82717-96-2

Basic information

• Product Name: N-[(S)-(+)-1-(Ethoxycarbonyl)-3-phenylpropyl]-L-alanine
• Synonyms: NEPA;(S)-N-(1-ETHOXYCARBONYL-3-PHENYLPROPYL)-(S)-ALANINE;(S,S)-N-(1-ETHOXYCARBONYL-3-PHENYLPROPYL)ALANINE;N-(1-S-CARBETHOXY-3-PHENYLPROPYL)-S-ALANINE;N-(1S)-ETHOXYCARBONYL-3-PHENYLPROPYL-ALANINE;N-[1-(S)-(ETHOXYCARBONYL)-3-PHENYLPROPYL]-L-ALANINE;N-[1-(S)-ETHOXYCARBONYL-3-PHENYLPROPYL]-(S)-ALANINE;N-[(S)-1-CARBOXYETHYL]-L-HOMOPHENYLALANINE ETHYL ESTER
• CAS NO: 82717-96-2
• Molecular Formula: C₁₅H₂₁NO₄
• Molecular Weight: 279.33
• EINECS: 1308068-626-2
• Product Categories: Miscellaneous;Various Intermediates;Amino Acids 13C, 2H, 15N;Amino Acids & Derivatives;Aromatics;Chiral Reagents;Intermediates;Intermediates & Fine Chemicals;Metabolites & Impurities;Pharmaceuticals;Alanine Derivatives;Peptide Synthesis;Unnatural Amino Acid Derivatives;Intermediates, Metabolites & Impurities, Pharmaceuticals, Intermediates & Fine Chemicals
• Mol File: 82717-96-2.mol
• Article Data: 20

Chemical Properties

• Melting Point: 150-152 °C(lit.)
• Boiling Point: 422.1°C (rough estimate)
• Flash Point: 220.6 °C
• Appearance: White/Crystalline Powder
• Density: 1.1083 (rough estimate)
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 29.5 ° (C=1, MeOH)
• Storage Temp.: -20°C Freezer
• Solubility: 6g/l
• PKA: 2.14±0.10(Predicted)
• Water Solubility: 100mg/L at 25℃
• BRN: 3619501
• CAS DataBase Reference: N-[(S)-(+)-1-(Ethoxycarbonyl)-3-phenylpropyl]-L-alanine(CAS DataBase Reference)
• NIST Chemistry Reference: N-[(S)-(+)-1-(Ethoxycarbonyl)-3-phenylpropyl]-L-alanine(82717-96-2)
• EPA Substance Registry System: N-[(S)-(+)-1-(Ethoxycarbonyl)-3-phenylpropyl]-L-alanine(82717-96-2)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 37/39-26-36
• WGK Germany: 3
• Hazardous Substances Data: 82717-96-2(Hazardous Substances Data)

Usage

Chemical Properties

White Solid

Uses

Different sources of media describe the Uses of 82717-96-2 differently. You can refer to the following data:
1. Moexipril intermediate; the main metabolite of Imidapril.
2. Moexipril intermediate; the main metabolite of Imidapril

Flammability and Explosibility

Nonflammable

InChI:InChI=1/C15H21NO4/c1-3-20-15(19)13(16-11(2)14(17)18)10-9-12-7-5-4-6-8-12/h4-8,11,13,16H,3,9-10H2,1-2H3,(H,17,18)/t11-,13-/m1/s1

Synthetic route

(1'S,2S)-2-(1'-Methyl-2'-oxo-2'-phenylmethoxy-ethylamino)-4-oxo-4-phenyl-buttersaeure-ethylester (87269-98-5) → [1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine (82717-96-2)

Conditions	Yield
With hydrogenchloride; palladium 10% on activated carbon; hydrogen; N,N-diphenylthiourea In 1,4-dioxane; isopropyl alcohol under 2250.23 Torr; Reagent/catalyst; Solvent; Autoclave;	96%
With sulfuric acid; hydrogen; palladium on activated charcoal In acetic acid at 25 - 30℃; under 760 Torr;	91%
With methanesulfonic acid; hydrogen; palladium on activated charcoal In isopropyl alcohol at 20 - 215℃; for 10h;

Benzyl (2S)-2-amino>propionate Hydrogenmaleate (97457-39-1) → [1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine (82717-96-2)

Conditions	Yield
With hydrogen; palladium In ethanol under 760 Torr; for 3h; Ambient temperature;	96%

N-<(S)-1-(ethoxycarbonyl)-3-phenylpropyl>-L-alanine tert-butylester (80828-38-2) → [1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine (82717-96-2)

Conditions	Yield
With trifluoroacetic acid for 2h; Ambient temperature;	90%
With trifluoroacetic acid

Benzyl (2S)-2-amino>propionate (82717-95-1) → [1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine (82717-96-2)

Conditions	Yield
With hydrogen; palladium on activated charcoal In ethanol under 760 Torr; Ambient temperature;
Multi-step reaction with 2 steps 1: ethyl acetate; diisopropyl ether 2: 96 percent / H2 / Pd / ethanol / 3 h / 760 Torr / Ambient temperature View Scheme

ethyl 2-amino-4-phenyl-(2S)-butyrate (46460-23-5) + (S)-2-(trifluoromethanesulphonyloxy)propionic acid benzyl ester (93836-48-7) → [1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine (82717-96-2) + (2R)-2-amino>propionic acid (85196-26-5)

Conditions	Yield
With formic acid; tributyl-amine; palladium on activated charcoal 1.) CH2Cl2, -20 deg C, 2 h, 2.) methanol, 2 h; Yield given. Multistep reaction;

(R)-ethyl 2-bromo-4-phenylbutyrate (121842-77-1) → [1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine (82717-96-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: H2O; nitromethane / 72 h / 50 °C / examined various solvent-base systems 2: 90 percent / CF3COOH / 2 h / Ambient temperature View Scheme

N-carbamyl (R)-2-amino-4-phenylbutyric acid (121842-75-9) → [1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine (82717-96-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.) NaNO2, 2N H2SO4; 2.) KBr, NaNO2, 3N H2SO4 / 1.) 50percent CH3COOH, r.t., 24 h; 2.) 50percent CH3COOH, 0-5 deg C, 1 h 2: 95 percent / SOCl2 / 24 h / Ambient temperature 3: H2O; nitromethane / 72 h / 50 °C / examined various solvent-base systems 4: 90 percent / CF3COOH / 2 h / Ambient temperature View Scheme

ethyl (E)-4-oxo-4-phenyl-2-butenoate (15121-89-8) → [1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine (82717-96-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: 77 percent / N(C2H5)3 / ethanol / Ambient temperature 2: 91 percent / H2, cc.H2SO4 / Pd/C / acetic acid / 25 - 30 °C / 760 Torr View Scheme

ethyl 2-hydroxy-4-phenylbutanoate (93921-85-8) → [1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine (82717-96-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: 84 percent / pyridine / CH2Cl2 / 0 °C 2: N(C2H5)3 / CH2Cl2 / Ambient temperature 3: H2 / Pd/C / ethanol / 760 Torr / Ambient temperature View Scheme

(R)-2-hydroxy4-phenylbutanoic acid (29678-81-7) → [1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine (82717-96-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: HCl 2: pyridine / CH2Cl2 / Ambient temperature 3: N(C2H5)3 / CH2Cl2 / Ambient temperature 4: H2 / Pd/C / ethanol / 760 Torr / Ambient temperature View Scheme

ethyl (R)-2-hydroxy-4-phenylbutyrate (90315-82-5) → [1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine (82717-96-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: pyridine / CH2Cl2 / Ambient temperature 2: N(C2H5)3 / CH2Cl2 / Ambient temperature 3: H2 / Pd/C / ethanol / 760 Torr / Ambient temperature View Scheme

(-)-α-[(Trifluoromethyl)sulfonyl]oxy-4-phenylbutyric acid,ethyl ester (90365-91-6, 150822-65-4) → [1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine (82717-96-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: N(C2H5)3 / CH2Cl2 / Ambient temperature 2: H2 / Pd/C / ethanol / 760 Torr / Ambient temperature View Scheme

ethyl (R)-4-phenyl-2-<<(trifluoromethyl)sulfonyl>oxy>butyrate (88767-98-0) → [1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine (82717-96-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: N(C2H5)3 / CH2Cl2 / Ambient temperature 2: H2 / Pd/C / ethanol / 760 Torr / Ambient temperature View Scheme

N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine N-carboxyanhydride (84793-24-8) + L-proline (147-85-3) → [1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine (82717-96-2) + enalaprilate (76420-72-9) + enalapril (75847-73-3) + (S)-2-((3S,8aS)-3-Methyl-1,4-dioxo-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-4-phenyl-butyric acid ethyl ester (115729-52-7)

Conditions	Yield
Stage #1: N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine N-carboxyanhydride; L-proline In water; ethyl acetate at 19 - 20℃; for 5h; pH=10 - 11; Stage #2: at 30℃; for 0.166667h; pH=4.3 - 4.7;	A 0.5 %Chromat. B 0.4 %Chromat. C 14 %Chromat. D 0.5 %Chromat.
Stage #1: N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine N-carboxyanhydride; L-proline In dichloromethane; water at 19 - 20℃; for 5h; pH=9.5 - 11.5; Stage #2: at 30℃; for 0.166667h; pH=4.3 - 4.7;	A 0.5 %Chromat. B 0.5 %Chromat. C 10 %Chromat. D 0.6 %Chromat.
Stage #1: N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine N-carboxyanhydride; L-proline In water; ethyl acetate at 19 - 20℃; for 5h; pH=9.5 - 11.5; Stage #2: at 30℃; for 0.166667h; pH=4.3 - 4.7;	A 0.6 %Chromat. B 0.5 %Chromat. C 14 %Chromat. D 0.4 %Chromat.

ethyl (R)-2-fluorosulfonyloxy-4-phenylbutanoate + H-Ala-OBzl (17831-01-5) → [1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine (82717-96-2)

Conditions	Yield
Stage #1: ethyl (R)-2-fluorosulfonyloxy-4-phenylbutanoate; H-Ala-OBzl With triethylamine In acetonitrile at 20 - 40℃; for 2.5h; Stage #2: With hydrogen; palladium In ethanol under 1810.07 Torr; for 0.2h;

2-oxo-4-phenylbutanoic acid ethyl ester (64920-29-2) + L-alanine benzyl ester p-toluenesulfonate (42854-62-6) → [1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine (82717-96-2)

Conditions	Yield
With 4-methyl-morpholine In methanol; cyclohexane

oxalyl dichloride (79-37-8) + ethyl 2-hydroxy-4-phenylbutanoate (93921-85-8) + 2-oxo-4-phenylbutanoic acid ethyl ester (64920-29-2) + tert-butyl L-alaninate hydrochloride (13404-22-3) → [1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine (82717-96-2)

Conditions	Yield
With sodium ethanolate; sodium cyanoborohydride; sodium hydrogencarbonate In ethanol

benzyl (R)-α-toluenesulfonyloxypropionate + ethyl 2-amino-4-phenyl-(2S)-butyrate (46460-23-5) → [1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine (82717-96-2)

Conditions	Yield
In water; potassium carbonate; acetonitrile

[1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine (82717-96-2) + chloroformic acid ethyl ester (541-41-3) → ethyl 2-(S)-{N-ethoxycarbonyl-N-[1-(S)-(ethoxycarbonyloxycarbonyl)-ethyI]-amino}-4-phenylbutyrate

Conditions	Yield
With triethylamine In acetone at -2 - 20℃; for 1.5h;	100%

(2S,3aS,6aS)-cyclopenta[b]pyrrole-2-carboxylic acid benzyl ester hydrochloride + [1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine (82717-96-2) → 2--L-alanyl>-(1S,3S,5S)-2-azabicyclo<3.3.0>octane-3-carboxylic acid benzylester (87269-88-3)

Conditions	Yield
Stage #1: [1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine With hydrogenchloride; thionyl chloride; N,N-dimethyl-formamide In dichloromethane at -10 - -5℃; for 0.00416667h; Inert atmosphere; Stage #2: (2S,3aS,6aS)-cyclopenta[b]pyrrole-2-carboxylic acid benzyl ester hydrochloride With sodium hydrogencarbonate In dichloromethane; water for 0.005h;	99.5%

[1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine (82717-96-2) + tert-butyl N-(2,3-dihydro-1H-inden-2-yl)glycinate (83402-63-5) + chlorophosphoric acid diphenyl ester (2524-64-3) → N-(2,3-dihydro-1H-inden-2-yl)-N--L-alanyl>-glycine t-butyl ester (83435-61-4)

Conditions	Yield
With sodium hydroxide; phosphoric acid; triethylamine In dichloromethane; water	98%

[1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine (82717-96-2) → (S)-N-[(S)-1-CARBAMOYL-3-PHENYLPROPYL]-ALANINE

Conditions	Yield
	96%

tert-butyl (2S,3aR,7aS)-octahydro-1H-indole-2-carboxylate + [1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine (82717-96-2) → tert-butyl (2S,3aR,7aS)-1-(((S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl)-L-alanyl)octahydro-1H-indole-2-carboxylate

Conditions	Yield
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In acetonitrile at 0 - 20℃; for 17h; Inert atmosphere;	95%

[1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine (82717-96-2) → N-[(S)-1-carbethoxy-3-phenyl-propyl]-S-alaninoyl chloride hydrochloride (114192-42-6)

Conditions	Yield
With hydrogenchloride; phosphorus pentachloride In 1,4-dioxane; dichloromethane at 0 - 20℃; for 16.5h;	93%
With phosphorus pentachloride In dichloromethane at 0℃;
With phosphorus pentachloride In dichloromethane at 0℃;

[1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine (82717-96-2) + (2S,3aS,7aS)-perhydroindole-2-carboxylic acid (80875-98-5) → ramipril

Conditions	Yield
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In DMF (N,N-dimethyl-formamide); acetonitrile at 20℃; for 0.5h;	92%

1-hydroxy-pyrrolidine-2,5-dione (6066-82-6) + [1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine (82717-96-2) → N-succinimidyl (2S)-2-{N-[(1S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino}propionate (89371-34-6)

Conditions	Yield
With sodium hydrogencarbonate; chlorophosphoric acid diphenyl ester In acetone at 50℃; for 1h;	86%
With dicyclohexyl-carbodiimide In tetrahydrofuran Ambient temperature;
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide for 18h; Ambient temperature;

[1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine (82717-96-2) + 2,2,2-Trichloroethyl chloroformate (17341-93-4) → N-[(1S)-1-Ethoxycarbonyl-3-Phenylpropyl]-N-(2,2,2-Trichloroethoxycarbonyl)-1-Alanine

Conditions	Yield
With pyridine; hydrogenchloride In dichloromethane; cyclohexane; water	70%
With triethylamine In dichloromethane

Upstream product

• 82717-95-1 Benzyl (2S)-2-amino>propionate 
• 87269-98-5 (1'S,2S)-2-(1'-Methyl-2'-oxo-2'-phenylmethoxy-ethylamino)-4-oxo-4-phenyl-buttersaeure-ethylester 
• 84793-24-8 N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine N-carboxyanhydride 
• 147-85-3 L-proline 
• 89396-94-1 Imidapril hydrochloride 
• 87679-37-6 trandolapril 
• 79-37-8 oxalyl dichloride 
• 93921-85-8 ethyl 2-hydroxy-4-phenylbutanoate 
• 64920-29-2 2-oxo-4-phenylbutanoic acid ethyl ester 
• 13404-22-3 tert-butyl L-alaninate hydrochloride 
• 17831-01-5 H-Ala-OBzl 
• 88767-98-0 ethyl (R)-4-phenyl-2-<<(trifluoromethyl)sulfonyl>oxy>butyrate 
• 90365-91-6 (-)-α-[(Trifluoromethyl)sulfonyl]oxy-4-phenylbutyric acid,ethyl ester 
• 90315-82-5 ethyl (R)-2-hydroxy-4-phenylbutyrate 

Downstream Products

• 89371-34-6 N-succinimidyl (2S)-2-{N-[(1S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino}propionate 
• 101820-40-0 N-benzyl-N--L-alanyl>glycine t-butyl ester 
• 80828-33-7 tert-butyl (2S,3aS,7aS)-1-(((S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl)-L-alanyl)octahydro-1H-indole-2-carboxylate 
• 80828-26-8 N-[1-(S)-(ethoxycarbonyl)-3-phenylpropyl]-L-alanine hydrochloride 
• 75847-73-3 enalapril 
• 80876-01-3 trandalopril 
• 114192-42-6 N-[(S)-1-carbethoxy-3-phenyl-propyl]-S-alaninoyl chloride hydrochloride 
• 1356847-95-4 C₃₀H₃₈N₂O₅ 
• 84793-24-8 N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine N-carboxyanhydride 
• 83551-92-2 1-[N-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl]-4-(S)-(phenylthio)-L-proline 
• 87679-37-6 trandolapril 
• 108428-39-3 N--L-alanyl>-L-proline tert butyl ester 
• 103733-40-0 tert-butyl (S)-2-(((S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl)-L-alanyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate 

Relevant articles and documents

Preparation method of N-[1-(S)-ethoxy carbonyl-3-phenyl propyl]-L-alanine

The invention provides a preparation method of N-[1-(S)-ethoxy carbonyl-3-phenyl propyl]-L-alanine. The preparation method comprises the following steps: performing addition reaction on a compound I and a compound II under the action of a first catalyst to obtain an addition product, wherein the first catalyst is selected from a first thiourea compound and/or a urea compound; performing hydrogenation reaction on the addition product to obtain the N-[1-(S)-ethoxy carbonyl-3-phenyl propyl]-L-alanine. The first catalyst (the first thiourea compound and/or the urea compound) can be added to the reaction system, the selectivity of the addition reaction is improved and the separation efficiency of the required product in the addition reaction process is improved, so that the yield of the final product N-[1-(S)-ethoxy carbonyl-3-phenyl propyl]-L-alanine is increased. The method has the advantages of being short in synthesis route, simple in aftertreatment, capable of being applied to industrialized production and the like.

Impurity profiling of trandolapril under stress testing: Structure elucidation of by-products and development of degradation pathway

Various regulatory authorities like International Conference on Harmonization (ICH), US Food and Drug Administration, Canadian Drug and Health Agency are emphasizing on the purity requirements and the identification of impurities in active pharmaceutical drugs. Qualification of the impurities is the process of acquiring and evaluating data that establishes biological safety of an individual impurity; thus, revealing the need and scope of impurity profiling of drugs in pharmaceutical research. As no stability-indicating method is available for identification of degradation products of trandolapril, a new angiotensin converting enzyme inhibitor (ACEI), under stress testing, the development of an accurate method is needed for quantification and qualification of degradation products. Ultra high performance liquid chromatography (UPLC) coupled to electrospray tandem mass spectrometry was used for the rapid and simultaneous analysis of trandolapril and its degradation products. Chromatographic separation was achieved in less than 4 min, with improved peak resolution and sensitivity. Thanks to this method, the kinetics of trandolapril degradation under various operating conditions and the characterization of the structure of the by-products formed during stress testing have been determined. Thereafter, a mechanism of trandolapril degradation in acid and neutral conditions, including all the identified products, was then proposed.

Conversion of a hydroxy group in certain alcohols into a fluorosulfonate ester or a trifluoromethylsulfonate ester

The present invention provides a method of converting a hydroxy group in alcohols containing an electron withdrawing group into perfluoroalkane sulfonate and fluorosulfonate esters, which are good leaving groups, with inversion of configuration where the hydroxyl-bearing carbon is chiral. The method consists of converting an alcohol to an O—N,N-dialkylsulfamate ester and reacting it with a perfluoroalkansulfonic or fluorosulfonic acid. The method has applications in the synthesis of pharmaceutical and agrochemical compounds.