72776-05-7

Basic information

• Product Name: (S)-BENZYL 2-AZETIDINONE-4-CARBOXYLATE
• Synonyms: AKOS 91388;BENZYL (S)-(-)-4-OXO-2-AZETIDINECARBOXYLATE;BENZYL (S)-4-OXO-2-AZETIDINECARBOXYLATE;(S)-BENZYL 2-AZETIDINONE-4-CARBOXYLATE;BENZYL (S)-(-)-4-OXO-2-AZETIDINECARBOXYL;(S)-2-Azetidinone-4-carboxylic acid benzyl ester;(S)-Benzyl 2-azetidinone-4-carboxylate,97%;(S)-benzyl 4-oxoazetidine-2-carboxylate
• CAS NO: 72776-05-7
• Molecular Formula: C₁₁H₁₁NO₃
• Molecular Weight: 205.21
• Product Categories: chiral;Chiral Building Blocks;Lactams;Organic Building Blocks
• Mol File: 72776-05-7.mol
• Article Data: 17

Chemical Properties

• Melting Point: 137-140 °C(lit.)
• Boiling Point: 404.7 °C at 760 mmHg
• Flash Point: 198.5 °C
• Appearance: white to light yellow crystalline powder
• Density: 1.268 g/cm³
• Vapor Pressure: 9.28E-07mmHg at 25°C
• Refractive Index: 1.565
• Storage Temp.: 0-6°C
• PKA: 13.75±0.40(Predicted)
• CAS DataBase Reference: (S)-BENZYL 2-AZETIDINONE-4-CARBOXYLATE(CAS DataBase Reference)
• NIST Chemistry Reference: (S)-BENZYL 2-AZETIDINONE-4-CARBOXYLATE(72776-05-7)
• EPA Substance Registry System: (S)-BENZYL 2-AZETIDINONE-4-CARBOXYLATE(72776-05-7)

Safety Data

• Safety Statements: 24/25
• WGK Germany: 3
• Hazardous Substances Data: 72776-05-7(Hazardous Substances Data)

Usage

Chemical Properties

white to light yellow crystal powde

Uses

Benzyl (S)-(-)-4-oxo-2-azetidinecarboxylate may be used in the preparation of its N-acetyl derivative, which can be a potential candidate as solid electrolyte interphase (SEI)-forming additive in lithium-ion batteries.

InChI:InChI=1/C11H11NO3/c13-10-6-9(12-10)11(14)15-7-8-4-2-1-3-5-8/h1-5,9H,6-7H2,(H,12,13)/t9-/m0/s1

Synthetic route

dibenzyl L-aspartate (2791-79-9) → (S)-benzyl 4-oxoazetidine-2-carboxylate (72776-05-7)

Conditions	Yield
Stage #1: dibenzyl L-aspartate With chloro-trimethyl-silane; triethylamine In diethyl ether at 0℃; for 1h; Stage #2: With tert-butylmagnesium chloride In diethyl ether at -5 - 0℃; for 2h;	47%
Stage #1: dibenzyl L-aspartate With chloro-trimethyl-silane In diethyl ether at -78 - 25℃; Stage #2: With tert-butylmagnesium bromide In diethyl ether at -78 - 25℃;	40%
With chloro-trimethyl-silane; tert-butylmagnesium chloride

(L)-N-(trimethylsilyl)dibenzyl aspartate (72776-06-8) → (S)-benzyl 4-oxoazetidine-2-carboxylate (72776-05-7)

Conditions	Yield
With tert-butylmagnesium chloride In diethyl ether at 0℃; Yield given;
With tert-butylmagnesium chloride 1.) 0 deg C, 2.) room temperature, overnight; Yield given;
With tert-butylmagnesium chloride In diethyl ether at 0℃;
With tert-butylmagnesium chloride In diethyl ether at -5 - 20℃; for 12.5h;	5.1 g

D-aspartic acid dibenzyl ester (4079-59-8) → (S)-benzyl 4-oxoazetidine-2-carboxylate (72776-05-7)

Conditions	Yield
With chloro-trimethyl-silane; tert-butylmagnesium bromide; triethylamine Yield given. Multistep reaction;

dibenzyl L-aspartate (2791-79-9) + methoxy poly(ethylene glycol) sodium salt → (S)-benzyl 4-oxoazetidine-2-carboxylate (72776-05-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: TEA; 4-dimethylaminopyridine / diethyl ether / 3 h / 0 °C 2: 5.1 g / tBuMgCl / diethyl ether / 12.5 h / -5 - 20 °C View Scheme

C16H21NO5 → (S)-benzyl 4-oxoazetidine-2-carboxylate (72776-05-7)

Conditions	Yield
With cytochrome P411 expressed in Escherichia coli In aq. phosphate buffer at 20℃; for 24h; pH=8; Catalytic behavior; Enzymatic reaction; enantioselective reaction;	n/a

(S)-benzyl 4-oxoazetidine-2-carboxylate (72776-05-7) → (S)-4-(hydroxymethyl)-2-azetidinone (72776-07-9)

Conditions	Yield
With sodium tetrahydroborate In methanol at 0 - 20℃; Inert atmosphere;	100%
With sodium tetrahydroborate In methanol	71%
With sodium tetrahydroborate In methanol
With lithium borohydride

(S)-benzyl 4-oxoazetidine-2-carboxylate (72776-05-7) → α-benzyl-L-aspartic acid poly(β-peptide); Monomer(s): α-benzyl-L-aspartic acid β-lactam

Conditions	Yield
With magnesium bis(hexamethyldisilazide) In dichloromethane for 0.2h; Product distribution; Further Variations:; Reagents; Solvents; concentrations;	100%
With magnesium bis(hexamethyldisilazide) In dichloromethane for 0.2h;	100%

(S)-benzyl 4-oxoazetidine-2-carboxylate (72776-05-7) → (S)-4-oxo-azetidine-2-carboxylic acid (16404-94-7)

Conditions	Yield
With hydrogen; palladium on activated charcoal In tetrahydrofuran for 14h;	98%
With hydrogen; palladium 10% on activated carbon In methanol at 25℃; under 760.051 Torr; for 0.5h;	93%
With hydrogen; palladium on activated charcoal In isopropyl alcohol at 20℃; under 1140.08 Torr; for 0.333333h;	85%
With hydrogen; palladium on activated charcoal In tetrahydrofuran at 25℃; for 0.75h;	11.8 g

(S)-benzyl 4-oxoazetidine-2-carboxylate (72776-05-7) + tert-butyldimethylsilyl chloride (18162-48-6) → (S)-benzyl-1-(tert-butyldimethylsilyl)-4-oxoazetidine-2-carboxylate (82938-49-6)

Conditions	Yield
With triethylamine	98%
With triethylamine	97%
With triethylamine In N,N-dimethyl-formamide	93%

(S)-benzyl 4-oxoazetidine-2-carboxylate (72776-05-7) + (S)-4-Oxo-azetidine-2-carboxylic acid 2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-ethyl ester (372515-10-1) → α-3,6,9,12-tetraoxatridecyl-L-aspartic acid, α-benzyl-L-aspartic acid diblock copoly(β-peptide); Monomer(s): α-3,6,9,12-tetraoxatridecyl-L-aspartic acid β-lactam; α-benzyl-L-aspartic acid β-lactam

Conditions	Yield
With tris(bistrimethylsilylamine)scandium(III) In dichloromethane at 20℃;	95%

di-tert-butyl dicarbonate (24424-99-5) + (S)-benzyl 4-oxoazetidine-2-carboxylate (72776-05-7) → (4S)-benzyl N-(tbutoxycarbonyl)-azetidin-2-one-4-carboxylate

Conditions	Yield
With dmap In acetonitrile for 17h; Ambient temperature;	94%

(S)-benzyl 4-oxoazetidine-2-carboxylate (72776-05-7) + ortho-toluoyl chloride (933-88-0) → benzyl (S)-1-(2-methylbenzoyl)-4-oxoazetidine-2-carboxylate

Conditions	Yield
With dmap; triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere;	86%

1,1,1,2,2,2-hexamethyldisilane (1450-14-2) + (S)-benzyl 4-oxoazetidine-2-carboxylate (72776-05-7) → (4S)-N-(trimethylsilyl)-2-oxoazetidine-4-carboxylic acid benzyl ester (100188-43-0)

Conditions	Yield
With saccharin In 1,2-dimethoxyethane for 2h; Heating;	78%

2,2-dimethyl-propanol-1 (75-84-3) + (S)-benzyl 4-oxoazetidine-2-carboxylate (72776-05-7) → (S)-4-(2,2'-dimethyl)propoxycarbonyl-2-azetidinone

Conditions	Yield
With tetrabutoxytitanium at 100℃; for 2h;	75%

(S)-benzyl 4-oxoazetidine-2-carboxylate (72776-05-7) + 2-tolyl isocyanate (614-68-6) → benzyl (S)-4-oxo-(o-tolylcarbamoyl)azetidine-2-carboxylate

Conditions	Yield
With potassium carbonate In acetonitrile at 20℃; for 2h; Inert atmosphere;	75%

phosgene (75-44-5) + (S)-benzyl 4-oxoazetidine-2-carboxylate (72776-05-7) → benzyl (S)-4-oxo-1-(phenylcarbamoyl)azetidine-2-carboxylate (911852-27-2)

Conditions	Yield
Stage #1: phosgene; aniline With triethylamine In dichloromethane; toluene at 0℃; for 0.5h; Stage #2: (S)-benzyl 4-oxoazetidine-2-carboxylate In tetrahydrofuran; dichloromethane; toluene	73%

(S)-benzyl 4-oxoazetidine-2-carboxylate (72776-05-7) + BOC-L-alanine-NCA (125814-30-4) → benzyl (S)-1-[(S)-N-(tert-butoxycarbonyl)-alanyl]-4-oxoazetidine-2-carboxylate (321863-81-4)

Conditions	Yield
Stage #1: (S)-benzyl 4-oxoazetidine-2-carboxylate With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.166667h; Stage #2: BOC-L-alanine-NCA In tetrahydrofuran; hexane at -78℃; for 1h;	71%

(S)-benzyl 4-oxoazetidine-2-carboxylate (72776-05-7) + butan-1-ol (71-36-3) → (S)-4-butoxycarbonyl-2-azetidinone

Conditions	Yield
With tetrabutoxytitanium at 100℃; for 2h;	69%

(S)-benzyl 4-oxoazetidine-2-carboxylate (72776-05-7) + 2,6-dimethyl-4-pyrimidinyl p-toluenesulfonate (40227-86-9) → (R)-benzyl 1-(2,6-dimethylpyrimidin-4-yl)-4-oxoazetidine-2-carboxylate (1233503-36-0)

Conditions	Yield
With 1,1'-bis-(diphenylphosphino)ferrocene; potassium carbonate; bis(dibenzylideneacetone)-palladium(0) In 1,4-dioxane at 100℃; for 16h; Inert atmosphere;	69%

(S)-benzyl 4-oxoazetidine-2-carboxylate (72776-05-7) + isopropyl alcohol (67-63-0) → (S)-4-isopropoxycarbonyl-2-azetidinone (155878-39-0)

Conditions	Yield
With tetrabutoxytitanium at 205℃; for 2h;	68%

methanol (67-56-1) + (S)-benzyl 4-oxoazetidine-2-carboxylate (72776-05-7) → methyl (S)-(-)-2-oxoazetidine-4-carboxylate (100188-44-1)

Conditions	Yield
With tetrabutoxytitanium at 86℃; for 4h;	64%

(S)-benzyl 4-oxoazetidine-2-carboxylate (72776-05-7) + Benzyl bromoacetate (5437-45-6) → benzyl (S)-1-[(benzyloxycarbonyl)methyl]-4-oxoazetidine-2-carboxylate

Conditions	Yield
Stage #1: (S)-benzyl 4-oxoazetidine-2-carboxylate With n-butyllithium; N,N,N,N,-tetramethylethylenediamine In tetrahydrofuran; hexane at -78℃; for 0.0333333h; Stage #2: Benzyl bromoacetate In tetrahydrofuran; hexane at -78 - 20℃;	59%

octanol (111-87-5) + (S)-benzyl 4-oxoazetidine-2-carboxylate (72776-05-7) → (S)-4-octoxycarbonyl-2-azetidinone

Conditions	Yield
With tetrabutoxytitanium at 80℃; for 2h;	58%

2-methyl-propan-1-ol (78-83-1) + (S)-benzyl 4-oxoazetidine-2-carboxylate (72776-05-7) → 2-methyl-1-propyl (S)-(-)-2-oxoazetidine-4-carboxylate (120260-62-0)

Conditions	Yield
With tetrabutoxytitanium at 85℃; for 2h;	58%
With tetrabutoxytitanium

1-dodecyl alcohol (112-53-8) + (S)-benzyl 4-oxoazetidine-2-carboxylate (72776-05-7) → (S)-4-dodecoxycarbonyl-2-azetidinone

Conditions	Yield
With tetrabutoxytitanium at 105℃; for 4h;	58%

Cyclopentanol (96-41-3) + (S)-benzyl 4-oxoazetidine-2-carboxylate (72776-05-7) → (S)-4-cyclopentoxycarbonyl-2-azetidinone

Conditions	Yield
With tetrabutoxytitanium at 85℃; for 2h;	56%

(S)-benzyl 4-oxoazetidine-2-carboxylate (72776-05-7) + cyclohexanol (108-93-0) → (S)-4-cyclohexoxycarbonyl-2-azetidinone

Conditions	Yield
With tetrabutoxytitanium at 105℃; for 3h;	56%

1-octadecanol (112-92-5) + (S)-benzyl 4-oxoazetidine-2-carboxylate (72776-05-7) → (S)-4-octadecoxycarbonyl-2-azetidinone

Conditions	Yield
With tetrabutoxytitanium at 91℃; for 4h;	51%

(S)-benzyl 4-oxoazetidine-2-carboxylate (72776-05-7) + hexan-1-ol (111-27-3) → (S)-4-hexoxycarbonyl-2-azetidinone

Conditions	Yield
With tetrabutoxytitanium at 85℃; for 2h;	47%

(S)-benzyl 4-oxoazetidine-2-carboxylate (72776-05-7) + 4-isopropyl-2,5-dioxo-oxazolidine-3-carboxylic acid-tert-butyl ester (141468-55-5) → benzyl (S)-1-[(S)-N-(tert-butoxycarbonyl)-valyl]-4-oxoazetidine-2-carboxylate

Conditions	Yield
Stage #1: (S)-benzyl 4-oxoazetidine-2-carboxylate With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.166667h; Stage #2: 4-isopropyl-2,5-dioxo-oxazolidine-3-carboxylic acid-tert-butyl ester In tetrahydrofuran; hexane at -78℃; for 1h;	41%

(S)-benzyl 4-oxoazetidine-2-carboxylate (72776-05-7) + Z-L-Ala-NCA → benzyl (S)-1-[(S)-N-(benzyloxycarbonyl)-alanyl]-4-oxoazetidine-2-carboxylate

Conditions	Yield
Stage #1: (S)-benzyl 4-oxoazetidine-2-carboxylate With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.166667h; Stage #2: Z-L-Ala-NCA In tetrahydrofuran; hexane at -78℃; for 1h;	37%

tert-butyl(4-(isocyanatomethyl)phenyl)carbamate + (S)-benzyl 4-oxoazetidine-2-carboxylate (72776-05-7) → benzyl (S)-1-(4-tert-butoxycarbonylaminobenzylcarbamoyl)-4-oxoazetidine-2-carboxylate

Conditions	Yield
Stage #1: (S)-benzyl 4-oxoazetidine-2-carboxylate With sodium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.25h; Inert atmosphere; Stage #2: tert-butyl(4-(isocyanatomethyl)phenyl)carbamate In tetrahydrofuran at -78℃; for 0.5h; Inert atmosphere;	37%

(S)-benzyl 4-oxoazetidine-2-carboxylate (72776-05-7) + tert-butyl 2-(fluorocarbonyl)pyrrolidine-1-carboxylate (133010-05-6) → benzyl N-[N-(tert-butoxycarbonyl)-prolyl]-4-oxoazetidine-2-carboxylate

Conditions	Yield
With n-butyllithium In tetrahydrofuran; hexane at -78 - 20℃;	20%

Upstream product

• 2791-79-9 dibenzyl L-aspartate 
• 72776-06-8 (L)-N-(trimethylsilyl)dibenzyl aspartate 
• 4079-59-8 D-aspartic acid dibenzyl ester 

Downstream Products

• 100188-43-0 (4S)-N-(trimethylsilyl)-2-oxoazetidine-4-carboxylic acid benzyl ester 
• 321863-81-4 benzyl (S)-1-[(S)-N-(tert-butoxycarbonyl)-alanyl]-4-oxoazetidine-2-carboxylate 
• 1620568-16-2 C₂₄H₂₇N₃O₆ 
• 1233503-36-0 (R)-benzyl 1-(2,6-dimethylpyrimidin-4-yl)-4-oxoazetidine-2-carboxylate 
• 911852-27-2 benzyl (S)-4-oxo-1-(phenylcarbamoyl)azetidine-2-carboxylate 
• 193959-27-2 (2S,3S)-1-[2-(3-Benzyloxycarbonyl-phenyl)-acetyl]-3-(4-hydroxy-benzyl)-4-oxo-azetidine-2-carboxylic acid benzyl ester 
• 193959-26-1 (3S,4S)-3-[4-[(1,1-dimethylethyl)diphenylsilyloxy]phenylmethyl]-4-benzyloxycarbonylazetidin-2-one 
• 342624-75-3 (3S,4S)-4-benzyloxycarbonyl-1-[3'-(benzyloxycarbonyl)phenylacetate]-3-[4'-(tert-butyldiphenylsilyloxy)benzyl]-2-azetidionone 
• 193959-25-0 (3S,4S)-4-benzyloxycarbonyl-1-(tert-butyldimethylsilyl)-3-[4'-(tert-butyldiphenylsilyloxy)benzyl]-2-azetidinone 
• 82938-49-6 benzyl (S)-1-(tert-butyldimethylsilyl)-4-oxoazetidine-2-carboxylate 
• 16404-94-7 (S)-4-oxo-azetidine-2-carboxylic acid 

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β-Lactam derivatives as enzyme inhibitors: N-substituted derivatives of (S)-4-oxoazetidine-2-carboxylate as inhibitors of elastase and papain

N-Alkyl and N-acyl substituted 4-oxoazetidine-2-carboxylates are synthesized and evaluated as inhibitors of the proteases porcine pancreatic elastase (PPE) and papain. The compounds are obtained by alkylation or acylation at the nitrogen of benzyl (S)-4-oxoazetidine-2-carboxylate, which is synthesized by a modified literature procedure. The enzymatic assays prove some derivatives to be effective inhibitors of PPE and/or papain. The N-BOC protected amino acid derivatives 10 and 13 inhibit PPE reversibly with K(I)-values in the micromolar range. On the other hand, papain is inactivated irreversibly by benzyl (S)-2-(benzyloxycarbonyl)azetidin-1-acetate (6).