Reaction Steps
A solution of 4-(3,3-difluoro-3-(2-pyridyl)propyl) piperidine (20 mg. 0.083 mmol, from EXAMPLE 202, Step E) and AcOH (0.0050 mL, 5.2 mg, 0.087 mmol) in 1,2-dichloroethane (1.1 mL) was transferred to a vial containing 2-(R)-(3-(R)-formyl-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)-3-(cyclopropyl)propanoic acid (4-methoxy)benzyl ester (30 mg, 0.076 mmol, from EXAMPLE 21, Step E). Molecular sieve pellets (100 mg, 3 Å) were added and the mixture was stirred for 10 min. at RT before the addition of sodium triacetoxyborohydride (19 mg, 0.090 mmol). After 3 h, the mixture was diluted with EtOAc (40 mL) and washed with saturated aq. NaHCO3 (20 mL) followed by saturated aq. NaCl (20 mL). The aq. layers were extracted with EtOAc (40 mL) and the combined organic layers were dried (Na2SO4), decanted, and evaporated. The crude product was purified by flash column chromatography on silica gel, eluting with 50:50 v/v CH2Cl2/EtOAc, to give 36 mg of the title compound. Further purification by preparative HPLC on a 20×250 mm Chiralcel OD column, eluting with 98:2 v/v hexanes/i-PrOH, gave 23 mg of the title compound: 1H NMR (500 MHz, CD3OD) δ 8.60 (d, J=5, 1H), 7.94 (td, J=8, 2, 1H), 7.66 (d, J=8, 1H), 7.48 (dd, J=8, 5, 1H), 7.35 (d, J=8, 2H), 7.25 (td, J=8, 6, 1H), 7.01-6.95 (m, 2H), 6.92-6.87 (m, 2H), 5.13 (s, 2H), 3.77 (s, 3H), 3.33 (dd, J=9, 6, 1H), 3.10 (q, J=9, 2H), 2.84-2.74 (m, 2H), 2.66-2.59 (m, 2H), 2.52 (dd, J=9,7, 1H), 2.36-2.21 (m, 5H), 1.81 (bt, J=12, 1H), 1.73 (bt, J=12, 1H), 1.71-1.51 (m, 4H), 1.30-1.24 (m, 2H), 1.21-0.99 (m, 3H), 0.72-0.64 (m, 1H), 0.45-0.55 (m, 2H), 0.07-0.00 (m, 2H); ESI-MS 650 (M+H); HPLC A: 3.33 min.
