181289-39-4

Basic information

• Product Name: Hexanoic acid, 3-cyano-5-methyl-, ethyl ester, (3S)-
• Synonyms: ethyl (S)-3-cyano-5-methylhexanoate;(S)-3-cyano-5-methyl hexanoic acid ethyl ester;(S)-ethyl 3-cyano-5-methylhexanoate;(S)-3-cyano-5-methyl-hexanoic acid ethyl ester;(S)-ethyl 3-cyano-5-methyl-hexanoate
• CAS NO: 181289-39-4
• Molecular Formula: C10H17NO2
• Molecular Weight: 183.25
• Mol File: 181289-39-4.mol
• Article Data: 9

Chemical Properties

• CAS DataBase Reference: Hexanoic acid, 3-cyano-5-methyl-, ethyl ester, (3S)-(CAS DataBase Reference)
• NIST Chemistry Reference: Hexanoic acid, 3-cyano-5-methyl-, ethyl ester, (3S)-(181289-39-4)
• EPA Substance Registry System: Hexanoic acid, 3-cyano-5-methyl-, ethyl ester, (3S)-(181289-39-4)

Safety Data

• Hazardous Substances Data: 181289-39-4(Hazardous Substances Data)

Usage

General Description

Hexanoic acid, 3-cyano-5-methyl-, ethyl ester, (3S)- is an organic compound that belongs to the class of esters. It is a colorless liquid with a fruity and pungent odor. This chemical is commonly used as a flavoring agent in various food and beverage products. It is also used in the manufacturing of perfumes and fragrances. In addition, this compound has applications in the pharmaceutical industry as well. It is important to handle and store this chemical with care, as it can be hazardous if not used properly.

Synthetic route

potassium cyanide + 5-methyl-2-hexenoic acid ethyl ester (34993-63-0, 79918-80-2, 2351-89-5) → (S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-39-4)

Conditions	Yield
With 1-(9-methylanthracene)-((R)-(6-hydroxy-4-quinolinyl)phenoxymethyl-2-yl)-5-ethenyl-1-azabicyclo[2.2.2]octane In hexane; water at 20℃; for 15h; Michael Addition; Green chemistry; stereoselective reaction;	93.4%

4-isobutyl-2-oxopyrrolidine-3-carboxylic acid → (S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-39-4)

Conditions	Yield
With hydrogenchloride; acetic acid In water at 80 - 110℃;	80%

(R,S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-17-8) → (S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-39-4)

Conditions	Yield
With sodium hydroxide; Candida antarctica lipase B In water at 15℃; pH=7.2; Aqueous phosphate buffer; Resolution of racemate;	77%

(E)-ethyl 3-cyano-5-methylhex-2-enoate (1335223-63-6) → (S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-39-4)

Conditions	Yield
With NADP In isopropyl alcohol at 30℃; for 96h; Enzymatic reaction; enantioselective reaction;	68.8%
With Citrobacter sp. N-ethylmaleimide reductase; NADPH; NADH In dimethyl sulfoxide at 30℃; for 22h; pH=7; Product distribution / selectivity; Enzymatic reaction; Aqueous phosphate buffer;	n/a
With nicotinamide-dependent cyclohexenone reductase from Zymomonas mobilis; NADH In aq. buffer at 30℃; for 24h; pH=7.5; Reagent/catalyst; Green chemistry; Enzymatic reaction; stereoselective reaction;	n/a

3-cyano-5-methyl-hex-3-enoic acid ethyl ester (350801-68-2) → 5-methyl-3-cyanohexanoic acid ethyl ester + (S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-39-4)

Conditions	Yield
With hydrogen; (Z,Z)-cycloocta-1,5-diene(R,R-1,2-bis(2,5-diethylphospholanyl)benzene)rhodium(I) tetrafluoroborate In methanol at 55℃; under 5171.48 Torr; Product distribution; Further Variations:; Reagents; Temperatures; Pressures;

(3S)-3-cyano-2-ethoxycarbonyl-5-methyl-hexanoic acid → 3-(S)-cyano-5-methyl-hexanoic acid (181289-37-2) + (S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-39-4)

Conditions	Yield
With water; sodium chloride In dimethyl sulfoxide at 88 - 135℃; for 20.5h;	A n/a B n/a

(S)-2-ethoxycarbonyl-3-cyano-5-methylhexanoic acid sodium salt → (S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-39-4)

Conditions	Yield
With water; sodium chloride In toluene at 75 - 85℃; for 2h; Heating / reflux;

L-leucine (61-90-5) → (S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-39-4)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: sodium nitrite; sulfuric acid; potassium bromide / water / 6.5 h / -14 - 20 °C 2.1: thionyl chloride / cyclohexane / 13 h / 60 - 80 °C / Inert atmosphere 2.2: 25 °C / Inert atmosphere 3.1: phosphorus pentoxide / 80 °C / 12 Torr 4.1: sodium hydride / N,N-dimethyl-formamide; paraffin oil (nujol) / 10 - 25 °C 5.1: potassium chloride / water; dimethyl sulfoxide / 4 h / 150 - 160 °C View Scheme
Multi-step reaction with 7 steps 1.1: sodium nitrite; sulfuric acid; potassium bromide / water / 6.5 h / -14 - 20 °C 2.1: thionyl chloride / cyclohexane / 13 h / 60 - 80 °C / Inert atmosphere 2.2: 25 °C / Inert atmosphere 3.1: phosphorus pentoxide / 80 °C / 12 Torr 4.1: sodium hydride / N,N-dimethyl-formamide; paraffin oil (nujol) / 10 - 25 °C 5.1: potassium chloride / water; dimethyl sulfoxide / 4 h / 150 - 160 °C 6.1: sodium ethanolate / ethanol / 25 - 85 °C 7.1: sodium hydroxide / Candida antarctica lipase B / water / 15 °C / pH 7.2 / Aqueous phosphate buffer; Resolution of racemate View Scheme

(S)-2-bromo-4-methylpentanoic acid (28659-87-2) → (S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-39-4)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: thionyl chloride / cyclohexane / 13 h / 60 - 80 °C / Inert atmosphere 1.2: 25 °C / Inert atmosphere 2.1: phosphorus pentoxide / 80 °C / 12 Torr 3.1: sodium hydride / N,N-dimethyl-formamide; paraffin oil (nujol) / 10 - 25 °C 4.1: potassium chloride / water; dimethyl sulfoxide / 4 h / 150 - 160 °C View Scheme
Multi-step reaction with 6 steps 1.1: thionyl chloride / cyclohexane / 13 h / 60 - 80 °C / Inert atmosphere 1.2: 25 °C / Inert atmosphere 2.1: phosphorus pentoxide / 80 °C / 12 Torr 3.1: sodium hydride / N,N-dimethyl-formamide; paraffin oil (nujol) / 10 - 25 °C 4.1: potassium chloride / water; dimethyl sulfoxide / 4 h / 150 - 160 °C 5.1: sodium ethanolate / ethanol / 25 - 85 °C 6.1: sodium hydroxide / Candida antarctica lipase B / water / 15 °C / pH 7.2 / Aqueous phosphate buffer; Resolution of racemate View Scheme

ethyl 2-cyano-4-methylpentanoate (7352-02-5) → (S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-39-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium hydride / N,N-dimethyl-formamide; paraffin oil (nujol) / 10 - 50 °C / Inert atmosphere 1.2: 20 °C / Inert atmosphere 2.1: dimethyl sulfoxide / 4 h / 150 - 160 °C 3.1: sodium hydroxide / Candida antarctica lipase B / water / 15 °C / pH 7.2 / Aqueous phosphate buffer; Resolution of racemate View Scheme
Multi-step reaction with 3 steps 1.1: sodium hydride / 1,2-dimethoxyethane; paraffin oil (nujol) / 10 - 50 °C 1.2: 20 °C 2.1: dimethyl sulfoxide / 4 h / 150 - 160 °C 3.1: sodium hydroxide / Candida antarctica lipase B / water / 15 °C / pH 7.2 / Aqueous phosphate buffer; Resolution of racemate View Scheme

(3R)-3-cyano-5-methylhexanoic acid → (S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-39-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: dicyclohexyl-carbodiimide / dichloromethane / 13 h / 0 - 25 °C 2: sodium ethanolate / ethanol / 25 - 85 °C 3: sodium hydroxide / Candida antarctica lipase B / water / 15 °C / pH 7.2 / Aqueous phosphate buffer; Resolution of racemate View Scheme

(S)-3-cyano-2-ethoxycarbonyl-5-methyl-hexanoic acid ethyl ester (1232146-79-0) → (S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-39-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium chloride / water; dimethyl sulfoxide / 4 h / 150 - 160 °C 2: sodium ethanolate / ethanol / 25 - 85 °C 3: sodium hydroxide / Candida antarctica lipase B / water / 15 °C / pH 7.2 / Aqueous phosphate buffer; Resolution of racemate View Scheme

(S)-3-cyano-2-ethoxycarbonyl-5-methyl-hexanoic acid ethyl ester (1232146-79-0) → 5-methyl-3-cyanohexanoic acid ethyl ester + (S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-39-4)

Conditions	Yield
With potassium chloride In water; dimethyl sulfoxide at 150 - 160℃; for 4h;	A n/a B n/a

(2S)-2-bromo-4-methylpentanamide (28659-89-4) → (S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-39-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: phosphorus pentoxide / 80 °C / 12 Torr 2: sodium hydride / N,N-dimethyl-formamide; paraffin oil (nujol) / 10 - 25 °C 3: potassium chloride / water; dimethyl sulfoxide / 4 h / 150 - 160 °C View Scheme
Multi-step reaction with 5 steps 1: phosphorus pentoxide / 80 °C / 12 Torr 2: sodium hydride / N,N-dimethyl-formamide; paraffin oil (nujol) / 10 - 25 °C 3: potassium chloride / water; dimethyl sulfoxide / 4 h / 150 - 160 °C 4: sodium ethanolate / ethanol / 25 - 85 °C 5: sodium hydroxide / Candida antarctica lipase B / water / 15 °C / pH 7.2 / Aqueous phosphate buffer; Resolution of racemate View Scheme

(2S)-2-bromo-4-methylpentanenitrile (28659-90-7) → (S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-39-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydride / N,N-dimethyl-formamide; paraffin oil (nujol) / 10 - 25 °C 2: potassium chloride / water; dimethyl sulfoxide / 4 h / 150 - 160 °C View Scheme
Multi-step reaction with 4 steps 1: sodium hydride / N,N-dimethyl-formamide; paraffin oil (nujol) / 10 - 25 °C 2: potassium chloride / water; dimethyl sulfoxide / 4 h / 150 - 160 °C 3: sodium ethanolate / ethanol / 25 - 85 °C 4: sodium hydroxide / Candida antarctica lipase B / water / 15 °C / pH 7.2 / Aqueous phosphate buffer; Resolution of racemate View Scheme

ethyl 3-carbamoyl-5-methylhexanoate (1350373-53-3) → (S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-39-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: thionyl chloride / 13 h / 80 °C 2: sodium hydroxide / Candida antarctica lipase B / water / 15 °C / pH 7.2 / Aqueous phosphate buffer; Resolution of racemate View Scheme

diethyl 2-cyano-2-isobutylsuccinate (1350373-50-0) → (S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-39-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: dimethyl sulfoxide / 4 h / 150 - 160 °C 2: sodium hydroxide / Candida antarctica lipase B / water / 15 °C / pH 7.2 / Aqueous phosphate buffer; Resolution of racemate View Scheme

3-(ethoxycarbonyl)-2-(2-methylpropyl)propanoic acid → (S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-39-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: thionyl chloride / cyclohexane / 13 h / 60 - 80 °C / Inert atmosphere 1.2: 25 °C / Inert atmosphere 2.1: thionyl chloride / 13 h / 80 °C 3.1: sodium hydroxide / Candida antarctica lipase B / water / 15 °C / pH 7.2 / Aqueous phosphate buffer; Resolution of racemate View Scheme

isopentanoyl chloride (108-12-3) → (S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-39-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: toluene; acetonitrile / 4 h / 100 - 105 °C 2.1: n-butyllithium / hexane; tetrahydrofuran / 0.5 h / 0 °C 2.2: 0 - 20 °C 3.1: NADH; NADPH; Citrobacter sp. N-ethylmaleimide reductase / dimethyl sulfoxide / 22 h / 30 °C / pH 7 / Enzymatic reaction; Aqueous phosphate buffer View Scheme
Multi-step reaction with 3 steps 1.1: toluene; acetonitrile / 4 h / 100 - 105 °C 2.1: n-butyllithium / hexane; tetrahydrofuran / 0.5 h / 0 °C 2.2: 0 - 20 °C 3.1: NADH; NADPH; Lycopersicon esculentum 12-oxophytodienoate reductase / dimethyl sulfoxide / 22 h / 30 °C / pH 7 / Enzymatic reaction; Aqueous phosphate buffer View Scheme

isopentanoyl chloride (108-12-3) → 5-methyl-3-cyanohexanoic acid ethyl ester + (S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-39-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: toluene; acetonitrile / 4 h / 100 - 105 °C 2.1: n-butyllithium / hexane; tetrahydrofuran / 0.5 h / 0 °C 2.2: 0 - 20 °C 3.1: NADPH; recombinant OPR1 reductase (tomato) / dimethyl sulfoxide / 45 h / 30 °C / pH 7 / Enzymatic reaction; Aqueous phosphate buffer View Scheme

4-methyl-2-pentanone (108-10-1) → (S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-39-4)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium hydride / tetrahydrofuran / 0.33 h / 5 - 15 °C / Inert atmosphere 1.2: 19 h / 15 - 25 °C 1.3: pH 6 2.1: tetramethyl ammoniumhydroxide / hexane; water / 0.67 h / 5 - 15 °C / Inert atmosphere 2.2: 2.5 h / 5 - 10 °C 3.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 15 h / 70 °C / Inert atmosphere 4.1: NADH; NADPH; Citrobacter sp. N-ethylmaleimide reductase / dimethyl sulfoxide / 22 h / 30 °C / pH 7 / Enzymatic reaction; Aqueous phosphate buffer View Scheme
Multi-step reaction with 4 steps 1.1: sodium hydride / tetrahydrofuran / 0.33 h / 5 - 15 °C / Inert atmosphere 1.2: 19 h / 15 - 25 °C 1.3: pH 6 2.1: tetramethyl ammoniumhydroxide / hexane; water / 0.67 h / 5 - 15 °C / Inert atmosphere 2.2: 2.5 h / 5 - 10 °C 3.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 15 h / 70 °C / Inert atmosphere 4.1: NADH; NADPH; Lycopersicon esculentum 12-oxophytodienoate reductase / dimethyl sulfoxide / 22 h / 30 °C / pH 7 / Enzymatic reaction; Aqueous phosphate buffer View Scheme
Multi-step reaction with 4 steps 1.1: sodium hydride / tetrahydrofuran / 0.33 h / 5 - 15 °C / Inert atmosphere 1.2: 19 h / 15 - 25 °C 1.3: pH 6 2.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 10 °C / Inert atmosphere 2.2: 1.5 h / 0 - 10 °C 3.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 15 h / 70 °C / Inert atmosphere 4.1: NADH; NADPH; Lycopersicon esculentum 12-oxophytodienoate reductase / dimethyl sulfoxide / 22 h / 30 °C / pH 7 / Enzymatic reaction; Aqueous phosphate buffer View Scheme

4-methyl-2-pentanone (108-10-1) → 5-methyl-3-cyanohexanoic acid ethyl ester + (S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-39-4)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium hydride / tetrahydrofuran / 0.33 h / 5 - 15 °C / Inert atmosphere 1.2: 19 h / 15 - 25 °C 1.3: pH 6 2.1: tetramethyl ammoniumhydroxide / hexane; water / 0.67 h / 5 - 15 °C / Inert atmosphere 2.2: 2.5 h / 5 - 10 °C 3.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 15 h / 70 °C / Inert atmosphere 4.1: NADPH; recombinant OPR1 reductase (tomato) / dimethyl sulfoxide / 45 h / 30 °C / pH 7 / Enzymatic reaction; Aqueous phosphate buffer View Scheme
Multi-step reaction with 4 steps 1.1: sodium hydride / tetrahydrofuran / 0.33 h / 5 - 15 °C / Inert atmosphere 1.2: 19 h / 15 - 25 °C 1.3: pH 6 2.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 10 °C / Inert atmosphere 2.2: 1.5 h / 0 - 10 °C 3.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 15 h / 70 °C / Inert atmosphere 4.1: NADPH; recombinant OPR1 reductase (tomato) / dimethyl sulfoxide / 45 h / 30 °C / pH 7 / Enzymatic reaction; Aqueous phosphate buffer View Scheme
Multi-step reaction with 4 steps 1.1: sodium hydride / tetrahydrofuran; mineral oil / 0 - 20 °C 1.2: 19 h / 0 - 20 °C 2.1: tetramethyl ammoniumhydroxide / water; hexane / 0.67 h / 5 - 15 °C / Inert atmosphere 2.2: 2.5 h / 5 - 10 °C / Inert atmosphere 3.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 15 h / 70 °C / Inert atmosphere 4.1: Saccharomyces pastorianus old yellow enzyme, isoenzyme OYE3; NADH / aq. buffer / 24 h / 30 °C / pH 7.5 / Green chemistry; Enzymatic reaction View Scheme

5-methyl-3-oxo-hexanoic acid ethyl ester (34036-16-3) → (S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-39-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 10 °C / Inert atmosphere 1.2: 1.5 h / 0 - 10 °C 2.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 15 h / 70 °C / Inert atmosphere 3.1: NADH; NADPH; Lycopersicon esculentum 12-oxophytodienoate reductase / dimethyl sulfoxide / 22 h / 30 °C / pH 7 / Enzymatic reaction; Aqueous phosphate buffer View Scheme
Multi-step reaction with 3 steps 1.1: tetramethyl ammoniumhydroxide / hexane; water / 0.67 h / 5 - 15 °C / Inert atmosphere 1.2: 2.5 h / 5 - 10 °C 2.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 15 h / 70 °C / Inert atmosphere 3.1: NADH; NADPH; Citrobacter sp. N-ethylmaleimide reductase / dimethyl sulfoxide / 22 h / 30 °C / pH 7 / Enzymatic reaction; Aqueous phosphate buffer View Scheme
Multi-step reaction with 3 steps 1.1: tetramethyl ammoniumhydroxide / hexane; water / 0.67 h / 5 - 15 °C / Inert atmosphere 1.2: 2.5 h / 5 - 10 °C 2.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 15 h / 70 °C / Inert atmosphere 3.1: NADH; NADPH; Lycopersicon esculentum 12-oxophytodienoate reductase / dimethyl sulfoxide / 22 h / 30 °C / pH 7 / Enzymatic reaction; Aqueous phosphate buffer View Scheme

5-methyl-3-oxo-hexanoic acid ethyl ester (34036-16-3) → 5-methyl-3-cyanohexanoic acid ethyl ester + (S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-39-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 0 - 10 °C / Inert atmosphere 1.2: 1.5 h / 0 - 10 °C 2.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 15 h / 70 °C / Inert atmosphere 3.1: NADPH; recombinant OPR1 reductase (tomato) / dimethyl sulfoxide / 45 h / 30 °C / pH 7 / Enzymatic reaction; Aqueous phosphate buffer View Scheme
Multi-step reaction with 3 steps 1.1: tetramethyl ammoniumhydroxide / hexane; water / 0.67 h / 5 - 15 °C / Inert atmosphere 1.2: 2.5 h / 5 - 10 °C 2.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 15 h / 70 °C / Inert atmosphere 3.1: NADPH; recombinant OPR1 reductase (tomato) / dimethyl sulfoxide / 45 h / 30 °C / pH 7 / Enzymatic reaction; Aqueous phosphate buffer View Scheme
Multi-step reaction with 3 steps 1.1: tetramethyl ammoniumhydroxide / water; hexane / 0.67 h / 5 - 15 °C / Inert atmosphere 1.2: 2.5 h / 5 - 10 °C / Inert atmosphere 2.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 15 h / 70 °C / Inert atmosphere 3.1: Saccharomyces pastorianus old yellow enzyme, isoenzyme OYE3; NADH / aq. buffer / 24 h / 30 °C / pH 7.5 / Green chemistry; Enzymatic reaction View Scheme

3-methylbutanoyl cyanide (66582-16-9) → (S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-39-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: n-butyllithium / hexane; tetrahydrofuran / 0.5 h / 0 °C 1.2: 0 - 20 °C 2.1: NADH; NADPH; Citrobacter sp. N-ethylmaleimide reductase / dimethyl sulfoxide / 22 h / 30 °C / pH 7 / Enzymatic reaction; Aqueous phosphate buffer View Scheme
Multi-step reaction with 2 steps 1.1: n-butyllithium / hexane; tetrahydrofuran / 0.5 h / 0 °C 1.2: 0 - 20 °C 2.1: NADH; NADPH; Lycopersicon esculentum 12-oxophytodienoate reductase / dimethyl sulfoxide / 22 h / 30 °C / pH 7 / Enzymatic reaction; Aqueous phosphate buffer View Scheme

3-methylbutanoyl cyanide (66582-16-9) → 5-methyl-3-cyanohexanoic acid ethyl ester + (S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-39-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: n-butyllithium / hexane; tetrahydrofuran / 0.5 h / 0 °C 1.2: 0 - 20 °C 2.1: NADPH; recombinant OPR1 reductase (tomato) / dimethyl sulfoxide / 45 h / 30 °C / pH 7 / Enzymatic reaction; Aqueous phosphate buffer View Scheme

(Z)-ethyl 5-methyl-3-(trifluoromethylsulfonyloxy)hex-2-enoate → (S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-39-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 15 h / 70 °C / Inert atmosphere 2: NADH; NADPH; Lycopersicon esculentum 12-oxophytodienoate reductase / dimethyl sulfoxide / 22 h / 30 °C / pH 7 / Enzymatic reaction; Aqueous phosphate buffer View Scheme
Multi-step reaction with 2 steps 1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 70 °C 2: NADP / isopropyl alcohol / 96 h / 30 °C / Enzymatic reaction View Scheme

(Z)-ethyl 5-methyl-3-(trifluoromethylsulfonyloxy)hex-2-enoate → 5-methyl-3-cyanohexanoic acid ethyl ester + (S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-39-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 15 h / 70 °C / Inert atmosphere 2: NADPH; recombinant OPR1 reductase (tomato) / dimethyl sulfoxide / 45 h / 30 °C / pH 7 / Enzymatic reaction; Aqueous phosphate buffer View Scheme

(Z)-ethyl 3-cyano-5-methylhex-2-enoate (1334950-50-3) → (S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-39-4)

Conditions	Yield
With Lycopersicon esculentum 12-oxophytodienoate reductase; NADPH; NADH In dimethyl sulfoxide at 30℃; for 22h; pH=7; Product distribution / selectivity; Enzymatic reaction; Aqueous phosphate buffer;
With NADP In isopropyl alcohol at 30℃; for 96h; Enzymatic reaction; enantioselective reaction;	n/a

(Z)-ethyl 3-cyano-5-methylhex-2-enoate (1334950-50-3) → 5-methyl-3-cyanohexanoic acid ethyl ester + (S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-39-4)

Conditions	Yield
With recombinant OPR1 reductase (tomato); NADPH In dimethyl sulfoxide at 30℃; for 45h; pH=7; Enzymatic reaction; Aqueous phosphate buffer;	A n/a B n/a

propan-1-ol (71-23-8) + (S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-39-4) → (S)-propyl 3-cyano-5-methylhexanoate (1415320-55-6)

Conditions	Yield
With hydrogenchloride In water for 24h; Reflux;	99%

(S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-39-4) → (S)-4-isobutyl-pyrrolidin-2-one (181289-23-6)

Conditions	Yield
With 5%-palladium/activated carbon; hydrogen In ethanol at 25℃; under 37503.8 Torr; for 6h; Reagent/catalyst; Temperature; Autoclave; Green chemistry;	97.2%

methanol (67-56-1) + (S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-39-4) → methyl (S)-3-cyano-5-methyl-hexanoate

Conditions	Yield
With hydrogenchloride In water for 24h; Reflux;	73%

(S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-39-4) → pregabilin (148553-50-8)

Conditions	Yield
Stage #1: (S)-3-cyano-5-methylhexanoic acid ethyl ester With potassium hydroxide; water In ethanol at 20 - 25℃; for 1.5h; Stage #2: With hydrogen; sponge nickel In ethanol; water under 2585.81 Torr; for 19h; Stage #3: With acetic acid In ethanol; water at 0 - 75℃;
Multi-step reaction with 3 steps 1: potassium hydroxide; water / 6 h / 25 °C 2: hydrogen / Raney Nickel / water / 30 °C 3: acetic acid / ethanol / 35 °C / pH 7.5 View Scheme
Stage #1: (S)-3-cyano-5-methylhexanoic acid ethyl ester With potassium hydroxide In Isopropyl acetate; water at 20℃; for 1h; Stage #2: With hydrogen; nickel In Isopropyl acetate; water for 5h;
Multi-step reaction with 2 steps 1: 5%-palladium/activated carbon; hydrogen / ethanol / 6 h / 25 °C / 37503.8 Torr / Autoclave; Green chemistry 2: sodium hydroxide; ethanol / 5 h / 40 °C / Green chemistry View Scheme

(S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-39-4) → potassium (S)-3-cyano-5-methylhexanoate

Conditions	Yield
With potassium hydroxide; water at 25℃; for 4h;
With water; potassium hydroxide at 25℃; for 6h;
With potassium hydroxide In ethanol at 20 - 25℃; for 5h;	4.8 g

(S)-3-cyano-5-methylhexanoic acid ethyl ester (181289-39-4) → pregabalin potassium salt (914254-26-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium hydroxide; water / 6 h / 25 °C 2: hydrogen / Raney Nickel / water / 30 °C View Scheme

Upstream product

• 108-12-3 isopentanoyl chloride 
• 108-10-1 4-methyl-2-pentanone 
• 34036-16-3 5-methyl-3-oxo-hexanoic acid ethyl ester 
• 66582-16-9 3-methylbutanoyl cyanide 
• 1335223-63-6 (E)-ethyl 5-methyl-3-cyanohex-2-enoate 
• 1334950-50-3 (Z)-ethyl 5-methyl-3-cyanohex-2-enoate 
• 760-58-7 2-cyano-4-methyl-pent-2-enoic acid 
• 18283-41-5 2-cyano-4-methylpentanoic acid 
• 1315460-56-0 (E)-ethyl 5-methyl-3-(trifluoromethylsulfonyloxy)hex-2-enoate 
• 186038-82-4 2-ethoxycarbonyl-3-cyano-5-methylhexanoic acid ethyl ester 
• 871577-68-3 (R)-2-ethoxycarbonyl-3-cyano-5-methylhexanoic acid ethyl ester 
• 34993-63-0 5-methyl-2-hexenoic acid ethyl ester 
• 181289-17-8 (R,S)-3-cyano-5-methylhexanoic acid ethyl ester 
• 181289-10-1 3-(ethoxycarbonyl)-2-(2-methylpropyl)propanoic acid 

Downstream Products

• 181289-23-6 (S)-4-isobutyl-pyrrolidin-2-one 
• 148553-50-8 pregabilin 

Relevant articles and documents

Synthetic method of environment-friendly and efficient pregabalin

The invention relates to a synthetic method of environment-friendly and efficient pregabalin. The synthetic method comprises the following steps: 1) dehydrating and condensing acetate and isopentyl aldehyde to obtain 5-methyl-2-hexenoate; 2) performing cyano addition on the 5-methyl-2-hexenoate to obtain (S)-5-methyl-3-cyanohexanoate; 3) performing hydrogen reduction cyclization on the (S)-5-methyl-3-cyanohexanoate to obtain (S)-4-isobutylpyrrolidin-2-one; and 4) performing hydrolysis and ring opening on the (S)-4-isobutylpyrrolidin-2-one to obtain the pregabalin. The synthetic route has the advantages of cheap and easily available raw materials, few reaction steps, mild process conditions, simple operation, high reaction yield and less environment pollution, and is more suitable for industrial production of bulk drug pregabalin.

Chemoenzymatic asymmetric synthesis of pregabalin precursors via asymmetric bioreduction of β-cyanoacrylate esters using ene-reductases

The asymmetric bioreduction of a library of β-cyanoacrylate esters using ene-reductases was studied with the aim to provide a biocatalytic route to precursors for GABA analogues, such as pregabalin. The stereochemical outcome could be controlled by substrate-engineering through size-variation of the ester moiety and by employing stereochemically pure (E)- or (Z)-isomers, which allowed to access both enantiomers of each product in up to quantitative conversion in enantiomerically pure form. In addition, stereoselectivities and conversions could be improved by mutant variants of OPR1, and the utility of the system was demonstrated by preparative-scale applications.

PROCESS FOR THE PREPARATION OF ( S ) - 3 - CYANO - 5 - METHYLHEXANOIC ACID DERIVATIVES ADN OF PREGABALIN

The invention provides a process for the manufacture of a compound of formula (I) using an enzyme catalysed reduction of a compound of formula (lla) or llb). Compounds of formula (I) are useful for preparing pregabalin.