Reaction Steps
A reaction flask was charged with L-proline (24.3 mg, 0.21 mmol), potassium carbonate (146.3 mg, 1.06 mmol), copper iodide (21 mg, 0.11 mmol) and (4aR,7aS)-1-(4-fluoro-benzyl)-4-hydroxy-3-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-1,4a,5,6,7,7a-hexahydro-[1]pyrindin-2-one (prepared as described in Example 39c, 300 mg, 0.53 mmol). The flask was degassed and backfilled with nitrogen, and then anhydrous dimethylsulfoxide (5 mL) was added followed by addition of piperidine (0.16 mL, 1.60 mmol). The resulting suspension was vigorously stirred at 90° C. for 60 h, and then allowed to cool to 25° C. The mixture was passed through a plug of Celite and rinsed with 10% methanol/dichloromethane. The filtrate was concentrated in vacuo, and the residue was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 40%-95% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, (4aR,7aS)-3-(1,1-dioxo-7-piperidin-1-yl-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-1-(4-fluoro-benzyl)-4-hydroxy-1,4a,5,6,7,7a-hexahydro-[1]pyrindin-2-one (160 mg, 0.31 mmol, 58%), as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.40-1.63 (9H, m), 1.96 (2H, m), 2.06 (1H, m), 3.23 (4H, m), 3.32 (1H, m), 3.83 (1H, m), 4.45 (1H, d, J=15.6 Hz), 4.89 (1H, d, J=14.8 Hz), 7.14 (3H, m), 7.32-7.44 (4H, m), 13.86 (1H, s). LC-MS (ESI) calcd for C27H29FN4O4S 524.19, found 525.3 [M+H+]. e.e. >97% based on the e.e. of the commercially available (1R,2S)-2-amino-cyclopentanecarboxylic acid (Example 40a).
