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Stage #1: 6-bromo-3-iodo-2-(1H-1,2,3,4-tetrazol-5-yl)benzene-1-sulfonamide; p-methoxybenzyl chloride With tetrabutyl-ammonium chloride; potassium carbonate; sodium iodide In chloroform; water at 50℃;
Stage #2: 2-trimethylsilylethanethiol With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 5h;
Stage #3: rac-tert-butyl (cis-3-fluoropiperidin-4-yl)carbamate; (2S)-N-tert-butoxycarbonyl-2-hydroxy-1,3-diaminopropane Further stages; |
36.I; 37.A; 37.B; 1.A; 1.B; 1.C; 1.D Step D: N1-((R)-3-amino-2-hydroxypropyl)-4-(cis-4-amino-3-fluoropiperidin-1-yl)-3-(2H- tetrazol-5-yl)benzene-1,2-disulfonamide
Into a 3000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-bromo-3-iodo-2-(1H-1,2,3,4-tetrazol-5-yl)benzene-1- sulfonamide (105 g, 244.17 mmol, 1.00 equiv), chloroform (1050 mL), potassium carbonate (168.9 g, 1.22 mol, 5.00 equiv), water (525 mL), NaI (11 g, 0.30 equiv), tetrabutyl(chloro)amine (20.4 g, 73.40 mmol, 0.30 equiv), 1-(chloromethyl)-4-methoxybenzene (230 g, 1.47 mol, 6.00 equiv). The resulting solution was stirred overnight at 50°C in an oil bath. The reaction mixture was cooled to RT. The resulting solution was extracted with 2x1000 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum to afford the title compounds. LC-MS: (ES, m/z): 790 [M+H]+ ; H-NMR: (300MHz, CDCl3, ppm): δ 7.956-7.928 (m, 0.5H), 7.852-7.824 (m, 1H), 7.656-7.612 (m, 1.5H), 7.323- 7.282 (m, 1.5H), 7.195-7.224 (m, 2H), 6.944-6.908 (m, 6H), 6.822-6.760 (m, 9H), 5.791 (m, 1H), 5.570-5.521 (m, 1H), 5.149-5.100 (m, 1H), 4.769-4.718 (m, 2H), 4.232-4.221 (m, 2H), 3.900-3.848 (m, 2H), 3.789-3.742 (m, 14H). 6-bromo-3-iodo-N,N-bis[(4-methoxyphenyl)methyl]-2-[1-[(4- methoxyphenyl)methyl]-1H-1,2,3,4-tetrazol-5-yl]benzene-1-sulfonamide, 6-bromo-3-iodo-N,N- bis[(4-methoxyphenyl)methyl]-2-[2-[(4-methoxyphenyl)methyl]-2H-1,2,3,4-tetrazol-5- yl]benzene-1-sulfonamide (500 mg, 0.633 mmol), 2-(trimethylsilyl)ethanethiol (170 mg, 1.265 mmol) and Cs2CO3 (618 mg, 1.898 mmol) were combined in DMF (1.5 mL). Then the mixture was stirred at RT for 5 hours. Then the mixture was poured onto ether (100 mL) with the organic layer collected and concentrated under vacuum to give the title compounds: LCMS [M + H]+: 844; 1H NMR (300 MHz, CDCl3): δ 4.71-4.40 (m, 1H), 4.13-4.00 (m, 1H), 3.83-3.67 (m, 1H), 2.81-2.72 (m, 1H), 2.32-2.21 (m, 2H), 2.08-1.74 (m, 2H), 1.44 (s, 9H). 3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)-6- ((2-(trimethylsilyl)ethyl)thio)benzenesulfonamide (480 mg, 0.569 mmol) and m-CPBA (491 mg, 2.84 mmol) were combined in dichloromethane (2 mL). The mixture was stirred at RT for 4 hours. The resulting mixture was poured onto ether (200 mL) and washed with brine (150 mL). The organic layers were collected, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was applied on a silica gel column with EA/PE (1/3) to give the title compounds: LCMS [M + H]+: 876; 1H NMR (300 MHz, CDCl3): δ 8.62 (d, J = 8.7 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 7.90-7.88 (m, 1H), 7.69-7.68 (m, 0.5H), 7.56-7.53 (m, 0.5H), 7.27-7.20 (m, 2H), 6.91-6.79 (m, 12H), 5.44-5.39 (m, 1H), 5.20-5.15 (m, 1H), 4.58-4.53 (m, 2H), 3.98-3.79 (m, 2H), 3.75-3.66 (m, 9H), 2.50-2.48 (m, 2H), 1.19-1.03 (m, 1H), 0.83-0.82 (m, 1H), 0.01 (s, 9H). A flask was charged with 3-iodo-N,N-bis(4-methoxybenzyl)-2-(2-(4- methoxybenzyl)-2H-tetrazol-5-yl)-6-((2-(trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide and 3-iodo-N,N-bis(4-methoxybenzyl)-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-6-((2- (trimethylsilyl)ethyl)sulfonyl)benzenesulfonamide (REFERENCE EXAMPLE 37) (400 mg, 0.457 mmol), racemic tert-butyl (cis-3-fluoropiperidin-4-yl)carbamate (498 mg, 2.283 mmol) and DABCO (256 mg, 2.283 mmol). The vial was sealed, degassed with N2, and filled with DMSO (3.1 mL). The resulting mixture was heated overnight at 110 °C. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography using (0- 100)% EtOAc/hexane as mobile phase to afford the title compound. LC/MS [M+H]+: 966.96. To a solution of tert-butyl (cis-1-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2-(2- (4-methoxybenzyl)-2H-tetrazol-5-yl)-4-((2-(trimethylsilyl)ethyl)sulfonyl)phenyl)-3- fluoropiperidin-4-yl)carbamate and tert-butyl (cis-1-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-2- (1-(4-methoxybenzyl)-1H-tetrazol-5-yl)-4-((2-(trimethylsilyl)ethyl)sulfonyl)phenyl)-3- fluoropiperidin-4-yl)carbamate (0.36 g, 0.373 mmol) in THF (3.73 mL) was added tetrabutylammonium fluoride (0.820 ml, 0.820 mmol) (1.0 M in THF) dropwise at 0 °C. The reaction mixture was stirred at RT under N2 for 0.5 hours. The reaction mixture was diluted with EtOAc, washed four times with sat’d aqeous KHSO4, twice with brine, dried over MgSO4, and concentrated to afford the title compound. LC/MS [M+H]+: 866.73. To a solution of 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-(cis-4-((tert- butoxycarbonyl)amino)-3-fluoropiperidin-1-yl)-3-(2-(4-methoxybenzyl)-2H-tetrazol-5- yl)benzenesulfinic acid and 2-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4-(cis-4-((tert- butoxycarbonyl)amino)-3-fluoropiperidin-1-yl)-3-(1-(4-methoxybenzyl)-1H-tetrazol-5- yl)benzenesulfinic acid (0.32 g, 0.370 mmol) in THF (2.58 mL) were added (S)-tert-butyl (3- amino-2-hydroxypropyl)carbamate (0.141 g, 0.739 mmol), TEA (0.103 mL, 0.739 mmol), and NCS (0.099 g, 0.739 mmol) in sequence at 0 °C under nitrogen. The mixture was stirred at the same temperature for 30 minutes. The reaction mixture was diluted with EtOAc, washed with NaHCO3 solution and brine. The organic layer was dried over MgSO4, evaporated, and the crude product was purified by silica gel column chromatography eluting with 0-100% EtOAc/hexanes to give the title compound. LC/MS [M+H]+: 1054.87. To the solution of tert-butyl (cis-1-(3-(N,N-bis(4-methoxybenzyl)sulfamoyl)-4- (N-((R)-3-((tert-butoxycarbonyl)amino)-2-hydroxypropyl)sulfamoyl)-2-(2-(4-methoxybenzyl)- 2H-tetrazol-5-yl)phenyl)-3-fluoropiperidin-4-yl)carbamate and tert-butyl (cis-1-(3-(N,N-bis(4- methoxybenzyl)sulfamoyl)-4-(N-((R)-3-((tert-butoxycarbonyl)amino)-2- hydroxypropyl)sulfamoyl)-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)phenyl)-3-fluoropiperidin- 4-yl)carbamate (360 mg, 0.341 mmol) in DCM (2.5 mL) was added anisole (0.371 mL, 3.41 mmol) and TFA (2.63 mL, 34.1 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes. After removing the volatile, the residue was dissolved in TFA (5.26 mL, 68.2 mmol). The resulting mixture was stirred at 80 °C for 1.0 hour. After removing the volatile, the residue was purified by reverse phase HPLC (1-25% MeCN/water, 0.1% NH4OH as additive) to give the title compound. LC/MS [M+H]+: 494.41. |
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