Acetic Acid → HCID 178522237, compound

Participants

Reaction Conditions

Reaction Steps

Pyrrolidine (0.230 mL, 2.78 mmol) and K2CO3 (0.524 g, 3.79 mmol) were added to a solution of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 6.2, 1 g, 2.53 mmol) in MeCN (5 mL) and the RM was stirred at 100° C. for 4 h. The product was filtered, suspended in MeCN and water, filtered and the filtrate was evaporated off under reduced pressure to give a residue. The residue (100 mg, 0.232 mmol) was suspended in dioxane (1 mL), treated with tributyl(1-ethoxyvinyl)stannane (101 mg, 0.279 mmol) and Pd(Ph3P)4 (26.9 mg, 0.023 mmol) and stirred at 110° C. for 2 h. The solvent was evaporated off under reduced pressure, the residue was dissolved in dioxane (2 mL), and filtered through a PS-Thiol cartridge. This solution was treated with HCl (4 N) and stirred at RT for 4 h. The solvent was evaporated off under reduced pressure and the residue was dissolved in EtOH (2 mL), treated with NaOEt (0.5 mL from a solution of 100 mg sodium dissolved in 5 mL EtOH), stirred 30 min and the treated with diethyl oxalate (0.069 mL, 0.508 mmol). The RM was stirred for 4 h at 80° C. The solvent was evaporated off under reduced pressure and the residue was treated with sat. aq. NH4Cl solution and extracted with DCM. The combined extracts were washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was dissolved in acetic acid (2 mL, 34.9 mmol), treated with hydrazine hydrate (0.030 mL, 0.956 mmol) and stirred at RT for 2 h. the solvent was evaporated off under reduced pressure to give a residue which was treated with MeCN/n-hexane and extracted with MeCN. The MeCN phase was separated and the solvent was evaporated off under reduced pressure to give a residue, which was dissolved in THF (1 mL), treated with LiAlH4 (20 mg, 0.527 mmol) and stirred at RT for 4 h. Additional LiAlH4 (3 eq.) were added and the RM was stirred overnight at RT. The RM was treated with an aq. solution of Rochelle salt's, filtered and the filtrate was evaporated off under reduced pressure to give a crude product which was purified by preparative SFC and lyophilized (water/MeCN) afforded the title product. UPLC-MS (Condition 3) tR=0.9 min, m/z=448.1 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 1.81 (br. s, 4H) 3.25 (br. s, 4H) 4.53 (s, 2H) 6.33 (s, 1H) 7.36 (d, J=8.66 Hz, 2H) 7.86 (d, J=9.03 Hz, 2H) 8.14 (s, 1H) 8.67 (s, 1H) 10.31 (br. s, 1H).

Provenance & Evidence