Hydrochloric Acid → N-[3-[(4aR,7aS)-4-hydroxy-2-oxo-1-[[4-(trifluoromethyl)phenyl]methyl]-5,6,7,7a-tetrahydro-4aH-cyclopenta[b]pyridin-3-yl]-1,1-dioxo-4H-1$l^{6},2,4-benzothiadiazin-7-yl]methanesulfonamide

Participants

Reaction Conditions

Reaction Steps

2-(4-Trifluoromethyl-benzylamino)-cyclopentanecarboxylic acid methyl ester (0.1 g, 0.33 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL). (7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.108 g, 0.33 mmol) was added followed by N-methylmorpholine (0.087 mL, 0.66 mmol). The mixture was stirred until everything dissolved, approximately 5 min. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.069 g, 0.36 mmol) was added and the mixture was stirred at 25° C. for 3 h. The solution was diluted with ethyl acetate (25 mL) and washed with 1.0 M aqueous hydrochloric acid solution (2×25 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a golden oil. The oil was dissolved in ethanol (4 mL) and a 21% w/w solution of sodium ethoxide in ethanol (1.3 mL, 3.6 mmol) was added, and the reaction mixture was heated to 60° C. for 2 h. Upon cooling to 25° C., the reaction mixture was acidified to pH 2-3 with 2.0 M aqueous hydrochloric acid solution, upon which the product precipitated while stirring. The solid was collected by vacuum filtration and purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 50%-70% in 8 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)-N-{3-[4-hydroxy-2-oxo-1-(4-trifluoromethyl-benzyl)-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.1 g, 0.171 mmol, 52%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.42-1.62 (3H, m), 1.96-2.15 (3H, m), 3.06 (3H, s), 3.90 (1H, d, J=7.2 Hz), 4.58 (1H, d, J=14.8 Hz), 5.00 (1H, d, J=15.6 Hz), 7.49 (4H, q, J=2.4 Hz), 7.57 (4H, m), 7.68 (2H, m), 10.18 (1H, s). LC-MS (ESI) calcd for C24H23F3N4O6S2 584.10, found 585.1 [M+H+]. [α]D=−50.6863.

Provenance & Evidence