ethyl 2-(cyclohexylamino)cyclopentane-1-carboxylate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4] thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.100 g, 0.300 mmol) and 2-cyclohexylamino-cyclopentanecarboxylic acid ethyl ester (0.072 g, 0.300 mmol) in N,N-dimethylformamide (1.5 mL) was treated with N-methylmorpholine (72.8 mg, 0.72 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (69.0 mg, 0.36 mmol) and stirred at 25° C. for 4 h. The solvent was removed in vacuo. The crude material was redissolved in ethyl acetate (75 mL) and washed twice with 1.0 M aqueous hydrochloric acid solution (50 mL). The organic layer was then dried over sodium sulfate, filtered and concentrated in vacuo. The crude intermediate was redissolved in ethanol (5 mL) and treated with a 21% w/w solution of sodium ethoxide in ethanol (448 μL, 1.2 mmol) and stirred for 2 h at 60° C. The reaction was allowed to cool to 25° C., treated with glacial acetic acid (0.4 mL), the solvents were removed in vacuo, and the residue was and purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 30%-90% 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, cis-N-[3-(1-cyclohexyl-4-hydroxy-2-oxo-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 (48 mg, 0.094 mmol, 31.5%), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.13-1.19 (2H, m), 1.31-1.40 (2H, m), 1.48-2.04 (12H, m), 3.06 (3H, s), 3.26-3.35 (1H, m), 3.91-4.05 (1H, m), 4.23-4.35 (1H, m), 7.50-7.57 (3H, m), 10.18 (1H, bs). LC-MS (ESI) calcd for C22H28N4O6S2 508.15, found 509.2 [M+H+]. The solvent was removed in vacuo The crude material was redissolved in ethyl acetate (75 mL) washed twice with 1.0 M aqueous hydrochloric acid solution (50 mL) The organic layer was then dried over sodium sulfate filtered concentrated in vacuo The crude intermediate was redissolved in ethanol (5 mL) stirred for 2 h at 60° C to cool to 25° C. the solvents were removed in vacuo purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 30%-90% in 7 min

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4] thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.100 g, 0.300 mmol) and 2-cyclohexylamino-cyclopentanecarboxylic acid ethyl ester (0.072 g, 0.300 mmol) in N,N-dimethylformamide (1.5 mL) was treated with N-methylmorpholine (72.8 mg, 0.72 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (69.0 mg, 0.36 mmol) and stirred at 25° C. for 4 h. The solvent was removed in vacuo. The crude material was redissolved in ethyl acetate (75 mL) and washed twice with 1.0 M aqueous hydrochloric acid solution (50 mL). The organic layer was then dried over sodium sulfate, filtered and concentrated in vacuo. The crude intermediate was redissolved in ethanol (5 mL) and treated with a 21% w/w solution of sodium ethoxide in ethanol (448 μL, 1.2 mmol) and stirred for 2 h at 60° C. The reaction was allowed to cool to 25° C., treated with glacial acetic acid (0.4 mL), the solvents were removed in vacuo, and the residue was and purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 30%-90% 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, cis-N-[3-(1-cyclohexyl-4-hydroxy-2-oxo-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 (48 mg, 0.094 mmol, 31.5%), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.13-1.19 (2H, m), 1.31-1.40 (2H, m), 1.48-2.04 (12H, m), 3.06 (3H, s), 3.26-3.35 (1H, m), 3.91-4.05 (1H, m), 4.23-4.35 (1H, m), 7.50-7.57 (3H, m), 10.18 (1H, bs). LC-MS (ESI) calcd for C22H28N4O6S2 508.15, found 509.2 [M+H+]. The solvent was removed in vacuo The crude material was redissolved in ethyl acetate (75 mL) washed twice with 1.0 M aqueous hydrochloric acid solution (50 mL) The organic layer was then dried over sodium sulfate filtered concentrated in vacuo The crude intermediate was redissolved in ethanol (5 mL) stirred for 2 h at 60° C to cool to 25° C. the solvents were removed in vacuo purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 30%-90% in 7 min

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-oxo-cyclopentanecarboxylic acid ethyl ester (2.01 g, 12.9 mmol) in ethanol (20 mL) was treated with cyclohexylamine (1.75 mL, 12.1 mmol), sodium cyanoborohydride (1.39 g, 22.2 mmol), and glacial acetic acid (10 drops) and stirred for 16 h at 50° C. After cooling to 25° C. the solvent was removed in vacuo, the crude material was redissolved in ethyl acetate (100 mL), washed with saturated aqueous sodium bicarbonate solution (100 mL). The aqueous layer was discarded and the organic layer was washed with 1.0 M aqueous hydrochloric acid solution (50 mL). The organic layer was discarded, 1.0 M aqueous sodium hydroxide solution (75 mL) was added and the aqueous layer was extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed in vacuo to afford the desired product 2-cyclohexylamino-cyclopentanecarboxylic acid ethyl ester (2.10 g, 8.77 mmol, 86.9%), as a light yellow oil. LC-MS (ESI) calcd for C14H25NO2239.19, found 240.2 [M+H+]. After cooling to 25° C. the solvent was removed in vacuo the crude material was redissolved in ethyl acetate (100 mL) washed with saturated aqueous sodium bicarbonate solution (100 mL) the organic layer was washed with 1.0 M aqueous hydrochloric acid solution (50 mL) 1.0 M aqueous sodium hydroxide solution (75 mL) was added the aqueous layer was extracted with ethyl acetate (100 mL) The organic layer was dried over sodium sulfate filtered the solvent was removed in vacuo

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4] thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.100 g, 0.300 mmol) and 2-cyclohexylamino-cyclopentanecarboxylic acid ethyl ester (0.072 g, 0.300 mmol) in N,N-dimethylformamide (1.5 mL) was treated with N-methylmorpholine (72.8 mg, 0.72 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (69.0 mg, 0.36 mmol) and stirred at 25° C. for 4 h. The solvent was removed in vacuo. The crude material was redissolved in ethyl acetate (75 mL) and washed twice with 1.0 M aqueous hydrochloric acid solution (50 mL). The organic layer was then dried over sodium sulfate, filtered and concentrated in vacuo. The crude intermediate was redissolved in ethanol (5 mL) and treated with a 21% w/w solution of sodium ethoxide in ethanol (448 μL, 1.2 mmol) and stirred for 2 h at 60° C. The reaction was allowed to cool to 25° C., treated with glacial acetic acid (0.4 mL), the solvents were removed in vacuo, and the residue was and purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 30%-90% 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, cis-N-[3-(1-cyclohexyl-4-hydroxy-2-oxo-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 (48 mg, 0.094 mmol, 31.5%), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.13-1.19 (2H, m), 1.31-1.40 (2H, m), 1.48-2.04 (12H, m), 3.06 (3H, s), 3.26-3.35 (1H, m), 3.91-4.05 (1H, m), 4.23-4.35 (1H, m), 7.50-7.57 (3H, m), 10.18 (1H, bs). LC-MS (ESI) calcd for C22H28N4O6S2 508.15, found 509.2 [M+H+]. The solvent was removed in vacuo The crude material was redissolved in ethyl acetate (75 mL) washed twice with 1.0 M aqueous hydrochloric acid solution (50 mL) The organic layer was then dried over sodium sulfate filtered concentrated in vacuo The crude intermediate was redissolved in ethanol (5 mL) stirred for 2 h at 60° C to cool to 25° C. the solvents were removed in vacuo purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 30%-90% in 7 min

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 2-oxo-cyclopentanecarboxylic acid ethyl ester (2.01 g, 12.9 mmol) in ethanol (20 mL) was treated with cyclohexylamine (1.75 mL, 12.1 mmol), sodium cyanoborohydride (1.39 g, 22.2 mmol), and glacial acetic acid (10 drops) and stirred for 16 h at 50° C. After cooling to 25° C. the solvent was removed in vacuo, the crude material was redissolved in ethyl acetate (100 mL), washed with saturated aqueous sodium bicarbonate solution (100 mL). The aqueous layer was discarded and the organic layer was washed with 1.0 M aqueous hydrochloric acid solution (50 mL). The organic layer was discarded, 1.0 M aqueous sodium hydroxide solution (75 mL) was added and the aqueous layer was extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed in vacuo to afford the desired product 2-cyclohexylamino-cyclopentanecarboxylic acid ethyl ester (2.10 g, 8.77 mmol, 86.9%), as a light yellow oil. LC-MS (ESI) calcd for C14H25NO2239.19, found 240.2 [M+H+]. After cooling to 25° C. the solvent was removed in vacuo the crude material was redissolved in ethyl acetate (100 mL) washed with saturated aqueous sodium bicarbonate solution (100 mL) the organic layer was washed with 1.0 M aqueous hydrochloric acid solution (50 mL) 1.0 M aqueous sodium hydroxide solution (75 mL) was added the aqueous layer was extracted with ethyl acetate (100 mL) The organic layer was dried over sodium sulfate filtered the solvent was removed in vacuo

Conditions: temp:0.00; pressure:0.00; stir: