Reaction Steps
Sodium triacetoxyborohydride (307 mg, 1.45 mmol) was added to a mixture of (1R*,3S*)-α,α-dimethyl-N-[3-fluoro-4-oxo-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide (Example 58, 490 mg, 0.97 mmol), 2-oxa-8-azaspiro[4.5]decane hydrochloride (Description 86, 204 mg, 1.37 mmol) and triethylamine (1.34 mL, 9.7 mmol) in 1,2-dichloroethane (15 mL) and the mixture was stirred at room temperature for 3 days. Further sodium triacetoxyborohydride (103 mg, 0.49 mmol) was added and the mixture was stirred at room temperature for 24 hours. The mixture was basified with aqueous sodium hydroxide (1M) and extracted with dichloromethane. The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by MPLC on silica gel, eluting with CH2Cl2/MeOH (97.5:2.5), to give (1R*,3S*,4R*)-α,α-dimethyl-N-[3-fluoro-4-(2-oxa-8-azaspiro[4.5]decan-8-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide as a colorless foam (18 mg, 3%); 1H NMR (400 MHz, CDCl3) δ 7.81 (1H, s), 7.70 (2H, s), 7.36–7.23 (5H, m), 5.13 (1H, s), 4.98 (1H, br d, J 48.5 Hz), 3.81 (2H, t, J 7.2Hz), 2.89–2.68 (3H, m), 3.67–2.42 (4H, m), 2.41–2.38 (2H, m), 1.89–1.86 (1H, m), 1.73–1.71 (1H, m), 1.68 (2H, t, J 7.2 Hz), 1.63–1.58 (6H, m), and 1.53 (6H, d, 3.4 Hz). m/z (ES+) 615 (M+1); and (1S*,3S*,4R*)-α,α-dimethyl-N-[3-fluoro-4-(2-oxa-8-azaspiro[4.5]decan-8-yl)-1-phenylcyclohexyl]-3,5-bis(trifluoromethyl)benzeneacetamide as a colorless foam (280 mg, 47%). 1H NMR (400 MHz, CDCl3) δ 7.81 (2H, s), 7.79 (1H, s), 7.32–7.21 (1H, s), 6.41 (1H, d, J 10.5 Hz), 5.06 (1H, br d, J 50.0 Hz), 3.87–3.83 (2H, m), 3.00–2.96 (1H, m), 2.60–2.39 (4H, m), 2.30–2.22 (2H, m), 2.01–1.93 (1H, m), 1.77–1.70 (3H, m), 1.65–1.50 (8H, m), and 1.60 (6H, d, J 6.9 Hz). m/z (ES+) 615 (M+1).
