Benzhydrylamine → Benzyl N-diphenylmethyl-2-azetidinecarboxylate

HRID 367046Notes

Reaction equation

HRID 367046 reaction equation
[CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](=[O:18])([O-])[O-:16].[K+].[K+]>C(O)C>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:14]2[CH2:13][CH2:8][CH:9]2[C:15]([O:16][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:18])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

4

Reactant 2

HCID 7036BenzhydrylamineHCID 11430Potassium Carbonate

Product 1

HCID 323845Benzyl N-diphenylmethyl-2-azetidinecarboxylateYield 52%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

An alternative to the procedures of Examples 1b-1c, (R)-1-t-butyloxycarbonyl-2-azetidinemethanol was prepared from γ-butyrolactone according to the procedure of Rodebaugh, R. M. and Cromwell, N. H., (J. Heterocyclic Chem., 1969, 435). In this literature procedure, γ-butyrolactone was treated with bromine and catalytic phosphorus tribromide, then subsequently with benzyl alcohol and gaseous hydrogen chloride to afford benzyl α,γ-dibromobutyrate in 62% yield. This dibromide in ethanol was treated with one equivalent of benzhydrylamine and potassium carbonate at reflux for about 16 hours to afford benzyl N-diphenylmethylazetidine-2-carboxylate in 52% yield. Hydrogenolysis in MeOH over Pd(OH)2 afforded racemic azetidine-2-carboxylic acid in 62% yield. Following the procedure of Rodebaugh, R. M. and Cromwell, N. H., (J. Heterocyclic Chem., 1969, 993), racemic azetidine-2-carboxylic acid was converted to the N-Cbz derivative by treatment with benzyl chloroformate in aqueous NaOH at 0-5° C. Following isolation in quantitative yield, the Cbz derivative in methanol was treated with one equivalent of L-tyrosine hydrazide to precipitate the tyrosine hydrazide salt of (R)-azetidine-2-carboxylic acid in 77-87% yield. (R)-1-Cbz-azetidine-2-carboxylic acid was liberated from the salt by normal extractive procedures. Hydrogenolysis of the free acid by treatment of a methanol solution with hydrogen gas at 4 atm in the presence of 10% Pd/C for 19 h afforded (R)-azetidine-2-carboxylic acid, which was isolated in 88% yield by trituration with methanol. This product was treated with di-tert -butyl dicarbonate and N-methylmorpholine in dioxane/H2O (1:1) to afford (R)-1-Boc-azetidine-2-carboxylic acid in quantitative yield. Treatment of a THF solution of (R)-1-Boc-azetidine-2-carboxylic acid with borane-methyl sulfide complex for 16 h at ambient temperature afforded the title compound in 92% yield.

Workup

  1. temperatureat reflux for about 16 hours

Sources & evidence

ORD record
ord-d8d3764d673b4e3ebbeefd0cd7296559
Source dataset
uspto-grants-2000_10
Patent number
US06133253

Reaction notes

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