Water → 4-(6-(4-Hydroxypiperidin-1-yl)-3-methylpicolinamido)-3,5-dimethylbenzoic acid

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Reaction Conditions

Reaction Steps

4-Hydroxypiperidine (171.2 g, 1660 mmoles) is added to a solution of methyl 4-[(6-chloro-3-methyl-pyridine-2-carbonyl)amino]-3,5-dimethyl-benzoate (69 g, 207.3 mmoles) in N-methylpyrrolidone (483 mL) and the mixture is stirred at 150° C. for 4 hours. The mixture is cooled to ambient temperature and poured into water (1000 mL). The mixture is washed with methyl t-butyl ether (300 mL). The aqueous layer is then acidified to pH 2 with aqueous 36% HCl. The mixture is extracted with a solution of 1/1 ethyl acetate/methyl-t-butyl ether (3×250 mL). The organic layer is evaporated to dryness. Water (500 mL) is added to the residue and the resulting mixture is stirred for 30 minutes, filtered and the filtered material dried in an oven vacuum at 45° C. overnight. The dried light brown solid is dissolved in acetone (500 mL) and heated to 50° C. Water (1000 mL) is slowly added and the mixture is stirred at 50° C. for 2 hours. The mixture is cooled to ambient temperature, filtered, and the filtered material dried under reduced pressure at 45° C. The dried material is stirred in ethyl acetate (600 mL) at 50° C. for two hours. The mixture is cooled to ambient temperature, filtered, and the filtered material dried under reduced pressure at 45° C. overnight to give the title compound as a white solid (50.8 g, 64%). Mass spectrum (m/z): 384.2 (M+1). 1H NMR (300 MHz, DMSO): 12.85 (s, 1H), 9.87 (s, 1H), 7.71 (s, 2H), 7.49 (d, J=8.7 Hz, 1H), 7.01 (d, J=8.7 Hz, 1H), 4.68 (d, J=4.1 Hz, 1H), 4.11-4.04 (m, 2H), 3.70 (m, 1H), 3.15-3.07 (m, 2H), 2.41 (s, 3H), 2.27 (s, 6H), 1.81-1.77 (m, 2H), 1.44-1.32 (m, 2H).

Provenance & Evidence