Potassium Phosphate, Tribasic → Methyl 7-(2-morpholinoethoxy)-2-(3-(trifluoromethyl)phenyl)-5h-pyrido[3,2-b]indole-4-carboxylate

Participants

Reaction Conditions

Reaction Steps

A mixture of 3-(trifluoromethyl)phenylboronic acid (51 mg, 0.27 mmol), methyl 2-bromo-7-(2-morpholinoethoxy)-5H-pyrido[3,2-b]indole-4-carboxylate (90 mg, 0.21 mmol), powdered potassium phosphate tribasic (114 mg, 0.539 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (17 mg, 0.041 mmol), and Pd(OAc)2 (4.7 mg, 0.021 mmol) in a microwave vial was flushed with nitrogen. THF (1 mL) was added, the vial was capped, and the reaction was heated in a 70° C. oil bath for 18 hr. Additional Pd(OAc)2 (4.7 mg, 0.021 mmol) and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (17 mg, 0.041 mmol) were added, the vial was resealed, and heating was continued for 16 hr. The reaction was filtered and the collected solid was washed with THF. The filtrate was applied onto an SCX column and washed with DCM and then MeOH. Release with 2 N NH3 in MeOH afforded crude methyl 7-(2-morpholinoethoxy)-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxylate (107 mg). This was suspended in 7 N NH3 in MeOH (5 mL) in a sealed microwave vial and heated at 80° C. overnight. Preparative HPLC (100×30 mm Luna C18 column, gradient elution with A:B=30:70 to A:B=0:100 [A=10 mM NH4OAc in 5% aqueous CH3CN; B=10 mM NH4OAc in 95% aqueous CH3CN] over 20 min) followed by removal of the solvents on a SPEEDVAC® gave 7-(2-morpholinoethoxy)-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxamide (48 mg, 0.094 mmol, 44% yield) as a yellow solid. MS (ESI) m/z 483.1 (M−H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.51 (1H, s), 8.62 (3H, s), 8.47 (1H, s), 8.16 (1H, d, J=8.55 Hz), 7.92 (1H, s), 7.69-7.83 (2H, m), 7.31 (1H, d, J=1.53 Hz), 6.92 (1H, dd, J=8.70, 1.68 Hz), 4.19 (2H, t, J=5.49 Hz), 3.61 (4H, t, J=4.43 Hz), 2.77 (2H, t, J=5.49 Hz), 2.51 (4H, br. s.).

Provenance & Evidence