p-Toluenesulfonic acid → HCID 11306618, compound

Participants

Reaction Steps

In a pressure tube was placed 562 mg cyclopentane-1,3-dione (5.73 mmol) followed by a solution of 2.3 g (3R,4S)-3-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-4-(4-fluorophenyl)pyrrolidine (5.46 mmol) (step E) in 12.5 mL benzene. To this solution was added 52 mg PTSA (0.027 mmol) and 4 Å bead molecular sieves (1 g). The tube was sealed and heated for 3 hr. The tube was cooled to RT and the resulting solution filtered and the solvent removed under vacuum. The resulting bright yellow oil was purified by column chromatography on silica gel eluting with EtOAc/hexanes (1/1), then EtOAc (100%), then methylene chloride/methanol (9/1). The fractions containing the desired product (as determined by TLC) were combined and the solvent removed under vacuum. The resulting yellow oil was purified by prep HPLC on Chiralcel OD eluting with heptanes/reagent alcohol (87.5/12.5) to afford the title compound as a white solid. 1H-NMR (CD3OD) rotamers: δ: 1.43 (d, 3H, 6.5 Hz), 2.46 (m, 2H), 2.7-2.85 (m, 2H), 3.40-3.65 (m, 3H), 3.78-4.20 (m, 3H), 4.76 (quin., 1H, 6.5 Hz), 4.97, 5.03 (2s 1H), 6.98 (t, 2H), 7.18 (br. s, 2H), 7.72 (s, 2H), 7.83 (s, 1H)ppm. MS: 502.2 (MH+) observed. Crystallization of 3-[(3R,4S)-3-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-4-(4-fluorophenyl)pyrrolidin-1-yl]cyclopent-2-en-1-one was achieved in aq. methanol (mp 45-46° C.). Alternatively, crystalline solid was obtained by crystallization in ether/hexanes mixture (mp 44-45° C.).

Provenance & Evidence