INTERMEDIATE A5 -Bromo-S-hydroxypyridine-l-carboxylic acid To a stirred suspension of 3-hydroxypyridine-2-carboxylic acid (2.00 g, 0.0144 mol) in DMF (30 mL) was added a solution of N-bromosuccinimide (2.56 g, 0.0144 mol) in DMF (30 mL). After 1 h, water (50 mL) and 1 M aqueous NaOH (25 mL) were added and the resulting mixture was extracted with chloroform (3 x 150 mL). The organic layers were combined and concentrated and the residue was purified by preparative HPLC (System D). Yield 366 mg (12percent). Analytical HPLC: purity 100percent (System A and B); LRESIMS (ESI6-BROMO-3-HYDROXYPICOLINIC ACID (17). To a mechanically stirred solution of methyl 3-hydroxypicolinate (30.6 g) in water (800 mL) was slowly added bromine (32 g) over a 30 minute period. After the addition was complete, stirring was continued for an additional hour. Ether (300mL) was added and stirring continued until all the solids had dissolved. The organic layer was separated and the aqueous phase extracted with ether (200mL). The organic phases were combined, dried (MgSO4) and the solvent evaporated to give 32.8 g of methyl 6-bromo-3-hydroxypicolinate as an off-white solid. Recrystallization from methanol/water gave an analytical sample, m.p. 115-117 C. To a stirred solution of this ester (2.32 g) in THF (15 mL) was added all at once a solution of LiOH.H2O (1 g) in water (7 mL). The resulting mixture was stirred for 2 hours at room temperature then poured into water (100 mL). The pH was adjusted to approximately 3 with 1N HCl, then the mixture was extracted with CH2Cl2 (3 x 100 mL). The organic extract was dried (MgSO4), filtered and concentrated to give 2.0 g of a white solid, whose 1H-NMR and MS were consistent with the desired title acid 17.EXAMPLE A526-Bromo-2- [(4- {6- [4-(methylsulfonyl)phenyl] -4H- 1 , 3-benzodioxin-2-yl}piperidin- 1- yl)carbonyl] pyridin-3-ol To a vial containing beta-bromo-S-hydroxypyridine-l-carboxylic acid (Intermediate A5; 61 mg, 0.28 mmol) was added a solution of 4-{6-[4-(methylsulfonyl)phenyl]-4H-l, 3- benzodioxin-2-yl}piperidine (Intermediate A4; 95 mg, 0.25 mmol) in TetaF (5 mL) and triethylamine (140 muL, 1.0 mmol) followed by etaOBT (69 mg, 0.51 mmol) and EDC (97 mg, 0.51 mmol). The resulting mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was purified by preparative etaPLC (System D). Yield 20 mg (14%). Analytical etaPLC: purity 91% (System A and B); etaRESIMS (ESI+) calcd for C26H25BrN2O6S 572.0618, found 572.0613.INTERMEDIATE A5 -Bromo-S-hydroxypyridine-l-carboxylic acid To a stirred suspension of 3-hydroxypyridine-2-carboxylic acid (2.00 g, 0.0144 mol) in DMF (30 mL) was added a solution of N-bromosuccinimide (2.56 g, 0.0144 mol) in DMF (30 mL). After 1 h, water (50 mL) and 1 M aqueous NaOH (25 mL) were added and the resulting mixture was extracted with chloroform (3 x 150 mL). The organic layers were combined and concentrated and the residue was purified by preparative HPLC (System D). Yield 366 mg (12%). Analytical HPLC: purity 100% (System A and B); LRESIMS (ESI+) m/z = 218/220 (M+H)+.To a stirred solution of this ester (2.32 g) in THF (15 mL) was added all at once a solution of LiOH.H2O (1 g) in water (7 mL). The resulting mixture was stirred for 2 hours at room temperature then poured into water (100 mL). The pH was adjusted to approximately 3 with 1N HCl, then the mixture was extracted with CH2Cl2 (3*100 mL). The organic extract was dried (MgSO4), filtered and concentrated to give 2.0 g of a white solid, whose 1H-NMR and MS were consistent with the desired title acid 17.
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