40320-60-3

Basic information

• Product Name: 1-BENZHYDRYLAZETIDIN-3-ONE
• Synonyms: 1-BENZHYDRYLAZETIDIN-3-ONE;1-Benzhydrylazetidin-3-one 95%;3-BENZHYDRYL-CYCLOBUTANONE;1-(DIPHENYLMETHYL)AZETIDIN-3-ONE;1-benzhdrylazetidin-3-one;1-Diphenylmethyl-3-azetidinone;1-(1,1-Diphenylmethyl)azetidin-3-one;1-Diphenylmethyl-3-azetid...
• CAS NO: 40320-60-3
• Molecular Formula: C₁₆H₁₅NO
• Molecular Weight: 237.3
• Product Categories: Ring Systems;Amines;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 40320-60-3.mol
• Article Data: 43

Chemical Properties

• Melting Point: 75.0 to 79.0 °C
• Boiling Point: 350-355℃
• Flash Point: 156°(313°F)
• Appearance: /
• Density: 1.182
• Vapor Pressure: 3.99E-05mmHg at 25°C
• Refractive Index: 1.626
• Storage Temp.: Sealed in dry,Room Temperature
• PKA: 3.10±0.20(Predicted)
• CAS DataBase Reference: 1-BENZHYDRYLAZETIDIN-3-ONE(CAS DataBase Reference)
• NIST Chemistry Reference: 1-BENZHYDRYLAZETIDIN-3-ONE(40320-60-3)
• EPA Substance Registry System: 1-BENZHYDRYLAZETIDIN-3-ONE(40320-60-3)

Safety Data

• Safety Statements: 24/25
• HazardClass: IRRITANT
• Hazardous Substances Data: 40320-60-3(Hazardous Substances Data)

Usage

Chemical Properties

White solid

Uses

1-Benzhydrylazetidin-3-one is used in the synthesis of azetidine derivatives as novel γ-aminobutyric acid uptake inhibitors.

InChI:InChI=1/C16H15NO/c18-15-11-17(12-15)16(13-7-3-1-4-8-13)14-9-5-2-6-10-14/h1-10,16H,11-12H2

Synthetic route

1-(diphenylmethyl)-3-hydroxyazetidine (18621-17-5) → N-benzhydryl 3-azetidinone (40320-60-3)

Conditions	Yield
Stage #1: 1-(diphenylmethyl)-3-hydroxyazetidine With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 1h; Stage #2: With triethylamine In dichloromethane	96%
With oxalyl dichloride; dimethyl sulfoxide at -78℃; Swern oxidation;	93%
With sulfur trioxide pyridine complex; triethylamine In dimethyl sulfoxide at 10 - 30℃;	92.4%

sulphur trioxide pyridine + 1-(diphenylmethyl)-3-hydroxyazetidine (18621-17-5) → N-benzhydryl 3-azetidinone (40320-60-3)

Conditions	Yield
With triethylamine In dimethyl sulfoxide	89%

1-(diphenylmethyl)-3-azetidinol hydrochloride (90604-02-7) → N-benzhydryl 3-azetidinone (40320-60-3)

Conditions	Yield
With sulfur trioxide pyridine complex; triethylamine In dimethyl sulfoxide at 0 - 20℃;	82%
With sulfur trioxide pyridine complex; triethylamine In tetrahydrofuran; dimethyl sulfoxide at 0 - 20℃; for 2h;	67%
With sulfur trioxide pyridine complex; triethylamine In dimethylsulfoxide-d6 for 2h;	66%

pyridine-2-sulfonic acid (15103-48-7) + 1-(diphenylmethyl)-3-hydroxyazetidine (18621-17-5) → N-benzhydryl 3-azetidinone (40320-60-3)

Conditions	Yield
With triethylamine In dimethyl sulfoxide at 50℃; for 0.666667h;	60%

aminodiphenylmethane hydrochloride (5267-34-5) → N-benzhydryl 3-azetidinone (40320-60-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: NaOH / H2O; CH2Cl2 / 12 h / 20 °C 1.2: 51 percent / methanol / 72 h / 20 °C 2.1: alkaline aq. solution; CH2Cl2 / 1 h / 20 °C 2.2: 50 percent / SO3*pyridine; TEA / dimethylsulfoxide / 2 h / 20 °C View Scheme

Benzhydrylamine (91-00-9) → N-benzhydryl 3-azetidinone (40320-60-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 2.) 1 N NaOH / 1.) a) RT, 3 d, b) reflux, 72 h, 2.) Et2O 2: 67 percent / pyridine, phosphoric acid, dicyclohexylcarbodiimide, DMSO / CH2Cl2 / 2 h / Ambient temperature View Scheme

1-benzhydryl-3-hydroxy-azetidine-3-carbonitrile (686347-59-1) → N-benzhydryl 3-azetidinone (40320-60-3)

Conditions	Yield
With sodium hydroxide; dihydrogen peroxide; dimethyl sulfoxide In methanol; water at 45℃; for 0.166667h; Product distribution / selectivity;

oxalyl dichloride (79-37-8) + 1-(diphenylmethyl)-3-azetidinol hydrochloride (90604-02-7) → N-benzhydryl 3-azetidinone (40320-60-3)

Conditions	Yield
With triethylamine In dichloromethane; dimethyl sulfoxide; ethyl acetate

N-benzhydryl 3-azetidinone (40320-60-3) + chloroformic acid ethyl ester (541-41-3) → 3-oxo-azetidine-1-carboxylic acid ethyl ester (105258-88-6)

Conditions	Yield
In benzene Heating;	100%

isonipecotic acid (498-94-2) + N-benzhydryl 3-azetidinone (40320-60-3) → 1-[1-(diphenylmethyl)azetidin-3-yl]piperidine-4-carboxylic acid (874800-95-0)

Conditions	Yield
With methanol; polymer-bound trimethyl ammonium cyanoborohydride; acetic acid at 120℃; for 0.0833333h; Polystyrene; Microwave irradiation;	100%

methyl magnesium iodide (917-64-6) + N-benzhydryl 3-azetidinone (40320-60-3) → 1-benzhydryl-3-methylazetidin-3-ol (40320-63-6)

Conditions	Yield
In tetrahydrofuran; diethyl ether at 0℃; for 1h;	100%
Stage #1: methyl magnesium iodide; N-benzhydryl 3-azetidinone In diethyl ether at 0℃; for 1h; Grignard Reaction; Stage #2: With methanol In diethyl ether; dichloromethane	68%

(2,8-bis-trifluoromethyl)-4-bromoquinoline (35853-45-3) + N-benzhydryl 3-azetidinone (40320-60-3) → 3-(2,8-bis(trifluoromethyl)-4-quinolinyl)-1-diphenylmethyl-3-azetidinol (260972-91-6)

Conditions	Yield
With n-butyllithium In water	100%

potassium cyanide + N-benzhydryl 3-azetidinone (40320-60-3) + methylamine hydrochloride (593-51-1) → 1-Benzhydryl-3-methylaminoazetidine-3-carbonitrile

Conditions	Yield
Stage #1: N-benzhydryl 3-azetidinone; methylamine hydrochloride With acetic acid In methanol at 20℃; for 0.0833333h; Stage #2: potassium cyanide at 60℃; for 19h;	100%
Stage #1: N-benzhydryl 3-azetidinone; methylamine hydrochloride With acetic acid In methanol at 20℃; for 0.0833333h; Stage #2: potassium cyanide at 60℃; for 19h;	100%
Stage #1: N-benzhydryl 3-azetidinone; methylamine hydrochloride With acetic acid In methanol at 20℃; for 0.0833333h; Stage #2: potassium cyanide In methanol at 60℃; for 19h;	100%

potassium cyanide + N-benzhydryl 3-azetidinone (40320-60-3) + dimethyl amine (124-40-3) → 1-Benzhydryl-3-dimethylaminoazetidine-3-carbonitrile (736994-11-9)

Conditions	Yield
Stage #1: N-benzhydryl 3-azetidinone; dimethyl amine In tetrahydrofuran for 0.0833333h; Stage #2: potassium cyanide With acetic acid In methanol at 20 - 60℃; for 19.0833h;	100%
Stage #1: N-benzhydryl 3-azetidinone; dimethyl amine In tetrahydrofuran for 0.0833333h; Stage #2: potassium cyanide With acetic acid In tetrahydrofuran; methanol at 60℃; for 19h;	100%

potassium cyanide + N-benzhydryl 3-azetidinone (40320-60-3) + N,N-diethylaniline (91-66-7) → 1-Benzhydryl-3-methylaminoazetidine-3-carbonitrile

Conditions	Yield
Stage #1: N-benzhydryl 3-azetidinone; N,N-diethylaniline With acetic acid In methanol at 20℃; for 0.0833333h; Stage #2: potassium cyanide In methanol at 60℃; for 19h;	100%

potassium cyanide + N-benzhydryl 3-azetidinone (40320-60-3) + ethanamine hydrochloride (557-66-4) → 1-benzhydryl-3-ethylamino-azetidine-3-carbonitrile (686344-60-5)

Conditions	Yield
Stage #1: N-benzhydryl 3-azetidinone; ethanamine hydrochloride With acetic acid In methanol at 20℃; for 0.25h; Stage #2: potassium cyanide In methanol at 60℃;	100%

N-benzhydryl 3-azetidinone (40320-60-3) + benzyltriphenylphosphonium bromide (1449-46-3) → 3-benzylidene-1-(diphenylmethyl)azetidine (897019-45-3)

Conditions	Yield
Stage #1: benzyltriphenylphosphonium bromide With potassium tert-butylate In dimethyl sulfoxide at 20℃; for 0.166667h; Stage #2: N-benzhydryl 3-azetidinone In dimethyl sulfoxide at 60℃;	100%

N-benzhydryl 3-azetidinone (40320-60-3) + (S)-1-amino-2-(methoxymethyl)pyrrolidine (59983-39-0) → C22H27N3O

Conditions	Yield
at 90℃; for 16h;	100%

N-benzhydryl 3-azetidinone (40320-60-3) → N-benzhydryl-3-(hydroxyimino)azetidine (40569-56-0)

Conditions	Yield
With sodium hydroxide; hydroxylamine hydrochloride In ethanol Heating;	99%
With hydroxylamine hydrochloride; sodium carbonate In water at 40℃; for 5h;
With hydroxylamine hydrochloride; sodium acetate In methanol Reflux;
With hydroxylamine hydrochloride; sodium carbonate In water at 40℃; pH=7 - 8;

4-carboxamidopiperidine (39546-32-2) + N-benzhydryl 3-azetidinone (40320-60-3) → 1-[1-(diphenylmethyl)azetidin-3-yl]piperidine-4-carboxamide (957054-82-9)

Conditions	Yield
With methanol; polymer-bound trimethyl ammonium cyanoborohydride; acetic acid at 120℃; for 0.0833333h; Polystyrene; Microwave irradiation;	99%

N-benzhydryl 3-azetidinone (40320-60-3) + methyl trifluoromethanesulfonate (333-27-7) → 1-(Diphenylmethyl)-1-methyl-3-oxoazetidinium trifluoromethanesulfonate

Conditions	Yield
In dichloromethane at 20℃;	98%

N-benzhydryl 3-azetidinone (40320-60-3) + methyl chloroformate (79-22-1) → methyl 3-oxoazetidine-1-carboxylate

Conditions	Yield
In dichloromethane for 15h; Heating;	97%

N-benzhydryl 3-azetidinone (40320-60-3) + 3-butene-1-amine (2524-49-4) + 2-Allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (72824-04-5) → (3-allyl-1-benzhydryl-azetidin-3-yl)-but-3-enyl-amine

Conditions	Yield
With 4A MS In toluene at 80℃;	96%

N-benzhydryl 3-azetidinone (40320-60-3) + methylmagnesium chloride (676-58-4) → 1-benzhydryl-3-methylazetidin-3-ol (40320-63-6)

Conditions	Yield
Stage #1: N-benzhydryl 3-azetidinone; methylmagnesium chloride In tetrahydrofuran at 0 - 20℃; for 1.83333h; Stage #2: With water; ammonium chloride In tetrahydrofuran; ethyl acetate	96%

N-benzhydryl 3-azetidinone (40320-60-3) → C16H16N2O*ClH (1375075-83-4)

Conditions	Yield
With hydroxylamine hydrochloride	96%

N-benzhydryl 3-azetidinone (40320-60-3) + t-butoxycarbonylhydrazine (870-46-2) → tert-butyl 2-[1-(diphenylmethyl)azetidin-3-ylidene]hydrazinecarboxylate (1025713-55-6)

Conditions	Yield
With acetic acid In methanol at 0℃; for 16h;	94%
With acetic acid In methanol for 18h;	82%
With acetic acid In methanol at 20℃;	30%

N-benzhydryl 3-azetidinone (40320-60-3) + (S)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (147081-29-6) → tert-butyl (3S)-4-(1-(diphenylmethyl)azetidin-3-yl)-3-methylpiperazine-1-carboxylate

Conditions	Yield
Stage #1: N-benzhydryl 3-azetidinone; (S)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester With acetic acid In tetrahydrofuran at 20℃; for 1.66667h; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 13.75h;	93%

N-benzhydryl 3-azetidinone (40320-60-3) + 2-((difluoromethyl)sulfinyl)pyridine (1219454-89-3) → 1-benzhydryl-3-(difluoro(pyridin-2-ylsulfonyl)methyl)azetidin-3-ol

Conditions	Yield
With lithium hexamethyldisilazane In tetrahydrofuran; N,N,N,N,N,N-hexamethylphosphoric triamide; hexane at -98℃; for 0.5h; Schlenk technique; Inert atmosphere;	93%

N-benzhydryl 3-azetidinone (40320-60-3) + methylmagnesium bromide (75-16-1) → 1-benzhydryl-3-methylazetidin-3-ol (40320-63-6)

Conditions	Yield
In tetrahydrofuran at -78 - 20℃;	92%
In tetrahydrofuran; diethyl ether at 0℃; for 2h;	89%
In tetrahydrofuran at 0 - 20℃; for 2.33333h;	84%

N-benzhydryl 3-azetidinone (40320-60-3) + dimethyl amine (124-40-3) → 3-(dimethylamino)-1-(diphenylmethyl)azetidine (55438-79-4)

Conditions	Yield
With hydrogen; 5% palladium over charcoal In methanol; water	92%
With hydrogen; 5% palladium over charcoal In methanol	92%
With hydrogen; 5%-palladium/activated carbon In methanol; water	92%

N-benzhydryl 3-azetidinone (40320-60-3) + dimethyl 2,2-di(but-2-yn-1-yl)malonate (107428-05-7) → (1Z,6Z)-dimethyl 3-benzhydryl-1,6-dimethyl-5-oxo-4,5,7,9-tetrahydro-2H-cyclopenta[d]azocine-8,8(3H)-dicarboxylate

Conditions	Yield
With bis(1,5-cyclooctadiene)nickel(0); 1,3-bis(2,6-diisopropylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene In toluene at 0℃; for 8h; Inert atmosphere;	92%

N-benzhydryl 3-azetidinone (40320-60-3) + trimethylsilyl cyanide (7677-24-9) → 1-(diphenylmethyl)-3-[(trimethylsilyl)oxy]azetidine-3-carbonitrile (151097-25-5)

Conditions	Yield
With triethylamine In dichloromethane at 20℃; for 2h;	91%
With triethylamine In dichloromethane at 20℃; for 2h;	91%
With triethylamine In dichloromethane at 20℃; for 2h;	91%

N-benzhydryl 3-azetidinone (40320-60-3) + 1-(but-2-yn-1-yloxy)but-2-yne (55833-53-9) → (3aE,9E)-6-benzhydryl-4,9-dimethyl-3,5,6,7-tetrahydrofuro[3,4-d]azocin-8(1H)-one

Conditions	Yield
With bis(1,5-cyclooctadiene)nickel(0); 1,3-bis(2,6-diisopropylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene In toluene at 0℃; for 8h; Inert atmosphere;	91%

N-benzhydryl 3-azetidinone (40320-60-3) + (R)-tert-butyl 2-methylpiperazine-1-carboxylate (170033-47-3) → tert-butyl (2R)-4-(1-(diphenylmethyl)azetidin-3-yl)-2-methylpiperazine-1-carboxylate

Conditions	Yield
Stage #1: N-benzhydryl 3-azetidinone; (R)-tert-butyl 2-methylpiperazine-1-carboxylate With acetic acid In tetrahydrofuran at 20℃; for 0.416667h; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 18.5h;	90%

N-benzhydryl 3-azetidinone (40320-60-3) + phenylacetylene (536-74-3) → C24H21NO

Conditions	Yield
Stage #1: phenylacetylene With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1h; Inert atmosphere; Stage #2: N-benzhydryl 3-azetidinone In tetrahydrofuran; hexane at -78℃; for 1h; Inert atmosphere;	90%

4-ethylpiperazine (5308-25-8) + N-benzhydryl 3-azetidinone (40320-60-3) → 1-(1-(diphenylmethyl)azetidin-3-yl)-4-ethylpiperazine

Conditions	Yield
Stage #1: 4-ethylpiperazine; N-benzhydryl 3-azetidinone With acetic acid In tetrahydrofuran at 20℃; for 0.75h; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 15h;	89%
Stage #1: 4-ethylpiperazine; N-benzhydryl 3-azetidinone With acetic acid In tetrahydrofuran at 20℃; for 0.75h; Stage #2: With sodium tris(acetoxy)borohydride at 20℃; for 15h;	89%

Upstream product

• 18621-17-5 1-(diphenylmethyl)-3-hydroxyazetidine 
• 79-37-8 oxalyl dichloride 
• 90604-02-7 1-(diphenylmethyl)-3-azetidinol hydrochloride 
• 15103-48-7 pyridine-2-sulfonic acid 
• 686347-59-1 1-benzhydryl-3-hydroxy-azetidine-3-carbonitrile 
• 5267-34-5 aminodiphenylmethane hydrochloride 
• 91-00-9 Benzhydrylamine 

Downstream Products

• 118972-98-8 methyl 3-oxoazetidine-1-carboxylate 
• 40320-63-6 1-benzhydryl-3-methylazetidin-3-ol 
• 61890-01-5 methyl 2-[1-(diphenylmethyl)azetidin-3-ylidene]acetate 
• 928038-35-1 3-(azetidin-1-yl)-1-benzhydrylazetidine 
• 686344-61-6 1-benzhydryl-3-ethylamino-azetidine-3-carboxylic acid amide 
• 617718-45-3 1-benzhydryl-3-fluoroazetidine 
• 261924-27-0 1-benzhydryl-3-[(3,5-difluorophenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-ol 
• 261924-08-7 1-benzhydryl-3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol 
• 261924-16-7 1-benzhydryl-3-[(3,5-dichlorophenyl)(methylsulfonyl)-methyl-(RS)]azetidin-3-ol 

Relevant articles and documents

A convenient method for the preparation of 3-azetidinylidene acetic acid

A facile route to novel 3-azetidinylidene acetic acid from commercially available epichlorohydrin is described.

Preparation method of tert-butyl-5-(hydroxymethyl)-7-oxa-2-azaspiro[3.5]nonane-2-formate

The invention relates to a preparation method of tert-butyl-5-(hydroxymethyl)-7-oxa-2-azaspiro[3.5]nonane-2-formate, and mainly solves the technical problem that no proper industrial synthesis methodexists at present. The product is synthesized by six steps, and the preparation method comprises the steps: a first step, a compound 1 is subjected to Swern oxidation reaction to generate a compound 2; a second step, a compound 3 is obtained through a Horner-Wadsworth-Emmons reaction; a third step, a compound 4 is obtained through Michael addition; a fourth step, a compound 5 is obtained through reduction of the compound 4 with lithium tetrahydroaluminum; a fifth step, the compound 5 is dehydrated and retained with a ring to obtain a compound 6 under the action of sodium hydrogen; and a sixthstep, hydrogenation is preformed to remove a protective group, and then a protective group is added to obtain the target compound 7. The obtained compound is a useful intermediate or product for synthesis of many drugs.

1-diphenylmethylazetidine-3-ketone synthesis process method

The invention discloses a 1-diphenylmethylazetidine-3-ketone synthesis process method, which comprises: using 1-diphenylmethyl-3-hydroxy azetidine as a raw material, dissolving in DMSO, adding triethylamine, cooling to a temperature of 0-10 DEGC, adding pyridine sulfur trioxide in batches, carrying out a stirring reaction for 2 h at a room temperature, detecting the reaction through TLC until the reaction is completely performed, slowly adding ice water, completely stirring, adding ethyl acetate, extracting three times, combining the three collected organic phases, washing three times with 1/3 volume of saturated edible salt water, drying with anhydrous sodium sulfate, filtering, carrying out pressure reducing organic solvent removing on the filtrate to obtain a residual oil-like material, adding petroleum ether having the volume 5 times the volume of the residual oil-like material, beating, precipitating a yellow solid, filtering, and collecting the solid to obtain the 1-diphenylmethylazetidine-3-ketone. According to the present invention, compared to the traditional swern oxidation, the method of the present invention has advantages of simple operation and less feeding variety; compared to the final product purification methods in the similar literatures in the prior art, the method of the present invention is simple and is suitable for enlargement production; and the process method has advantages of low solvent consumption, emission reducing, and cost saving.