Sodium Hydroxide → (2-(5,5-Dimethyl-1-cyclopenten-1-yl)-2'-fluoro-5'-(methyloxy)-1,1'-biphenyl-4-yl)methanol

Temperature

100 °C

A mixture of compound T2.5 (1.80 g, 5.80 mmol), 2-(5,5-dimethylcyclopent-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (T2.2)(1.40 g, 6.4 mmol), S-Phos (0.48 g, 1.20 mmol), tripotassium phosphate (3.10 g, 15.0 mmol) and palladium acetate (0.13 g, 0.58 mmol) in DMF (10.0 mL) and water (1.0 mL), was purged with N2 three times. The resulting mixture was heated at 100° C. overnight. EtOAc (120 mL) was added, and the mixture was washed with brine (25×2 mL). The organic layer was dried with MgSO4. The residue was purified by CombiFlash® silica gel column chromatography, eluting with hexane/EtOAc, 9/1 to give the Suzuki coupling product as an intermediate, ethyl 2-(5,5-dimethyl-1-cyclopenten-1-yl)-2′-fluoro-5′-(methyloxy)-1,1′-biphenyl-4-carboxylate. MS ESI (pos.) m/e: 369.1 (M+H)+. To a solution of ethyl 2-(5,5-dimethyl-1-cyclopenten-1-yl)-2′-fluoro-5′-(methyloxy)-1,1′-biphenyl-4-carboxylate (1.00 g, 3.0 mmol) in THF (10.0 mL), was slowly added LAH, (1.0M solution in diethyl ether, 4.0 mL, 4.0 mmol) at 0° C. After the addition, the reaction mixture was stirred at 40° C. for 1.5 hours, and then at room temperature for 2 hours. A mixture of water (0.22 mL) in THF (2.0 mL) was slowly added and then 15% sodium hydroxide (0.22 mL) was added at 0° C. Finally, water (0.65 mL) was added at room temperature. The solid was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by CombiFlash® silica gel column chromatography, eluting with hexane/EtOAc, 90/10 to 70/30) to give the title compound T2.6. 1H NMR (400 MHz, CDCl3) δ ppm. 7.24 (s, 2H), 7.09-7.21 (m, 1H), 6.84-6.96 (m, 1H), 6.68-6.72 (m, 2H), 5.43 (s, 1H), 4.65 (s, 2H), 3.66 (s, 3H), 2.17 (td, 2H), 1.77 (b, 1H), 1.58 (t, 2H), 0.78 (s, 6H). MS ESI (pos.) m/e: 309.1 (M−HO)+, 345.2 (M+H3O)+.

1. customwas purged with N2 three times
2. additionEtOAc (120 mL) was added
3. washthe mixture was washed with brine (25×2 mL)
4. dry with materialThe organic layer was dried with MgSO4
5. customThe residue was purified by CombiFlash® silica gel column chromatography
6. washeluting with hexane/EtOAc, 9/1
7. customto give the Suzuki coupling product as an intermediate
8. customat 0° C
9. additionAfter the addition
10. waitat room temperature for 2 hours
11. additionwas slowly added
12. customThe solid was removed by filtration
13. customthe solvent was removed under reduced pressure
14. customThe residue was purified by CombiFlash® silica gel column chromatography
15. washeluting with hexane/EtOAc, 90/10 to 70/30)

ORD record

ord-b5d49669d6fc4574837e397ee3eacfb0

Source dataset

uspto-grants-2014_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08748462B2