p-Toluenesulfonic acid monohydrate → N-((2R)-2,3-Dihydroxypropoxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide

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Reaction Steps

N-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide (22.3 g, 42.7 mmol) was suspended in methanol (223 mL, 10 mL/g), and a solution of pTsOH.H2O (4.1 g, 21.35 mmol) in water (22.3 mL) was added. The mixture was stirred at ambient temperature for 18 hrs, during which all solids dissolved to give a colorless, clear solution. The solution was concentrated and extracted with ethyl acetate (2×300 mL). The organic solution was washed with sodium bicarbonate, dried over MgSO4. After filtration, the filtrate was concentrated, and co-evaporated with heptane to give a foaming solid. To this solid was added hexane-CH2Cl2 (1:1, 100 mL) and the mixture was stirred for 30 min. A white solid formed, which was filtered, washed with hexane. The solid was recrystallized from hexane-AcOEt to give N-((R)-2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide as white crystals, 13.57 g (65.9%), after drying at 60° C. vacuum oven for 3 days. A second crop of 5.05 g was obtained from the mother liquor, after recrystallization from the same solvent system. The total yield was 18.62 g (90.4%): m.p. 89-90° C. (Form II of Compound B). The combined crystals were ground with a set of mortar and pestle to fine powder, and dried at 60° C. in a vacuum oven for 3 days: m.p. 117-118° C. (Form I of Compound B); [α]=−2.05° (c=1.12, methanol); Analysis: Calcd. For: C16H14F3I1N2O4: C, 39.85; H, 2.93; N, 5.81; F, 11.82; I, 26.32. Found: C, 39.95; H, 2.76; N, 5.72; F, 11.71; I, 26.53. 1NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.69 (s, 1H), 7.54 (dd, 1H, J=10.9, 1.5), 7.32-7.38 (m, 2H), 7.17 (dd, 1H, J=16.8, 9.0), 6.61-6.66 (cm, 1H), 4.82 (bs, 1H), 4.58 (bs, 1H), 3.84-3.85 (m, 1H), 3.71-3.64 (cm, 2H), 3.33 (2H, partially hidden by HDO).

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