36476-78-5

Basic information

• Product Name: 3-Azetidinecarboxylic acid
• Synonyms: AZETIDINE-3-CARBOXYLIC ACID;L-AZETIDINE-3-CARBOXYLIC ACID;H-AZE(3)-OH;3-AZETANECARBOXYLIC ACID;3-AZETIDINECARBOXYLIC ACID;3-CARBOXYAZETIDINE;RARECHEM BK PT 0277;azetidine-3-carboxylic
• CAS NO: 36476-78-5
• Molecular Formula: C₄H₇NO₂
• Molecular Weight: 101.1
• EINECS: 1308068-626-2
• Product Categories: Pharmaceutical Raw Materials;Unusual amino acids;Heterocycles series;Miscellaneous;Carboxylic Acids;Amino Acids 13C, 2H, 15N;Azetidines;Simple 4-Membered Ring Compounds;Peptide;Amino Acids & Derivatives;Carboxylic Acids;Ring Systems;Alicyclic Amino Acids;Peptide Synthesis;Unnatural Amino Acid Derivatives;B-Amino
• Mol File: 36476-78-5.mol
• Article Data: 14

Chemical Properties

• Melting Point: 286 °C (dec.)(lit.)
• Boiling Point: 189.47°C (rough estimate)
• Flash Point: 100.1 °C
• Appearance: light yellow powder
• Density: 1.2245 (rough estimate)
• Vapor Pressure: 0.0116mmHg at 25°C
• Refractive Index: 1.4540 (estimate)
• Storage Temp.: 2-8°C
• Solubility: Water (Slightly)
• PKA: 2.74±0.20(Predicted)
• Water Solubility: Soluble in water.
• CAS DataBase Reference: 3-Azetidinecarboxylic acid(CAS DataBase Reference)
• NIST Chemistry Reference: 3-Azetidinecarboxylic acid(36476-78-5)
• EPA Substance Registry System: 3-Azetidinecarboxylic acid(36476-78-5)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 24/25-22-36-26
• WGK Germany: 3
• RTECS: CM4310600
• HazardClass: IRRITANT
• Hazardous Substances Data: 36476-78-5(Hazardous Substances Data)

Usage

Chemical Properties

light yellow powder

Uses

Different sources of media describe the Uses of 36476-78-5 differently. You can refer to the following data:
1. 3-Azetidinecarboxylic acid is a useful intermediate in the synthesis of polypeptides.
2. Azetidine-3-carboxylic acid derivatives has potential biological and foldameric applications. Azetidine-3-carboxylic acid, a fairly strained molecule provides oxadiazoles in good yields. Azetidine-3-carboxylic acid is used as a chemical hybridising agent
3. Azetidine and its derivatives are valuable compounds in pharmaceutical and agrochemical research.

InChI:InChI=1/C4H7NO2/c6-4(7)3-1-5-2-3/h3,5H,1-2H2,(H,6,7)

Synthetic route

N-benzyl azetidine-3-carboxylic acid (94985-27-0) → 3-azetidinecarboxylic acid (36476-78-5)

Conditions	Yield
palladium In methanol	90%
With hydrogen; palladium dihydroxide In methanol; water at 60℃; under 2068.59 Torr; for 16h;	806.2 g
palladium In methanol

1-acetylazetidine-3-carboxylic acid (97628-91-6) → 3-azetidinecarboxylic acid (36476-78-5)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen In ethanol at 40℃; under 15001.5 Torr; for 24h;	27.9%

1-nitrosoazetidine-3,3-dicarboxylic acid → 3-azetidinecarboxylic acid (36476-78-5)

Conditions	Yield
With formic acid In water

N-benzyl-3,3-bis-(hydroxymethyl)-azetidine (26096-30-0) + tartaric acid (87-69-4) + N-benzyl azetidine-3-carboxylic acid (94985-27-0) → 3-azetidinecarboxylic acid (36476-78-5)

Conditions	Yield
With potassium hydroxide; phosphoric acid; ammonium formate; palladium on charcoal In methanol; water

1-(t-butyloxycarbonyl)-azetidine-3-carboxylic acid (142253-55-2) → 3-azetidinecarboxylic acid (36476-78-5)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen In ethanol at 50℃; under 18751.9 Torr; for 30h;	13.8 g

3-azetidinecarboxylic acid (36476-78-5) + benzyl chloroformate (501-53-1) → 1-benzyloxycarbonyl-3-azetidinecarboxylic acid (97628-92-7)

Conditions	Yield
Stage #1: 3-azetidinecarboxylic acid; benzyl chloroformate With sodium hydroxide In water at 0℃; for 16h; Stage #2: With hydrogenchloride In water	100%
With potassium carbonate In water at 0 - 20℃;	91%
Stage #1: 3-azetidinecarboxylic acid; benzyl chloroformate With potassium carbonate In 1,4-dioxane; water at 20℃; for 6h; Stage #2: With piperazine In 1,4-dioxane; water for 0.5h;	83%

di-tert-butyl dicarbonate (24424-99-5) + 3-azetidinecarboxylic acid (36476-78-5) → 1-(t-butyloxycarbonyl)-azetidine-3-carboxylic acid (142253-55-2)

Conditions	Yield
With triethylamine In methanol at 20℃; for 18h;	100%
With triethylamine In methanol at 20℃; for 18h;	100%
With sodium hydroxide In tetrahydrofuran; water at 20℃; for 24h; Product distribution / selectivity;	95%

ethyl 6-chloro-5-cyano-2-(difluoromethyl)nicotinate (919354-88-4) + 3-azetidinecarboxylic acid (36476-78-5) → 1-[3-cyano-6-(difluoromethyl)-5-(ethoxycarbonyl)pyridin-2-yl]azetidine-3-carboxylic acid (919354-92-0)

Conditions	Yield
With triethylamine In ethanol; water at 120℃; for 0.166667h; Microwave irradiation;	100%

3-azetidinecarboxylic acid (36476-78-5) + trifluoroacetic anhydride (407-25-0) → 1-(trifluoroacetyl)azetidine-3-carboxylic acid (1001026-41-0)

Conditions	Yield
at 0℃; for 3.33333h;	100%
at 0℃; for 2.83333h;	100%

methanol (67-56-1) + 3-azetidinecarboxylic acid (36476-78-5) → methyl 3-azetidinecarboxylate hydrochloride (100202-39-9)

Conditions	Yield
With thionyl chloride In acetonitrile at 0 - 20℃; for 2.33333h;	100%
With thionyl chloride at 0 - 25℃; for 2.25h;	100%
With thionyl chloride at 5 - 65℃;	100%

methanol (67-56-1) + 3-azetidinecarboxylic acid (36476-78-5) → methyl azetidine-3-carboxylate (343238-58-4)

Conditions	Yield
With thionyl chloride at 0 - 20℃; for 10h;	100%
With chloro-trimethyl-silane Heating / reflux;
With chloro-trimethyl-silane Heating / reflux;

2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzaldehyde + 3-azetidinecarboxylic acid (36476-78-5) → 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidine carboxylic acid

Conditions	Yield
Stage #1: 2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzaldehyde; 3-azetidinecarboxylic acid With acetic acid In tetrahydrofuran at 20℃; for 2h; Stage #2: With methanol; sodium cyanoborohydride In tetrahydrofuran at 15 - 20℃; for 17h; Temperature; Concentration; Solvent;	92.6%
Stage #1: 2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzaldehyde; 3-azetidinecarboxylic acid With acetic acid In methanol at 20℃; for 2h; Large scale; Stage #2: With sodium cyanoborohydride In methanol at 20℃; for 17h; Large scale;	79%
Stage #1: 2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzaldehyde; 3-azetidinecarboxylic acid With acetic acid In tetrahydrofuran; methanol at 20℃; for 2h; Stage #2: With methanol; sodium cyanoborohydride In tetrahydrofuran at 20℃; for 16h;	2 g

4-[(1E)-1-([[4-cyclohexyl-3-(trifluoromethyl)phenyl]methoxy]imino)ethyl]-2-ethylbenzaldehyde (1230487-01-0) + 3-azetidinecarboxylic acid (36476-78-5) → Siponimod (1230487-00-9)

Conditions	Yield
Stage #1: 4-[(1E)-1-([[4-cyclohexyl-3-(trifluoromethyl)phenyl]methoxy]imino)ethyl]-2-ethylbenzaldehyde; 3-azetidinecarboxylic acid In methanol at 20 - 25℃; for 0.5h; Stage #2: With methanol; sodium tris(acetoxy)borohydride	89%
Stage #1: 4-[(1E)-1-([[4-cyclohexyl-3-(trifluoromethyl)phenyl]methoxy]imino)ethyl]-2-ethylbenzaldehyde; 3-azetidinecarboxylic acid In methanol at 20 - 25℃; for 0.5h; Stage #2: With sodium tris(acetoxy)borohydride In methanol Reagent/catalyst; Temperature;	89%
Stage #1: 4-[(1E)-1-([[4-cyclohexyl-3-(trifluoromethyl)phenyl]methoxy]imino)ethyl]-2-ethylbenzaldehyde; 3-azetidinecarboxylic acid With acetic acid In methanol at 20℃; for 0.333333h; Stage #2: With sodium cyanoborohydride In methanol at 20℃;	20%

3-(3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)isoxazole (1446358-48-0) + 3-azetidinecarboxylic acid (36476-78-5) → C21H16F2N6O3

Conditions	Yield
With triethylamine In tetrahydrofuran at 75℃; for 18h;	88%

2-(6-(3-(difluoromethoxy)-5-fluorophenyl)-1-((3-(trifluoromethyl)phenyl)sulfonyl)indolin-2-yl)acetic acid + 3-azetidinecarboxylic acid (36476-78-5) → 1-(2-(6-(3-(difluoromethoxy)-5-fluorophenyl)-1-((3-(trifluoromethyl)phenyl)sulfonyl)indolin-2-yl)acetyl)azetidine-3-carboxylic acid

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane at 30℃;	88%

N-butyl-2-fluoro-N-(5-(4-formylphenyl)-1,3,4-thiadiazol-2-yl)benzamide (1220708-88-2) + 3-azetidinecarboxylic acid (36476-78-5) → 1-(4-(5-(N-butyl-2-fluorobenzamido)-1,3,4-thiadiazol-2-yl)benzyl)azetidine-3-carboxylic acid (1220709-59-0)

Conditions	Yield
Stage #1: N-butyl-2-fluoro-N-(5-(4-formylphenyl)-1,3,4-thiadiazol-2-yl)benzamide; 3-azetidinecarboxylic acid With acetic acid In methanol at 20℃; for 1h; Stage #2: With methanol; sodium cyanoborohydride at 20℃; Stage #3: With acetic acid In methanol pH=3 - 4;	87%
Stage #1: N-butyl-2-fluoro-N-(5-(4-formylphenyl)-1,3,4-thiadiazol-2-yl)benzamide; 3-azetidinecarboxylic acid With acetic acid In methanol at 20℃; for 1h; Stage #2: With sodium cyanoborohydride In methanol at 20℃;	87%

6-(2,3-dihydro-1H-inden-2-ylmethoxy)-1-methyl-3,4-dihydro-2-naphthalenecarbaldehyde + 3-azetidinecarboxylic acid (36476-78-5) → 1-{[6-(2,3-dihydro-1H-inden-2-ylmethoxy)-1-methyl-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylic acid hydrochloride (847585-32-4)

Conditions	Yield
Stage #1: 6-(2,3-dihydro-1H-inden-2-ylmethoxy)-1-methyl-3,4-dihydro-2-naphthalenecarbaldehyde; 3-azetidinecarboxylic acid With sodium hydroxide; trimethyl orthoformate In tetrahydrofuran; methanol at 0℃; for 4h; Stage #2: With sodium tetrahydroborate In tetrahydrofuran; methanol at 0℃; for 0.5h; Stage #3: With hydrogenchloride In tetrahydrofuran; water at 20℃; for 0.5h;	87%

3-azetidinecarboxylic acid (36476-78-5) + 2,2,2-Trichloroethyl chloroformate (17341-93-4) → 1-((2,2,2-trichloroethoxy)carbonyl)azetidine-3-carboxylic acid

Conditions	Yield
Stage #1: 3-azetidinecarboxylic acid With sodium hydroxide In water at -10℃; Stage #2: 2,2,2-Trichloroethyl chloroformate In water at -10 - 24℃; for 3h;	87%

3-azetidinecarboxylic acid (36476-78-5) + 4-methoxy-benzaldehyde (123-11-5) → 1-(4-methoxy-benzyl)-azetidine-3-carboxylic acid (1127402-49-6)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen In methanol at 20℃; under 1034.32 Torr;	85%
With palladium 10% on activated carbon; hydrogen In methanol at 25℃; under 760.051 Torr; for 1h;	82%

3-azetidinecarboxylic acid (36476-78-5) + acetone (67-64-1) → 1-isopropyl-azetidine-3-carboxylic acid (959238-28-9)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen In methanol at 20℃; under 1034.32 Torr;	85%

4-(5-(4-(2-fluoroethoxy)phenyl)-1,2,4-oxadiazol-3-yl)benzaldehyde + 3-azetidinecarboxylic acid (36476-78-5) → 1-(4-(5-(4-(2-fluoroethoxy)phenyl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid

Conditions	Yield
Stage #1: 4-(5-(4-(2-fluoroethoxy)phenyl)-1,2,4-oxadiazol-3-yl)benzaldehyde; 3-azetidinecarboxylic acid With acetic acid In methanol for 0.5h; Stage #2: With sodium cyanoborohydride In methanol	85%

ethyl 6-chloro-5-cyano-2-(trifluoromethyl)nicotinate (175277-73-3) + 3-azetidinecarboxylic acid (36476-78-5) → 1-[3-cyano-5-(ethoxycarbonyl)-6-(trifluoromethyl)pyridin-2-yl]azetidine-3-carboxylic acid (919354-83-9)

Conditions	Yield
With triethylamine In ethanol for 0.333333h; Microwave irradiation;	84%
With triethylamine In ethanol for 0.333333h; Microwave irradiation;	84%

4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzaldehyde (635701-88-1) + 3-azetidinecarboxylic acid (36476-78-5) → 1-{4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidine carboxylic acid

Conditions	Yield
Stage #1: 4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzaldehyde; 3-azetidinecarboxylic acid With acetic acid In tetrahydrofuran; methanol at 20℃; for 2h; Stage #2: With sodium cyanoborohydride In tetrahydrofuran; methanol at 20℃; for 16h;	82%
Stage #1: 4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzaldehyde; 3-azetidinecarboxylic acid With acetic acid In methanol at 20℃; for 0.333333h; Stage #2: With sodium cyanoborohydride In methanol for 1h;	74%
Stage #1: 4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzaldehyde; 3-azetidinecarboxylic acid With acetic acid In methanol at 20℃; for 0.333333h; Stage #2: With sodium cyanoborohydride In methanol for 1h;	74%
Stage #1: 4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzaldehyde; 3-azetidinecarboxylic acid With acetic acid In methanol at 20℃; for 0.333333h; Stage #2: With sodium cyanoborohydride In methanol for 1h;	74%

N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1396776-39-8) + 3-azetidinecarboxylic acid (36476-78-5) → 6-(1-(azetidine-3-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1396772-06-7)

Conditions	Yield
Stage #1: N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide; 3-azetidinecarboxylic acid With triethylamine In dimethyl sulfoxide at 20℃; for 0.25h; Stage #2: With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate In dimethyl sulfoxide	81.9%

Upstream product

• 36476-87-6 1-benzhydrylazetidine-3-carboxylic acid 
• 97628-91-6 1-acetylazetidine-3-carboxylic acid 
• 142253-55-2 1-(t-butyloxycarbonyl)-azetidine-3-carboxylic acid 
• 26096-30-0 N-benzyl-3,3-bis-(hydroxymethyl)-azetidine 
• 87-69-4 tartaric acid 
• 94985-27-0 N-benzyl azetidine-3-carboxylic acid 

Downstream Products

• 635701-59-6 1-{4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidine carboxylic acid 
• 100202-39-9 methyl 3-azetidinecarboxylate hydrochloride 
• 1236144-55-0 1-(4-cyanobenzyl)azetidine-3-carboxylic acid 
• 97628-92-7 1-benzyloxycarbonyl-3-azetidinecarboxylic acid 
• 1236148-58-5 1-(4-(5-(1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid 

Relevant articles and documents

A practical process for the preparation of azetidine-3-carboxylic acid

A practical and convenient synthesis of azetidine-3-carboxylic acid (1) that proceeded in 55% overall yield from commercially available diethylbis(hydroxymethyl)malonate (3) is reported. Azetidine ring-formation was achieved in high yield by cyclization of bistrifiate of the diol (3) and benzylamine. Decarboxylation under carefully pH-controlled conditions gave the mono acid azetidine that was hydrogenated to give the title compound.

Production methods of nitrogen heterocyclic carboxylic acid intermediate and 3-azetidine carboxylic acid

The invention discloses production methods of a nitrogen heterocyclic carboxylic acid intermediate and 3-azetidine carboxylic acid, and relates to the technical field of pharmaceutical and chemical industry. The production method of the nitrogen heterocyclic carboxylic acid intermediate used for producing the 3-azetidine carboxylic acid comprises the steps of mixing a nitrogen heterocyclic compound and a Wittig reaction agent, carrying out a Wittig reaction, and conducting separation to obtain a nitrogen heterocyclic formaldehyde intermediate; and subjecting the nitrogen heterocyclic formaldehyde intermediate to an oxidation reaction, and conducting separation to obtain the nitrogen heterocyclic carboxylic acid intermediate, wherein the nitrogen heterocyclic compound is selected from at least one of 1-benzhydrylazetidin-3-one, 1-benzylazetidin-3-one, 1-Boc-3-azetidinone and 1-acetylazetidin-3-one. According to the production method of the 3-azetidine carboxylic acid, the nitrogen heterocyclic carboxylic acid intermediate is subjected to hydrogenolysis, a production cycle is short, a production process is safe and reliable, the production cost is low, the purity is higher than 98%,and the yield can reach 82.8%.

Catalytic hydrogenolysis

Preparation of azetidine-3-carboxylic acid or a salt thereof from N-benzylazetidine-3-carboxylic acid or a salt thereof by catalytically hydrogenating the N-benzylazetidine-3-carboxylic compound in the presence of water, formate ions, and ammonium and/or alkylammonium ions. Novel ammonium and alkylammonium salts are claimed.