| 99% |
With hydrogenchloride; In water; for 0.5h; |
First 4-isothiocyanato-benzenesulfonyl fluoride, which has the structural formula was prepared. According to a method from MCKEE et AL., J. Am. Chem. Soc. , 48 (1946), 2506-2507, sulfanilyl fluoride (6.00 g, 34.3 MMOL, from Sigma-Aldrich Chemical--discontinued ; see Krazer Helv. Chim. Acta. 43, 1513-1519 (1960) ) was dissolved in water (60 mL) containing 38% HCI (14.4 mL). Thiophosgene (2.7 mL, 36.0 MMOL) was added in one portion. The resultant mixture was stirred rapidly for a half hour, then diluted with water (200 mL). The resultant white precipitate was filtered off, washed with water, and dried under high vacuum to obtain 7.28 G (99%) of white powder, which was used without further purification. 1HNMR (DMSO-D6) : 8 8. 03 (2H, d, J = 9. 3 HZ), 7.44 (2H, d, J = 9. 3 HZ). FABMS: (M-H+) : 216. 2-Bromo-2', 6'-difluoroacetophenone, which has the structural formula was prepared as follows. To a mechanically stirring solution of 2', 6'-difluoroacetophenone (100.0 G, 640.0 mmol ; Melford Laboratories, Ltd. ) in ethyl acetate (1300 mL) were added freshly milled copper (II) bromide (300 G, 1.35 mol) and bromine (1.6 mL, 32 MMOL). The mixture was heated at reflux for 2.25 hours and allowed to cool to ambient temperature. The resultant green mixture was filtered and the solids rinsed with ethyl acetate (4x100 mL). The filtrate was concentrated with a rotary evaporator under reduced pressure, diluted with methyl t-butyl ether (MTBE; 650 mL), filtered through a pad of silica gel (230-400 ; 9.5 cm diam. X4 cm. ht. ), and solids rinsed with MTBE (5x200 mL). Concentration of the filtrate gave a pale green oil, which was purified by fractional vacuum distillation to give 117 g of pale yellow oil, bp 88-97C (2.0 mm Hg) in 78% yield. Matched that previously described in World Patent APPLICATION W099/21845 (in Example C (79) ) and was used without any further purification or characterization. 1H NMR: 8 7.48 (1H, ddd, J = 6.3, 8.5, 14.8 Hz), 7.01 (2H, ddd, J = 4.6, 5.8, 16.6 Hz), 4.37 (2H, t, J = 0. 7 HZ). 4- [4-AMINO-5- (2, 6-DIFLUORO-BENZOYL)-THIAZOL-2-YLAMINO]-BENZENESULFONYL FLUORIDE, which has the structural formula was then made as follows. To 4-isothiocyanato-benzenesulfonyl fluoride (4.00 G, 18.4 MMOL) and cyanamide (851 mg, 20.3 MMOL) in CH3CN (20 mL), in a vessel placed in a cold-water bath, was added 1,8- diazabicyclo [5.4. 0] undec-7-ene (DBU; 3.0 mL, 20 MMOL). After 15 minutes, a solution of 2- bromo-2', 6'-difluoro-acetophenone (4.54 g, 19.3 mmol ; from Example A (1)) in CH3CN (1 mL) and DBU (3.0 mL, 20. 3 MMOL) were sequentially added. The mixture was stirred at ambient temperature for a half-hour, then partitioned between CH2C12 and water, and acidified to pH=4 with 1 N HCI. The organic layer was separated, washed with brine, and dried over NA2SO4. The solvent was evaporated to give a hard foam, which was purified via column chromatography with 1: 1 ethyl acetate (EtOAc) and hexane (hex) as eluant to afford 6.2 G (82% yield) of a yellow powder. 1H NMR (DMSO-D6) : 8 11.50 (1 H, s), 8.35 (2H, bm), 8.10 (2H, d, J = 9.0 Hz), 7.96 (2H, d, J = 9. 0 HZ), 7.58 (1H, m), 7.24 (2H, dd, J = 7. 8,8. 2 HZ). Anal. calcd. for C16H10F2N3O3S2No.0. 1 EtOAc: C, 46.65 ; H, 2.58 ; N, 9.95 ; S, 15.19. Found: C, 46.65 ; H, 2 : 55 ; N, 9.80 ; S, 15.02. The title compound was prepared as follows. A mixture of 4- [4-AMINO-5- (2, 6-DIFLUORO- benzoyl)-thiazol-2-ylamino]-benzenesulfonyl fluoride (200 mg, 0.484 MMOL), piperazine (125 mg, 1.45 MMOL), CH3CN (2 mL), and 4- (N, N-dimethylamino)-pyridine (DMAP; 5 mg) was refluxed for 2 hours. The solvent was removed under reduced pressure, the residue was taken up into MeOH (2 mL), then precipitated with water, filtered, and washed with water. Further purification with column chromatography gave 91 mg (43% yield) of a yellow powder. 1H NMR (DMSO-D6) : 8 8.22 (2H, bs), 7.83 (2H, d, J = 8.7 Hz), 7.68 (2H, d, J = 8.7 Hz), 7.56 (1H, m), 7.22 (2H, dd, J = 7. 8,8. 2 HZ). HRESIMS : calcd. for C2OH2OF2N503S2 (M+H+) : 480.0976. Found: 480.0988. Anal. CALCD. for C2OHI9F2NS03S2 0. 7 MeOH : C, 49.53 ; H, 4.38 ; N, 13.95 ; S, 12.78. Found: C, 49.51 ; H, 4.39 ; N, 13.84 ; S, 12.93. |
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