4-BROMOMETHYL-BENZENESULFONAMIDE

4.1 Acylsulfonamide (SZ2TA1)[ 0382 ] Ammonia gas was passed through a solution of compound 1 (1 g, 3.7 mmol) in DCM (100 mL) at 0 °C for 10 minutes. Brine (20 mL) was added. The separated organic phase was dried over anhydrous sodium sulfate and concentrated. The product 17 (900 mg, 96.8percent) was isolated by flash chromatography (hexanes: EtOAc = 2: 1). 1H-NMR (250 MHz, Acetone- 6) δ: 7.91 (d, J= 10.0 Hz, 2H), 7.67 (d, J= 10.0 Hz, 2H), 6.63 (bs, 2H), 4.74 (s, 2H) ppm.1.9 Sulfonyl azide (SZ 10) [ 0304 ] The solution of commercially available compound 6 (1 g, 3.74 mmol) in DCM was bubbled by ammonia gas at 0 C for 10 min. After mixed with DCM (20 mL) and water (20 mL), the system was extracted by DCM (20 mL x 3). The combined organic phase was dried by anhydrous sodium sulfate and concentrated. Product 7 (900 mg, 96 percent) was obtained by flash chromatography (hexane: EtOAc = 3: 1; Rf = 0.5 in hexane: EtOAc = 1 : 1). 1H-NMR (400 MHz, DMSO- 6) δ: 7.81 (d, J= 8.4 Hz, 2H), 7.63 (d, J= 8.4 Hz, 2H), 7.39 (s, 2H), 4.76 (s, 2H) ppm. Step 2: 4-bromomethyl-benzene-sulphonamide 4-hydroxymethyl-benzene-sulphonamide (0.105 mg, 0.56 mmoles) was dissolved in DCM (5 mL). Polymer supported triphenylphosphine (294 mg, 2.4 mmoles/g, 1.12 mmoles) was added, and the mixture was stirred with a shaker at room temperature for 10 minutes. CBr4 (557 mg, 1.68 mmoles) was then added, and stirring was continued for 3 hours. The supported reagent was removed by filtration, the solvent was evaporated, and the crude material was purified by flash chromatography (SiO2, petroleum ether/AcOEt 9/1) to yield the title compound as a light-yellow solid (70 mg). Alkylating agents K3 and K4 were synthesised as described in step 2 of this same Example 4, starting from the corresponding commercially available alcohol derivatives.Intermediate 105 tert-Butyl (5R, S)-3-oxo-2-(4-sulphamoylbenzyl)-2, 3, 5, 6, 7, 8-hexahydro[1, 2, 4]triazolo[4, 3-a]pyridine-5-carboxylate (Racemate) To tert-butyl (5RS)-3-oxo-2, 3, 5, 6, 7, 8-hexahydro[1, 2, 4]triazolo[4, 3-a]pyridine-5-carboxylate (racemate) (500 mg, 2.09 mmol) in 10 ml of acetonitrile were added caesium carbonate (1.02 g, 3.13 mmol) and