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

Temperature

100 °C

A reaction mixture of compound T1.6 (1.80 g, 5.80 mmol), 2-(5,5-dimethylcyclopent-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (T1.3) (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. for 16 hours. 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 chromatography (eluting with hexane/EtOAc, 9/1) to give 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® chromatography (silica gel column, eluent with hexane/EtOAc, 90/10 to 70/30) to give the title compound T1.7. 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)1, 345.2 (M+H3O)1.

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 chromatography (eluting with hexane/EtOAc, 9/1)
6. customto give Suzuki coupling product as an intermediate
7. customat 0° C
8. additionAfter the addition
9. waitat room temperature for 2 hours
10. additionwas slowly added
11. customThe solid was removed by filtration
12. customthe solvent was removed under reduced pressure
13. customThe residue was purified by CombiFlash® chromatography (silica gel column, eluent with hexane/EtOAc, 90/10 to 70/30)

ORD record

ord-bd1b57b3e47449688a6b2228f121654c

Source dataset

uspto-grants-2013_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08450522B2