Formic Acid → 4-(Isopropylamino)piperidine-4-carboxamide

Participants

Reaction Steps

A mixture of the 1-benzyl-4-isopropylamino-4-piperidinecarboxamide (250 mg, 0.91 mmol) (commercially available from Aldrich Chemical, Milwaukee, Wis.), 10% palladium on charcoal (30% by weight, 81 mg) and formic acid (5 mmol) in methanol (4 ml) was stirred vigorously overnight at room temperature. The reaction mixture was filtered through a celite pad and concentrated in vacuo to provide the product 4-carbamoyl-4-(isopropylamino)piperidine (191 mg, 90%) as a formic acid salt. A mixture of the chloride I-1f (100 mg, 0.28 mmol), 4-carbamoyl-4-(isopropylamino)-piperidine (85 mg, 0.306 mmol) and triethylamine (0.13 ml, 0.92 mmol) in dry ethanol (2 ml) was refluxed for 3 hrs. The reaction mixture was cooled to room temperature and water was added to precipitate out solids. The filtrate was acidified and washed with ethyl acetate to remove impurities. The aqueous layer was basified with 1 N NaOH and extracted with dichloromethane, dried and concentrated to give crude solid. This was combined with the filtered solids and purified using short plug silica gel with 10% MeOH:EtOAc as eluant to provide the desired product 1A-1 (46 mg, 30%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 8.78 (s, 1H), 7.68–7.41 (m, 6H), 7.19–7.14 (t, 2H), 4.42 (br d, 2H), 4.16–4.13 (br t, 2H), 2.95–2.92 (m, 1H), 2.17–2.12 (m, 2H), 1.83–1.80 (br d, 2H), 1.10 (d, 6H); MS (m/z): 524.5 (M+H); Ret time (RT): 1.7 min.

Provenance & Evidence