Diosgenin → 1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-ethylamine

Participants

Reaction Conditions

Reaction Steps

In a 40 mL vial equipped with a stir bar was placed methylmagnesium bromide (3M in diethyl ether) (1.32 mL, 3.96 mmol), nitrogen in/out lines attached and the solution was cooled to 0-5° C. After the addition of a solution of 5-(3′-Chloro2-fluoro-6-difluoromethoxy-biphenyl-3-ylmethyl)-pyridine-2-carbonitrile (P-355, 700 mg, 1.98 mmol) in tetrahydrofuran (10 mL), the reaction was warmed to ambient temperature and stirred for 40 minutes. Additional methylmagnesium bromide (3M in diethyl ether) (660 uL, 1.98 mmol) was introduced and the reaction was heated to 60° C. for 3 hours. The reaction was cooled to 0-5° C. and a slurry of lithium aluminum hydride (150 mg, 3.96 mmol) in tetrahydrofuran (1 mL) was added. The reaction was heated to 60° C. for 1 hour and then partially concentrated, cooled to 0-5° C. and quenched with water (5 mL) and 1M NaOH (3 mL). After the addition of ethyl acetate (10 mL), the reaction was filtered through Celite and the filtrate layers were separated. The aqueous portion was extracted with ethyl acetate (30 mL), the organic portions were combined, dried (MgSO4), concentrated and purified by a 50 gram silica gel SNAP cartridge (Biotage SP4 Flash Chromatography instrument) utilizing gradient elution of 5-40% MeOH/dichloromethane to produce 124 mg of P-606 as a yellow viscous oil in 17% yield. 1H NMR (400 MHz, DMSO-d6) δ 1.26 (d, J=7 Hz, 3H), 3.72 (s, 3H), 3.94 (s, 2H), 3.99 (q, J=6 Hz, 1H), 6.94 (d, J=8 Hz, 1H), 7.27-7.29 (m, 1H), 7.32-7.38 (m, 3H), 7.41-7.47 (m, 2H), 7.57 (dd, J=8, 2 Hz, 1H), 8.39 (s, 1H). MS (APCI+): 372.3 (M+2). LC-MS: 95%

Provenance & Evidence