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

Temperatur

2.5 °C

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%

1. customIn a 40 mL vial equipped with a stir bar
2. temperaturethe reaction was warmed to ambient temperature
3. temperaturethe reaction was heated to 60° C. for 3 hours
4. temperatureThe reaction was cooled to 0-5° C.
5. temperatureThe reaction was heated to 60° C. for 1 hour
6. concentrationpartially concentrated
7. temperaturecooled to 0-5° C.
8. customquenched with water (5 mL) and 1M NaOH (3 mL)
9. additionAfter the addition of ethyl acetate (10 mL)
10. filtrationthe reaction was filtered through Celite
11. customthe filtrate layers were separated
12. extractionThe aqueous portion was extracted with ethyl acetate (30 mL)
13. dry with materialdried (MgSO4)
14. concentrationconcentrated
15. custompurified by a 50 gram silica gel SNAP cartridge (Biotage SP4 Flash Chromatography instrument)
16. washelution of 5-40% MeOH/dichloromethane
17. customto produce 124 mg of P-606 as a yellow viscous oil in 17% yield

ORD-Eintrag

ord-3fd530f034e0443082630fc2b6f742e1

Quelldatensatz

uspto-grants-2014_07

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08791267B2