Dimethylformamide → 5-(5-(tert-Butoxycarbonyl)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-4-cyclobutyl-2-methylbenzoic acid

HRID 541436Notes

Reaction equation

[CH:1]1([C:5]2[C:13](C=O)=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:16])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Br[CH:18]1[C:23](=O)[CH2:22][CH2:21][N:20]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19]1.[OH-].[NH4+:33].C[N:35]([CH3:38])C=O>C(OCC)(=O)C>[C:28]([O:27][C:25]([N:20]1[CH2:21][CH2:22][C:23]2[N:33]=[C:38]([C:13]3[C:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)=[CH:6][C:7]([CH3:16])=[C:8]([CH:12]=3)[C:9]([OH:11])=[O:10])[NH:35][C:18]=2[CH2:19]1)=[O:26])([CH3:31])([CH3:30])[CH3:29]

Participants

Conditions

Temperature: 130 °C

Procedure

To a solution of 4-cyclobutyl-5-formyl-2-methylbenzoic acid (compound 392.1, 2.00 g, 9.16 mmol, 1.00 equiv) in N,N-dimethylformamide (15 mL) were added tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (9.00 g, 16.2 mmol, 2.00 equiv), ammonium hydroxide (3.84 g, 27.4 mmol, 3.00 equiv, 25%), and NH4OAc (3.18 g, 41.3 mmol, 4.50 equiv). The resulting mixture was stirred overnight at 130° C. under nitrogen. After cooling to ambient temperature, the mixture was diluted with 50 mL of ethyl acetate, washed with 3×30 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with dichloromethane/methanol (20:1) as eluent to furnish 2.00 g (27%) of the title compound as a brown solid.

Workup

temperatureAfter cooling to ambient temperature
washwashed with 3×30 mL of brine
dry with materialdried over anhydrous sodium sulfate
concentrationconcentrated under reduced pressure
customThe residue was purified

Sources & evidence

ORD record: ord-1e1a59669d9544e7b1ac7478a833f7a2
Source dataset: uspto-grants-2014_10
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08871790B2

Reaction notes

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