4-(4-chlorophenylsulfonyl)-5,8-difluoro-2H-chroMene synthesis

Yield:944950-71-4 64%

Reaction Conditions:

Stage #1: 4-(4-chloro-phenylsulfanyl)-5,8-difluoro-chroman-3-olwith 3-chloro-benzenecarboperoxoic acid in dichloromethane at 20; for 3 h;
Stage #2: with methanesulfonyl chloride;triethylamine in dichloromethane at 20; for 1 h;

Steps:

Step 3: 4-(4-Chloro-benzenesulfonyl)-5, 8-difluoro-2H-chromene 4-(4-Chloro-phenylsulfanyl)-5,8-difluoro-chroman-3-ol 63 (23.2 g, 71 mmol) was dissolved in 200 mL of dichloromethane and 31.7 g (77%, 142 mmol) of MCPBA was added. The reaction was stirred at room temperature for 3 hours, then quenched with a solution of 10 g of Na₂S₂O₃ in 50 mL water. The organic layer was washed with 2 100-mL portions of 1 N NaOH solution, 100 mL of brine, dried over Na₂SO₄ and concentrated. The residue was dissolved in 200 mL of dichloromethane, 16.1 g of mesyl chloride (142 mmol) and 14.3 g of triethylamine (142 mmol) were added. The reaction was stirred at room temperature for one hour. The reaction solution was washed with 100 mL of brine, dried over Na₂SO₄ and concentrated. The residue was recrystalized from EtOAc/Hexane solution to give 8.4 g pure vinyl sulfone product 64. The residue from mother liquor was purified by column chromatography eluting with a gradient from hexanes to 25% EtOAc/hexane over 55 minute to give an additional 7.1 g vinyl sulfone 64A. Total yield: 15.5 g, 64%. ¹H NMR (CDCI₃400 MHz δ 7.84 (dd, J = 8.8 and 2.2 Hz, 2H), 7.51 (d, J = 8.1 Hz, 2H)₁ 7.30 (t, J = 4.4Hz, 1 H), 7.00 (m, 1 H), 6.54 (m, 1 H), 4.99 (d, J = 4.4 Hz, 2H).

References:

WO2009/8980,2009,A2 Location in patent:Page/Page column 229-231