312745-91-8

Basic information

• Product Name: Ethyl (S)-4-cyano-3-hydroxybutyrate
• Synonyms: (S)-ETHYL-4-CYANO-3-HYDROXYBUTYRATE;(S)-4-CYANO-3-HYDROXYBUTANOATE ETHYL;BUTANOIC ACID 4-CYANO-3-HYDROXY-ETHYL ESTER, (S);ETHYL (S)-(+)-4-CYANO-3-HYDROXYBUTYRATE;ETHYL(S)-4-CYANO-3-HYDROXY-BUTYRATE;ETHYL (S)-4-CYANO-3-HYDROXYBUTANOATE;(3S)-4-Cyano-3-hydroxy-butanoic Acid Ethyl Ester;ETHYL (S)-(+)-4-CYANO-3-HYDROXYBUTYRATE , EE 98%
• CAS NO: 312745-91-8
• Molecular Formula: C₇H₁₁NO₃
• Molecular Weight: 157.17
• Product Categories: API intermediates;All Aliphatics;Aliphatics;Chiral Reagents
• Mol File: 312745-91-8.mol
• Article Data: 4

Chemical Properties

• Boiling Point: 270°C
• Flash Point: >110°C
• Appearance: /
• Density: 1,114 g/cm3
• Vapor Pressure: 1.75E-05mmHg at 25°C
• Refractive Index: 1.4480
• Storage Temp.: 2-8°C
• Solubility: Chloroform, Methanol (Slightly)
• PKA: 13.03±0.20(Predicted)
• Water Solubility: Not miscible or difficult to mix with water.
• CAS DataBase Reference: Ethyl (S)-4-cyano-3-hydroxybutyrate(CAS DataBase Reference)
• NIST Chemistry Reference: Ethyl (S)-4-cyano-3-hydroxybutyrate(312745-91-8)
• EPA Substance Registry System: Ethyl (S)-4-cyano-3-hydroxybutyrate(312745-91-8)

Safety Data

• Statements: 36/37/38
• Safety Statements: 26-36
• Hazardous Substances Data: 312745-91-8(Hazardous Substances Data)

Usage

Uses

It is an important raw material and intermediate used in organic synthesis, pharmaceuticals, agrochemicals and dyestuff.

InChI:InChI=1/C7H11NO3/c1-2-11-7(10)5-6(9)3-4-8/h6,9H,2-3,5H2,1H3/t6-/m0/s1

Synthetic route

(S)-3-hydroxyglutaric acid monoamidemonoethyl ester → (S)-3-hydroxy-4-cyanobutyric acid ethyl ester (312745-91-8)

Conditions	Yield
With pyridine; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In tetrahydrofuran at 20℃; for 96h;	90%

ethanol (64-17-5) + (R)-3-hydroxy-4-cyano-butyric acid (287955-93-5) → (R)-ethyl 4-cyano-3-hydroxybutyrate (141942-85-0) + (S)-3-hydroxy-4-cyanobutyric acid ethyl ester (312745-91-8)

Conditions	Yield
With hydrogenchloride at 20℃; for 0.5h; Title compound not separated from byproducts.;

diethyl 3-hydroxyglutarate (32328-03-3) → (S)-3-hydroxy-4-cyanobutyric acid ethyl ester (312745-91-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 95 percent / Novozym 435 2: 90 percent / 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide; pyridine / tetrahydrofuran / 96 h / 20 °C View Scheme

3-hydroxyglutaronitrile (13880-89-2) → (S)-3-hydroxy-4-cyanobutyric acid ethyl ester (312745-91-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: nitrilase III; phosphate buffer / 22 h / 22 °C / pH 7 2: HCl / 0.5 h / 20 °C View Scheme

sodium cyanide (773837-37-9) + ethyl (2-chloroaceto)acetate (638-07-3) → (R)-ethyl 4-cyano-3-hydroxybutyrate (141942-85-0) + (S)-3-hydroxy-4-cyanobutyric acid ethyl ester (312745-91-8)

Conditions	Yield
With vector pCDFDuet-HF and vector pET30-(S)-alcohol dehydrogenase in Escherichia coli BL21(DE3) In aq. buffer at 30℃; for 10h; pH=7; Enzymatic reaction; stereoselective reaction;	A n/a B n/a
With halohydrin dehalogenase; NAD; magnesium chloride; alcohol dehydrogenase In tert-butyl methyl ether at 40℃; under 760.051 Torr; for 10h; pH=8; Solvent; Reagent/catalyst; Concentration; Time; Electrolysis; Sealed tube; Inert atmosphere; Enzymatic reaction;	A n/a B n/a

(S)-3-hydroxy-4-cyanobutyric acid ethyl ester (312745-91-8) → (S)-3-hydroxyglutaric acid monoamidemonoethyl ester

Conditions	Yield
With Wilkinson's catalyst; (E)-acetaldoxime In toluene Reflux;	95.2%

acetic acid tert-butyl ester (540-88-5) + (S)-3-hydroxy-4-cyanobutyric acid ethyl ester (312745-91-8) → tert-butyl (5S)-6-cyano-5-hydroxy-3-oxohexanoate (312745-90-7)

Conditions	Yield
With lithium diisopropyl amide In tetrahydrofuran at -78℃;	77%
Stage #1: acetic acid tert-butyl ester; (S)-3-hydroxy-4-cyanobutyric acid ethyl ester With tert-butyl magnesium (1+); chloride In tetrahydrofuran; toluene at 0 - 5℃; for 1h; Stage #2: With lithium diisopropyl amide In tetrahydrofuran; hexane; toluene at 5 - 20℃; for 16.5h;	57%
Stage #1: acetic acid tert-butyl ester; (S)-3-hydroxy-4-cyanobutyric acid ethyl ester With magnesium chloride In tetrahydrofuran at 0 - 5℃; Stage #2: With lithium diisopropyl amide In tetrahydrofuran; hexane at 5 - 20℃; for 16.5h;	46%
With lithium diisopropyl amide In tetrahydrofuran; hexane at 5 - 20℃; for 16.5h;	26%

(S)-3-hydroxy-4-cyanobutyric acid ethyl ester (312745-91-8) → (S)-4-Hydroxy-piperidin-2-one

Conditions	Yield
With hydrogen; nickel; triethylamine In ethanol at 20℃;

(S)-3-hydroxy-4-cyanobutyric acid ethyl ester (312745-91-8) → C8H16INO2Si (1510832-55-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogen; triethylamine; nickel / ethanol / 20 °C 2: iodine; N,N,N,N,-tetramethylethylenediamine / dichloromethane View Scheme

(S)-3-hydroxy-4-cyanobutyric acid ethyl ester (312745-91-8) → 3α,4α-epoxy-2-piperidone (159934-17-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogen; triethylamine; nickel / ethanol / 20 °C 2: iodine; N,N,N,N,-tetramethylethylenediamine / dichloromethane 3: sodium methylate View Scheme

(S)-3-hydroxy-4-cyanobutyric acid ethyl ester (312745-91-8) → C5H10N2O2 (1510832-58-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: hydrogen; triethylamine; nickel / ethanol / 20 °C 2: iodine; N,N,N,N,-tetramethylethylenediamine / dichloromethane 3: sodium methylate 4: ammonium hydroxide / water / 20 °C View Scheme

(S)-3-hydroxy-4-cyanobutyric acid ethyl ester (312745-91-8) → (S)-3-tert-butyldimethylsiloxyglutaric acid monoamidemonoethyl ester

Conditions	Yield
Multi-step reaction with 2 steps 1: (E)-acetaldoxime; Wilkinson's catalyst / toluene / Reflux 2: 1H-imidazole / N,N-dimethyl-formamide / 6 h / 25 °C View Scheme

(S)-3-hydroxy-4-cyanobutyric acid ethyl ester (312745-91-8) → (S)-3-(tert-butyl dimethylsilyloxy) glutaric acid monoamide

Conditions	Yield
Multi-step reaction with 3 steps 1: (E)-acetaldoxime; Wilkinson's catalyst / toluene / Reflux 2: 1H-imidazole / N,N-dimethyl-formamide / 6 h / 25 °C 3: sodium hydroxide; water / ethanol / 1.17 h / 45 - 50 °C View Scheme

Upstream product

• 773837-37-9 sodium cyanide 
• 638-07-3 ethyl (2-chloroaceto)acetate 
• 13880-89-2 3-hydroxyglutaronitrile 
• 32328-03-3 diethyl 3-hydroxyglutarate 
• 64-17-5 ethanol 
• 287955-93-5 (R)-3-hydroxy-4-cyano-butyric acid 

Relevant articles and documents

Absolute configurations of monoesters produced by enzyme catalyzed hydrolysis of diethyl 3-hydroxyglutarate

Biocatalytic asymmetrizations of diethyl 3-hydroxyglutarate furnish a route to the enantiomers of ethyl 4-cyano-3-hydroxybutanoate. The enantiopreference of different enzymes has been established by chiral chromatography. Conclusive evidence for absolute configurations has been provided by X-ray crystallographic structure determination of co-crystals of the predominant monoester with (R)-phenylethylamine. The predominant enantiopure monoester produced by ammonolysis of diethyl 3-hydroxyglutarate catalyzed by immobilized lipase B from Candida antarctica (Novozym 435) was ethyl (3S)-4-carbamoyl-3-hydroxybutanoate. This was converted to ethyl (3S)-4-cyano-3-hydroxybutanoate in high yield and enantiomeric excess. Growing cells of Acinetobacter lwoffii gave low ee and predominance of the (S)-enantiomer when used for hydrolysis of diethyl 3-hydroxyglutarate as opposed to previous reports. When Novozym 435 was used for hydrolysis it could be re-used 10 times without loss of activity and selectivity.

Multi-enzymatic biosynthesis of chiral β-hydroxy nitriles through co-expression of oxidoreductase and halohydrin dehalogenase

To establish a system for the efficient one bacterial multi-enzymatic biosynthesis of both (R)- and (S)-β-hydroxy nitriles, we co-expressed alcohol dehydrogenases with opposite stereoselectivities, cofactor regeneration enzymes, and a halohydrin dehalogenase in Escherichia coli. By researching cofactor recycling and various co-expression strategies and by selecting and engineering the halohydrin dehalogenase, we engineered two E. coli strains, which were subsequently used in a cascade of reactions to produce chiral β-hydroxy nitriles with high enantiomeric excess directly from prochiral α-halo ketones. Three valuable pharmaceutical intermediates were prepared by means of this catalytic system, and substrate conversion reached about >99%. More importantly, the system is of low cost because there is no need for expensive cofactors or for expression and purification of the component enzymes. Copyright