Potassium Hydroxide → [5'-Isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol

Temperature

0 °C

To a solution of 1.08 g of 5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-carbonitrile (EXAMPLE 3) in 25 mL of n-PrOH, was added 0.97 g of KOH. The mixture was heated to reflux and stirred at this temperature for 36 h, then cooled and concentrated to a clear oil. This oil was partitioned between 15 mL of water and 10 mL of Et2O. The aqueous phase was extracted with 10 mL of Et2O. The combined organics were washed with brine (15 mL), dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on a Biotage Horizon 40S column, eluting with 1 CV of 95% hexanes-5% of a mixture of 5% formic acid in acetone, followed by a linear gradient of the acetone mixture in hexanes from 5 to 100% over 10 CV. The resulting white solid was dissolved in 10 mL of 9:1 benzene-MeOH and excess TMSCH2N2 was added. The mixture was stirred for 10 min at room temperature, then quenched with trifluoroacetic acid and concentrated. The residue was dissolved in 15 mL of Et2O and cooled to 0° C. A 1-M solution of LiAlH4 in Et2O (5.4 mL) was added dropwise via addition funnel. The cooling bath was removed once the addition was complete, and the mixture was stirred 2 h at room temperature, then recooled to 0° C. and quenched by dropwise addition of 0.2 mL of water, 0.2 mL of 15% aqueous NaOH, and 0.5 mL of water. The cooling bath was removed once the addition was complete, and the mixture was stirred 30 min at room temperature, filtered (washing the solids liberally with Et2O), and concentrated. Flash chromatography on a Biotage Horizon, 40S column, eluting with 1 CV of 4% EtOAc in hexanes, followed by a linear gradient of EtOAc in hexanes from 4 to 100% over 10 CV provided the title compound. Mass spectrum (ESI) 307.2 (M−17). 1H NMR (500 MHz, CDCl3): δ 7.85 (s, 1H), 7.60 (d, J=8 Hz, 1H), 7.33 (d, J=8 Hz, 1H), 7.25 (dd, J=2 Hz, 9 Hz, 1H), 6.99 (d, J=2.5 Hz, 1H), 6.93 (d, J=8.5 Hz, 1H), 4.49 (m, 2H), 3.74 (s, 3H), 2.90 (septet, J=7 Hz, 1H), 1.25 (d, J=7 Hz, 6H).

1. temperatureThe mixture was heated
2. temperatureto reflux
3. temperaturecooled
4. concentrationconcentrated to a clear oil
5. customThis oil was partitioned between 15 mL of water and 10 mL of Et2O
6. extractionThe aqueous phase was extracted with 10 mL of Et2O
7. washThe combined organics were washed with brine (15 mL)
8. dry with materialdried over Na2SO4
9. concentrationconcentrated
10. customThe residue was purified by flash chromatography on a Biotage Horizon 40S column
11. washeluting with 1 CV of 95% hexanes-5% of a mixture of 5% formic acid in acetone
12. dissolutionThe resulting white solid was dissolved in 10 mL of 9:1 benzene-MeOH
13. additionexcess TMSCH2N2 was added
14. stirringThe mixture was stirred for 10 min at room temperature
15. customquenched with trifluoroacetic acid
16. concentrationconcentrated
17. dissolutionThe residue was dissolved in 15 mL of Et2O
18. additionA 1-M solution of LiAlH4 in Et2O (5.4 mL) was added dropwise via addition funnel
19. customThe cooling bath was removed once the addition
20. stirringthe mixture was stirred 2 h at room temperature
21. customrecooled to 0° C.
22. customquenched by dropwise addition of 0.2 mL of water, 0.2 mL of 15% aqueous NaOH, and 0.5 mL of water
23. customThe cooling bath was removed once the addition
24. stirringthe mixture was stirred 30 min at room temperature
25. filtrationfiltered (
26. washwashing the solids liberally with Et2O), and
27. concentrationconcentrated
28. washFlash chromatography on a Biotage Horizon, 40S column, eluting with 1 CV of 4% EtOAc in hexanes

ORD record

ord-5ee62a69e2794e6f880d81ab85cea742

Source dataset

uspto-grants-2014_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08735435B2