36476-78-5

Usage

Uses

Used in Pharmaceutical and Agrochemical Research:
3-Azetidinecarboxylic acid is used as a valuable compound in pharmaceutical and agrochemical research, contributing to the development of new drugs and agrochemicals.
Used in Synthesis of Polypeptides:
3-Azetidinecarboxylic acid is used as an intermediate in the synthesis of polypeptides, which are essential for various biological functions and have potential applications in drug development.
Used in Chemical Hybridization:
3-Azetidinecarboxylic acid is used as a chemical hybridizing agent, allowing for the creation of new compounds with unique properties and potential applications.
Used in the Production of Oxadiazoles:
3-Azetidinecarboxylic acid provides oxadiazoles in good yields, which are important compounds in various chemical and pharmaceutical applications.

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

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

Downstream Products

• 1309208-82-9 1-(azetidin-3-yl)ethan-1-one 
• 97628-92-7 1-benzyloxycarbonyl-3-azetidinecarboxylic acid 
• 635701-59-6 1-{4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl}-3-azetidine carboxylic acid 

Relevant academic research and scientific papers

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.

Method for synthesizing azetidine -3 - formic acid

The invention relates to the field of organic synthesis and particularly relates to a synthetic method of azetidine-3-formic acid. The synthetic method comprises the following steps of adopting 2,2-bis(hydroxymethyl)malonic acid-1,3-diethyl ester to react with benzhydrylamine after protection of methylsulfonyl chloride, and then by decarboxylation and diphenylmethyl-removing protection, obtaininga final product, namely the azetidine-3-formic acid. The synthetic method has the advantages that the 2,2-bis(hydroxymethyl)malonic acid-1,3-diethyl ester is adopted as a raw material, and is cheap and easy to obtain; compared with the original synthesis route, the cost of the whole synthesis route is reduced by 30% or more, and a highly-toxic substance (sodium cyanide) is not adopted, so that theindustrial production prospect is great.

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%.

PROCESS FOR MAKING AZETIDINE-3-CARBOXYLIC ACID

The present invention is directed to an improved process for synthesizing azetidine-3-carboxylic acid, comprising triflating diethylbis(hydroxymethyl)malonate followed by azetidine ring-formation by intramolecular cyclization using an amine, decarboxylation to give the mono acid azetidine and hydrogenation to give the title compound. Azetidine-3-carboxylic acid is useful as an intermediate for making certain S1P?1#191/Edg1 receptor agonists, which are immunosupressive agents.

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.

Azetidine-3-carboxylic acid derivatives

The novel ester, N-benzylazetidine-3-carboxylic acid methyl ester and its use in the preparation of the corresponding free acid by a process which comprises reacting N-benzyl-3-cyanozetidine with methanol and hydrolyzing the resulting methyl ester with hot water.

Process for preparing azetidine derivatives; and intermediates therein

Process for the preparation of a compound of formula or a salt thereof STR1 wherein R1 represents a hydrogen atom or a group of formula R2 SO2 or phenyl--CH(R3)--wherein R2 represents a phenyl, tolyl or C1-4 alkyl group and R3 represents a hydrogen atom or a phenyl of C1-4 alkyl group, which process comprises contacting nickel in an oxidation state of at least 3 with a 3-hydroxymethyl azetidine derivative of formula STR2 wherein R4 represents a group of formula R2 SO2 or phenyl--CH(R3)--and R5 represents a hydrogen atom or a hydroxymethyl group or a group of formula COOH or a salt thereof, followed, where R5 is not a hydrogen atom, by the decarboxylation of the compound of the 3,3-dicarboxylic intermediate product or a salt thereof and, if desired to produce a compound in which R1 represents a hydrogen atom, by deprotection of the N-atom. Also, novel N-substituted azetidine carboxylate derivatives of the formula STR3 wherein X represents a group CH2 OH or COOY where Y represents a hydrogen or an alkali or alkaline earth metal atom.

Method for sterilizing male parts of plants

3-Carboxyazetidine or a hydrate, salt or lower alkyl ester thereof is used to sterilize male parts of plants.

Process for preparing azetidine derivatives and intermediates thereof

The invention provides a process for preparing azetidine-3-carboxylic acid or salts thereof; useful as chemical hybridizing agents, which comprises treating a compound of the formula STR1 wherein R represents a hydrogen atom or a group of formula R1 R2 CH-- wherein R1 and R2 are independently selected from hydrogen, alkyl or optionally substituted phenyl moieties, with nitric acid and subjecting the resulting initial product to acid conditions to produce an acid-addition salt of azetidine-3-carboxylic acid, and thereafter, if desired, converting the acid-addition salt to the free acid or another salt of the acid, 1-nitrosoazetidine-3,3-dicarboxylic acid, 1-nitrosoazetidine-3-carboxylic acid and salts thereof being intermediates in the process.

Preparation of 1-benzylazetidine-3-ol derivatives

A process for the preparation of 1-substituted azetidin-3-ol derivatives of the formula: STR1 in which R1 represents a hydrogen atom or an alkyl, aryl or aralkyl group in which the alkyl moiety contains up to eight carbon atoms, by cyclizing a solution in triethylamine of an aminoalcohol of the formula: STR2 in which Hal represents a halogen atom and the use of such derivatives as intermediates for the preparation of azetidine-3-carboxylic acid derivatives.