Triethylamine → Piperidin-4-yl8-carbamoyl-6-(3-methoxyphenyl)-9H-carbazol-2-ylcarbamate

Participants

Reaction Conditions

Reaction Steps

To a suspension of 8-carbamoyl-6-(3-methoxyphenyl)-9H-carbazole-2-carboxylic acid (36 mg, 0.100 mmol, Example 82B) and 4 A° molecular sieves (36 mg) in 1,4-dioxane (1.5 mL) at 50° C. was added triethylamine (0.034 mL, 0.247 mmol) and diphenylphosphoryl azide (70.0 mg, 0.247 mmol). The mixture was stirred for 1.5 h and at that point tert-butyl 4-hydroxypiperidine-1-carboxylate (201 mg, 0.999 mmol) was added. The reaction mixture was stirred at 80° C. for 5 h. The reaction was cooled, diluted with ethyl acetate, and filtered. The solvent was removed from the filtrate and the Boc-protected product was isolated by preparative HPLC (100×30 mm Luna C18 column, flow rate 42 ml permin, gradient elution starting with A:B=80:20 and ending with A:B=0:100 [A=10 mM NH4OAc in 5% aqueous acetonitrile; B=10 mM NH4OAc in 95% aqueous acetonitrile] over 20 min) followed by removal of the solvents. It was treated with a mixture of DCM (6 mL) and TFA (3 mL) at rt for 2 h. The solvent was removed and the crude product was purified by preparative HPLC (100×30 mm Luna C18 column, flow rate 42 ml permin, gradient elution starting with A:B=90:10 and ending with A:B=30:70 [A=10 mM NH4OAc in 5% aqueous acetonitrile; B=10 mM NH4OAc in 95% aqueous acetonitrile] over 20 min) The HPLC fractions that contained the product were applied onto a cartridge of PHENOMENEX® Strata-X-C 33 um cation mixed-mode polymer. This was washed with methanol and product was eluted with 2 N solution of ammonia in methanol. Removal of the solvents left 29.4 mg of piperidin-4-yl 8-carbamoyl-6-(3-methoxyphenyl)-9H-carbazol-2-ylcarbamate as a solid. MS (ESI) m/z 459.2 (M+H). 1H NMR (MeOD) δ ppm 8.40 (1H, s), 8.11 (1H, s), 8.04 (1H, d, J=8.55 Hz), 7.88 (1H, br. s.), 7.30-7.43 (3H, m), 7.15-7.27 (2H, m), 6.86-6.97 (1H, m), 3.89 (3H, s), 3.37 (1H, s), 3.04-3.14 (2H, m), 2.67-2.80 (2H, m), 2.00 (2H, dd, J=9.00, 4.12 Hz), 1.63-1.74 (2H, m).

Provenance & Evidence