Formamide → 4-Azetidin-1-yl-3-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester

HRID 2066503Notes

Reaction equation

C[O:2][C:3]([CH:5]1[CH:10]([N:11]2[CH2:14][CH2:13][CH2:12]2)[CH2:9][CH2:8][N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6]1)=O.C([NH2:24])=O.C[O-].[Na+].CO>CN(C=O)C>[C:18]([O:17][C:15]([N:7]1[CH2:8][CH2:9][CH:10]([N:11]2[CH2:14][CH2:13][CH2:12]2)[CH:5]([C:3](=[O:2])[NH2:24])[CH2:6]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]

Participants

Conditions

Temperature: 100 °C

Procedure

To a solution of 4-azetidin-1-yl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (0.66 g. 2.21 mmol) in anhydrous DMF (13 mL) was added formamide (370 μL, 9.32 mmol). The mixture was heated to 100° C. and a solution of sodium methoxide in MeOH (25 w/w. 330 μL, 1.44 mmol) was added with heating being continued for 2 h. The reaction mixture was cooled to RT, then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH then eluted with 2 M NH3 in MeOH to give 4-azetidin-1-yl-3-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester. To a solution of 4-azetidin-1-yl-3-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester in DCM (40 mL) was added TFA (5 mL) and the resulting mixture was stirred at RT for 1 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to give a 1:1 cis:trans mixture of the title compound as a colourless oil (280 mg, 69%).

Workup

temperaturewith heating
temperatureThe reaction mixture was cooled to RT
washThe cartridge was washed with MeOH
washthen eluted with 2 M NH3 in MeOH

Sources & evidence

ORD record: ord-f56a223634cf4f86bd4ab2b447c3831d
Source dataset: uspto-grants-2012_10
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08293735B2

Reaction notes

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