3-(N-IsopropylsulfaMoyl)benzoic acid synthesis

Yield:-

Reaction Conditions:

in ethyl acetate at 25; for 3 h;

Steps:

Compound 73 To an iced-cooled solution of 3-(chlorosulfonyl)benzoic acid (50.0 g, 226.6 mmol) in ethylacetate (1000 mL) was added isopropylamine (67.0 g, 1.13 mol) in one portion. The reaction mixture was stirred at 25°C for 3 hours. The resulting mixture was diluted with IN HC1 (500 mL) and extracted with ethyl acetate (2 x 500 mL). The combined organic layers were washed with brine (400 mL), dried over anhydrous Na₂S0₄ and concentrated under reduced pressure resulting 3-(N-isopropylsulfamoyl)benzoic acid (46 g). To an ice-cooled mixture of 3-(N-isopropylsulfamoyl)benzoic acid (7.0 g, 28.77 mmol), 4-fiuoro-3-methylaniline (3.6 g, 28.77 mmol) and DIPEA (18.6 g, 143.91 mmol) in CH₂C1₂ (70 mL) HATU (12.0 g, 31.56 mmol) was added under N₂ atmosphere. The resulting mixture was stirred at 20° for 16 hours. The solvent was removed in vacuo. The mixture was washed with saturated aqueous critic acid (30 mL), brine (20 mL) and dried over Na₂S0₄. The solvent was removed in vacuo. The residue was purified by preparative high performance liquid chromatography on SYNERGI 250*50 lOum (eluent: CH₃CN in H₂0 (0.05% TFA) from 35% to 65%, v/v). The pure fractions were collected and adjusted to pH=7 with Amberlite IRA-900(OH) anionic exchange resin. The resin was filtered off. The filtrate was lyophilized to dryness resulting in compound 73 (7.5 g). Method B; Rt: 3.44 min. m/z : 351.1 (M+H)⁺ Exact mass: 350.1 1H NMR (400 MHz, DMSO-d₆) δ ppm 10.49 (1 H, br. s), 8.36 (1 H, t, J=1.5 Hz), 8.19 (1 H, ddd, J=7.8, 1.5, 1.0 Hz), 8.01 (1 H, ddd, J=7.8, 1.5, 1.0 Hz), 7.76 (1 H, t, J=7.8 Hz), 7.68 (1 H, dd, J=7.0, 3.0 Hz), 7.75 (1 H, bs), 7.59 (1 H, ddd, J=9.0, 4.5, 3.0 Hz), 7.15 (1 H, t, J=9.0 Hz), 3.14 - 3.33 (1 H, m), 2.25 (3 H, d, J=1.5 Hz), 0.96 (6 H, d, J=6.5 Hz).

References:

WO2014/33170,2014,A1 Location in patent:Page/Page column 54; 55