate in a cyclohexane solvent by taking a mixture of di-n-propylamine and acetic acid as a catalyst; carrying out Michael addition on the product obtained in the step one in an alkaline alcohol solvent; carrying out deacidifying reaction on the product obtained in the step two in a solvent prepared from DMSO and water by taking lithium chloride as a catalyst under the condition of heating; carrying out hydrolytic reaction on the product obtained in the step three under alkaline conditions; carrying out catalytic hydrogenation on the product obtained in the step four by taking Raney nickel as a catalyst; and carrying out chiral resolution on the product obtained in the step five by adopting lipase Lipolase 100T. According to the method, isovaleraldehyde, which is cheap and is readily available, serves as a raw material and is subjected to Knoevenagel condensation reaction, Michael addition, decarboxylation, hydrolysis, hydrogenation reaction and chiral resolution, thereby obtaining Pregabalin. The reaction route is simple, and the yield of reaction of each step is relatively high, so that the total yield and purity of final Pregabalin are guaranteed.

PROCESS FOR THE PREPARATION OF PREGABALIN

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 pa (V) to racemic 3-cyano-5-methyl-hexanoic acid or salt thereof of formula (VI) with a genetically modified nitrilase enzyme (Nit pt 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.

PROCESS FOR SYNTHESIS OF (S) - PREGABALIN

Improved process for the synthesis of (S)-pregabalin having more than 99% ee through (S) 3-cyano-5-methyl-hexanoic acid has been developed. In addition to above, a novel process for resolution of (RS) - 3-cyano-5-methyl-hexanoic acid through diastereomeric salt formation with cinchonidine to obtain (S) - 3-cyano-5-methyl-hexanoic acid in high yield and high optical purity has been developed and furthermore process for recovery/ reuse of cinchonidine is also developed to improve the overall process efficiency.

NOVEL METHOD FOR RACEMIZATION OF OPTICALLY PURE β-CYANO ESTER TO CORRESPONDING RACEMIC β-CYANO ACID

A novel process for racemization of (R)-3-cyano-5 -methyl hexanoic acid ethyl ester directly to (RS)-3-cyano-5 -methyl hexanoic acid has been developed through a base catalyzed mechanism in a specific solvent system.

PREPARATION OF (S)-PREGABALIN-NITRILE

Provided are processes for the preparation of (3S)-cyano-5-methylhexanoic acid, an intermediate in the synthesis of (S)-pregabalin.