2-Bromo-4-quinolinecarboxylic acid

A mixture of 2-hydroxyquinoline-4-carboxylic acid a (4.0 g, 21.2 mmol), POBrTo a solution of 2.07 g (9.16 mmol) 4-[(4-amino-3, 5-dimethyl-1H-pyrazol-1- yl)methyl]benzonitrile (intermediate 2C-2) in 41.5 mL DMSO was added 3.83 g (10.1 mmol) HATU, 3.19 mL N, N-diisopropylethylamine and 2.31 g (9.16 mmol) 2- bromoquinoline-4-carboxylic acid ([CAS-No. 15733-87-6], commercially available at e.g. Fluorochem, Combi-Blocks Inc.).The reaction mixture was stirred for 2 hours at 25C. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate and saturated aqueous ammonium chloride, then dried over sodium sulfate, filtrated and evaporated to dryness. The residue was purified using three subsequent Biotage Chromatography system (50 g snap KP-Sil column, hexane / 0- 100% ethyl acetate, then ethyl acetate / 0- 10% methanol) to obtain 3.0 g (64% yield) of the desired title compound. 1H NMR (400 MHz, DMSO d6): delta (ppm) = 2.14 (s, 3H), 2.16 (s, 3H), 5.37 (s, 2H), 7.30 (d, 2H), 7.76 (ddd, 1H), 7.81 - 7.93 (m, 3H), 7.95 (s, 1H), 8.06 (d, 1H), 8.15 (d, 1H), 10.06 (s, 1H).750 mg (3.42 mmol) 1-(4-fluorobenzyl)-3, 5-dimethyl-1H-pyrazol-4-amine (intermediate 1C-2) was dissolved in 20 ml tetrahydrofuran and 1.03 g (4.10 mmol) 2- bromoquinoline-4-carboxylic acid ([CAS-No. 15733-87-6], commercially available at e.g. Fluorochem, Combi-Blocks Inc.), 894 muL (5.13 mmol) N, N-diisopropylethylamine and 1.65 g (5.13 mmol) TBTU were added. The reaction mixture was stirred for 2 h at 25C. Then the reaction mixture was evaporated and the residue partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted two further times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was dissolved in dichloromethane and under evaporation adsorbed on Isolute HM-N (Biotage). The isolute was given on a Biotage SNAP cartridge (100 g; KP-Sil) preequilibrated with hexane and purified via column chromatography on silica gel (solvent: hexane/0- 100% ethyl acetate) to obtain 1.47 g (3.24 mmol, 95% yield) of the desired title compound. 1H NMR (400 MHz, DMSO d6): delta (ppm) = 2.14 (s, 3 H), 2.18 (s, 3 H), 5.24 (s, 2 H), 7.15 - 7.27 (m, 4 H), 7.77 (ddd, 1 H), 7.90 (ddd, 1 H), 7.94 (s, 1 H), 8.06 (d, 1 H), 8.16 (dd, 1 H), 10.02 (s, 1 H).To a stirred solution of Example 33; 7-{1-[(2-chloroquinolin-4-yl)carbonyl]piperidin-4-yl}-3, 3-dimethyl-2-oxa-7-azaspiro[4.5]decan-1-one; [Show Image] To a solution of

Molecular Weight:252.06
XLogP3:3.3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:250.95819
Monoisotopic Mass:250.95819
Topological Polar Surface Area:50.2
Heavy Atom Count:14
Complexity:234
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes