Hydrochloric Acid → HCID 68509182, compound

Participants

Reaction Conditions

Reaction Steps

To a solution of 4-(4-allyloxycarbonyl-2-amino-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (50.0 g, 133.17 mmol, 1.0 equiv; example 1/step 4) in methanol (400 mL) was added conc. HCl (27.7 mL, 266.33 mmol, 2.0 equiv) and the reaction mixture stirred at 0° C. for 2 h. Another portion of conc. HCl (27.7 mL, 266.33 mmol, 2.0 equiv) was added and stirring was continued for an additional time period of 3 h. The reaction mixture was cooled to 0° C., diluted with water (25 mL), treated with a sat. solution of NaNO2 (10.11 g, 146.48 mmol, 1.1 equiv) and stirred at rt for 30 min. The reaction mixture was cooled to 0° C., basified by addition of a sat. solution of NaHCO3, concentrated by evaporation under reduced pressure and the aqueous phase extracted with ethyl acetate (3×150 mL). The organic solvents were to a large extent evaporated under reduced pressure and the aqueous layer was extracted with ethyl acetate (3×150 ml). The organic phase was washed with water, dried over Na2SO4 and evaporated under reduced pressure. The residue which was a mixture of the desired product and the de-boc analogue was treated with di-tert-butyl dicarbonate (29.06 g, 133.17 mmol, 1.0 equiv) and N-ethyl-diisopropylamine (20.65 g, 159.80 mmol, 1.2 equiv) in dichloromethane (200 mL). The solvent was evaporated under reduced pressure, water was added and the reaction mixture extracted with ethyl acetate (3×100 mL). The organic layer was washed with water, dried over Na2SO4 and evaporated under reduced pressure. The crude material was purified with silica column chromatography eluting with a gradient of hexane/ethyl acetate (9:1→4:1) to obtain 37.1 g (72%) of the title compound. 1H NMR (400 MHz, DMSO): δ 1.44 (s, 9H), 2.02-2.16 (m, 4H), 3.05 (br s, 2H), 4.12-4.15 (m, 2H), 4.87 (d, J=5.2 Hz, 2H), 5.16-5.22 (m, 1H), 5.30 (d, J=10.7, 1H), 5.45 (dd, J=17.2 Hz, J=1.0 Hz, 1H), 6.06-6.13 (m, 1H), 8.08-8.15 (m, 2H), 8.68 (s, 1H). 13C-NMR (100 MHz, DMSO): δ 28.91, 32.21, 56.66, 66.25, 79.82, 112.04, 118.86, 122.44, 126.56, 128.09, 133.42, 135.42, 145.66, 154.72, 165.86. MS (ISP): 387.3 [M+H]+.

Provenance & Evidence