IMIDAZO[1,2-A]PYRIDINE-6-CARBOXYLIC ACID

Step 2. Imidazo[ l , 2-a]pyridine-6-carboxylic acid hydrochloride salt ( 1 70 g) was diluted with water (600 mL) and heated until a clear solution resulted, then an aqueous solution of NaOH (2 M) was added slowly to adjust the pH = 5-6. The reaction mixture was cooled to 0 °C using an ice-H2O bath. The resulting precipitate was collected by vacuum filtration, then washed with ethanol and dried under vacuum to give the title product ( 107.2 g, 77percent) as a light yellow powder. 1H NMR (400 MHz, DMSO-d6) 6 1 3.76-1 2.82 (br, 1 H), 9.28 (s, 1 H), 8. 10 (s, 1 H), 7.68 (s, 1 H), 7.64-7.56 (m, 2H). MS (ESI+) m z: 1 63 [M+H]Step 2. Imidazo[ l , 2-a]pyridine-6-carboxylic acid hydrochloride salt ( 1 70 g) was diluted with water (600 mL) and heated until a clear solution resulted, then an aqueous solution of NaOH (2 M) was added slowly to adjust the pH = 5-6. The reaction mixture was cooled to 0 °C using an ice-H>0 bath. The resulting precipitate was collected by vacuum filtration, then washed with ethanol and dried under vacuum to give the title product ( 107.2 g, 77percent) as a light yellow powder. NMR (400 MHz, DMSO-c/Step 2. Imidazo[ l , 2-a]pyridine-6-carboxylic acid hydrochloride salt ( 1 70 g) was diluted with water (600 mL) and heated until a clear solution resulted, then an aqueous solution of NaOH (2 M) was added slowly to adjust the pH = 5-6. The reaction mixture was cooled to 0 °C using an ice-H>0 bath. The resulting precipitate was collected by vacuum filtration, then washed with ethanol and dried under vacuum to give the title product ( 107.2 g, 77percent) as a light yellow powder. 1H NMR (400 MHz, DMSO-d6) 6 1 3.76-1 2.82 (br, 1 H), 9.28 (s, 1 H), 8. 10 (s, 1 H), 7.68 (s, 1 H), 7.64-7.56 (m, 2H). MS (ESI+) m z: 1 63 [M+H]Step 2. Imidazo[l, 2-a]pyridine-6-carboxylic acid hydrochloride salt (170 g) was diluted with water (600 mL) and heated until a clear solution resulted, then an aqueous solution of NaOH (2 M) was added slowly to adjust the pH = 5-6. The reaction mixture was cooled to 0 °C using an ice-HTo a solution of ethyl imidazo[l , 2-a]pyridine-6-carboxylate (6.0 g, 36 mmol) in tetrahydrofuran (30 mL) and water (30 mL) was added lithium hydroxide hydrate (2.7 g, 63 mmol). The reaction mixture was stirred at 25 °C for 2 hours. On completion, the mixture was acidified with 36percent hydrochloric acid. The solid was collected, washed with water and dried in vacuo to give compound B-266 (4.0 g, 78percent yield) as a yellow solid.[1148] A mixture of bromoacetaldehyde diethylacetal (8.0 ml, 52.5 mmol), H2O (60 ml), and conc. HCl (2.6 ml) is heated to 90° C. with an oil bath for 2 h. 6-aminonicotinic acid (2.5 g, 18.1 mmol) and sodium bicarbonate (4.3 g, 50.7 mmol) are added to the solution at rt, followed by heating the resulting mixture to 60° C. with an oil bath for 30 min. Upon cooling to rt a white ppt. is formed. The resulting off white solid is recrystallized from H2O/EtOH/Et2O to afford white crystals (2.3 g, 10.6 mmol, 59percent) for imidazo[1, 2-a]pyridine-6-carboxylic acid. HRMS (FAB) calcd for C8H6N2O2+H 163.0508, found 163.0492.A. A solution of imidazo[1 , 2-a]pyridine-6-carboxylic acid (0.100 g, 0.62 mmol), 5-(3-chlorobenzyl)pyridin-2-amine (0.161 g, 0.74 mmol), 1 -[b/s(dimethylamino)methylene]- 7/-/-1 , 2, 3-triazolo[4, 5-b]pyridinium 3-oxid hexafluorophosphate (0.353 g, 0.93 mmol) and A/-A/, A/-diisopropylethylamine (0.240 g, 1 .86 mmol) in A/, A/-dimethylformamide (3 ml_) was stirred at room temperature for 2 h. The crude sample was dissolved in minimal A/, A/-dimethylformamide and purified via prep-HPLC (Boston C18 21 *250 mm 10 pm column; acetonitrile/0.01 % aqueous trifluoroacetic acid) to give A/-(5-(3-chlorobenzyl)pyridin-2-yl)imidazo[1 , 2-a]pyridine-6-carboxamide (0.048 g, 0.1 12 mmol, 18.0%) as a faint yellow solid. 1 H NMR (500 MHz, Dimethylsulfoxide-c/6) d 1 1 .26 (s, 1 H), 9.57 (s, 1 H), 8.41 (d, J = 1 .8 Hz, 1 H), 8.37 (d, J = 2.5 Hz, 1 H), 8.34 (dd, J = 4.8, 4.8Hz, 1 H), 8.22 (d, J = 2.0 Hz, 1 H), 8.12 (d, J = 8.5 Hz, 1 H), 8.02 (d, J = 9.4 Hz, 1 H), 7.77 (dd, J = 8.5, 2.3 Hz, 1 H), 7.36- 7.33 (m, 2H), 7.29-7.25 (m, 2H), 4.00 (s, 2H); LCMS (ESI) m/z: 363.0 [M+H]+.To a solution of imidazo[1 , 2-a]pyridine-6-carboxylic acid (0.151 g, 0.75 mmol) and 5-(3-fluorobenzyl)pyridin-2-amine (0.120 g, 0.75 mmol) in pyridine (4 ml_) at 0 C was added phosphorus(V) oxychloride (1 .5 ml_). Reaction was stirred at room temperature for 1 h. The reaction mixture was poured into ice water and extracted with ethyl acetate (100 ml_ x 2). Combined organic layers were washed with brine (50 ml_), dried over sodium sulfate, filtered and concentrated. The crude sample was dissolved in minimal A/, A/-dimethylformamide and purified via prep-HPLC (Boston C18 21 *250 mm 10 pm column; acetonitrile/0.01 % aqueous trifluoroacetic acid) to give A/-(5-(3-fluorobenzyl)pyridin-2-yl)imidazo[1 , 2-a]pyridine-6-carboxamide (0.0314 g, 0.0908 mmol, 12.1 %) as a yellow solid. 1 H NMR (500 MHz, Dimethylsulfoxide-c/6) d 1 1 .27 (s, 1 H), 9.58 (s, 1 H), 8.43 (d, J = 1 .7 Hz, 1 H), 8.36 (d, J = 9.7 Hz, 2H), 8.24 (d, J = 1 .7 Hz, 1 H), 8.13 (d, J = 8.5 Hz, 1 H), 8.03 (d, J = 9.4 Hz, 1 H), 7.78 (dd, J = 8.5, 2.2 Hz, 1 H), 7.38-7.34 (m, 1 H), 7.185- 7.12 (m, 2H), 7.07-7.03 (m, 1 H), 4.01 (s, 2H); LCMS (ESI) m/z: 347.1 [M+H]+.Imidazo[1, 2-a]pyridine-6-carboxylic acid (50 mg, 0.28 mmol) was dissolved in DCM.Add II-1 (100 mg, 0.28 mmol), EDCI (91 mg, 0.48 mmol), HOBt (47.25 mg, 0.35 mmol), triethylamine (0.07 ml, 0.48 mmol), The reaction was stirred at room temperature for 5 h. After the reaction was over, water (20 ml) was added.Extracted with ethyl acetate (20 ml × 3), combined organic phase, Wash with saturated NaHCO3 solution (10 mL).Wash with saturated ammonium chloride solution (10 mL), Washed (10 mL), dried over anhydrous sodium sulfate and concentrated.Column chromatography gave the title compound (116 mg, 85%).To a stirred solution of compound D (2.5 g, 15.4 mmol, 1 eq) in DMF (50 mL) were added compound E (2.3g, 23.1 mmol, 1.5 eq), triethylamine (15.6 g, 154.3 mmol, 10 eq) and T3P (-50% in ethyl acetate, 14.8 g, 23.1 mmol, 1.5 eq) at 23 C and the resulting mixture was heated at 120 C for 18 h. The reaction mixture was cooled to RT, quenched with water and the organic components were extracted with 10% methanol/ CH2CI2. The organic layer was concentrated in vacuo and the crude material was purified by flash chromatography (Combiflash) using 100-200 mesh silica gel eluting with 10% MeOH/ CH2CI2 to obtain the compound F (600 mg, 20%) as off white solid. (0302) [0292] lH NMR (400 MHz, OMSO-d6) delta 9.03 (s, 1 H), 8.06 (s, 1 H), 7.64 (m, 1 H), 7.59 (d, / = 8 Hz, 1 H), 7.47-7.44 (m, 1 H), 3.61 (s, 3 H), 3.32 (s, 3 H); (0303) [0293] LCMS : m/z = 206.2 [M+H], RT = 0.54 minutes; (Program Rl , Column W).

Molecular Weight:162.15
XLogP3:1.3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:162.042927438
Monoisotopic Mass:162.042927438
Topological Polar Surface Area:54.6
Heavy Atom Count:12
Complexity:196
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes