5-BROMO-6-HYDROXYNICOTINIC ACID

Light green solid

8A. 5-bromo-6-hydroxynicotinic acid: To 2-hydroxynicotinic acid (8 g, 57.6 mmol) suspended in water (30 mL) cooled in an ice bath was added bromine (4.2 mL, 81.4 mmol). After the addition was complete the reaction was stirred at rt for 24 h. The solid was collected by filtration, washed with water and dried at 40 8B. 5-Bromo-6-chloro-nicotinic acid: To 8A (10 g, 45 mmol) was added tetra-methylammonium chloride (5.4 g, 49 mmol) and phosphorous oxychloride (20 mL) and the reaction was heated at reflux for 3 h. The reaction was poured onto ice and stirred 2 h. The solid was filtered off, dissolved in EtOAc (300 mL) and dried (Na2SO4). After filtration and concentration, 10.5g (97%) of 8B as a pink solid was collected. 1HNMR (400 MHz, DMSO-d6) delta: 8.53 (d, J = 2.02 Hz, 1H) 8.85 (d, J = 2.02 Hz, 1 H) 13.57 (s, 1 H).8A. Preparative Example 11.; To a stirred suspension of 6-hydroxynicotinic acid (6.95 g, 50 mmol) in acetic acid (12.5 mL) was added bromine (3.8 mL, 75 mmol). The solution EPO Reaction scheme 7 above shows a general process for synthesizing compounds 349 and 350 of the present invention, and other compounds of the present invention can also be prepared according to reaction scheme 7 above. As shown in reaction scheme 7, key intermediate compound 29 can be synthesized in the following manner with reference to the literature (US 2010/0081673 Al). The starting material 6-hydroxynicotinic acid is allowed to react with bromine (Br2) to obtain compound 24 which is then esterified, thus synthesizing compound 25. The obtained compound 25 is allowed to be reacted with Meerwein's salt (US 5929094 Al) to synthesize compound 26. The obtained compound 26 is reduced with diisobutylaluminum hydride (DIBAL-H) to obtain compound 27 which is then chlorinated with titanium chloride (TiCl4), thus synthesizing compound 28. The resulting compound 28 is reacted with the reagents described in the paper (Akio Baba et al., Tetrahedron 2009, 65, 5462), thus synthesizing key intermediate compound 29. Then, compound 29 are subjected to the reactions shown in reaction schemes 4 and 6, thereby preparing the desired compounds 349 and 350.; As shown in reaction scheme 7, Compound 31, an intermediate compound, was synthesized, and then Compound 349 (0.28 g, 69.5%) as white solid foam was obtained according to the similar method to the synthesis of compound 285.1H NMR (400 MHz, DMSO-d6); atropisomer mixture; 6 7.86 (m, 1 H), 7.81 , 7.83 (2d, 1 H, J= 1.77, 1.83 Hz), 7.74 - 7.75 (m, 2 H), 7.02, 7.05 (2d, 1 H, J= 1.77, 1.77 Hz), 5.60, 5.63 (2d, 1 H, J= 5.94, 6.00 Hz), 3.91 - 4.03 (m, 2 H), 3.85, 3.88 (2d, 3 H), 3.64, 3.65 (2s, 3 H), 3.46- 3.52 (m, 1 H), 2.73 - 2.80 (m, 2 H), 1.90 - 1.95 (m, 2 H), 1.43 - 1.48 (m, 2 H), 1.16 - 1.20 (m, 6 H), 1.01 - 1.09 (m, 6 H), 0.28, 0.49 (2d, 3 H, J= 4.89, 4.89 Hz); MS (ESI) m/z 657.2 (M+ + H).Methyl 3-(5-(2-(((4S, 5R)-5-(3, 5-bis(trifluoromethyl)phenyl)-4-methyl-2-oxooxazolidin-3-yl)methyl)-4, 4-dimethylcyclohex-1-enyl)-6-methoxypyridin-3-yl)-2, 2-dimethylpropanoate [0562] As shown in reaction scheme 7, Compound 31, an intermediate compound, was synthesized, and then Compound 349 (0.28 g, 69.5%) as white solid foam was obtained according to the similar method to the synthesis of compound 285. [0563] 1H NMR (400 MHz, DMSO-d6); atropisomer mixture; delta7.86 (m, 1H), 7.81, 7.83 (2d, 1H, J=1.77, 1.83 Hz), 7.74-7.75 (m, 2H), 7.02, 7.05 (2d, 1H, J=1.77, 1.77 Hz), 5.60, 5.63 (2d, 1H, J=5.94, 6.00 Hz), 3.91-4.03 (m, 2H), 3.85, 3.88 (2d, 3H), 3.64, 3.65 (2s, 3H), 3.46-3.52 (m, 1H), 2.73-2.80 (m, 2H), 1.90-1.95 (m, 2H), 1.43-1.48 (m, 2H), 1.16-1.20 (m, 6H), 1.01-1.09 (m, 6H), 0.28, 0.49 (2d, 3H, J=4.89, 4.89 Hz); MS (ESI) m/z 657.2 (M++H)5.0 g of A suspension of A suspension of

Molecular Weight:218.00
XLogP3:0.4
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:216.93746
Monoisotopic Mass:216.93746
Topological Polar Surface Area:66.4
Heavy Atom Count:11
Complexity:280
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes