1H-INDAZOLE-7-CARBOXYLIC ACID

A solution of the indazole (8.30 g, 33.0 mmol) in methanol (100 mL) at 0 C was treated with an 29percent aqueous solution of potassium hydroxide (20 mL). The reaction mixture was allowed to warm to rt and was maintained for 18 h. The pH of the solution was adjusted to 5.5 by the addition of concentrated hydrochloric acid and the volatiles were removed under reduced pressure. The residue was partitioned between brine (100 mL) and ethyl acetate (200 mL) and the aqueous layer was extracted with additional warm ethyl acetate (200 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated. The residue was triturated with ethyl acetate (30 mL) and the solids were isolated by filtration, thus providing 5.86 g (94percent) of the acidA mixture of 2-amino-3-methylbenzoic acid (15.2 g, 0.10 mol), dimethylformamide (333 mL) and CsCOTo a solution of 2-amino-3-methylbenzoic acid (66.9 mmol) in N, N-dimethylformamide (200 mL) was added cesium carbonate (102 mmol). The mixture was stirred for 30 min. A solution of methyl iodide (67.0 mmol) in NN-dimethylformamide (50 mL) was added dropwise and the reaction mixture was maintained for 18 h at rt. The reaction mixture was partitioned between water (1 L) and ether (200 mL) and the water layer was extracted with an additional volume of ether (100 mL). The combined extracts were washed with brine (500 mL), dried over anhydrous potassium carbonate, and concentrated, thus providing methyl 2-amino-3-methylbenzoate in 92percent yield.'H NMR (400 MHz, CDC13) 6 7.77 (d, 1H), 7.19 (d, 1H), 6.59 (t, 1H), 5.82 (bs, 2H), 3.86 (s, 3H), 2.17 (s, 3H). To a solution of the ester (106 mmol) in chloroform (300 mL) was added acetic anhydride (239 mmol) while maintaining the temperature below 40 °C. The reaction mixture was maintained at room temperature for 1 h when potassium acetate (30.6 mmol) and isoamyl nitrite (228 mmol) was added. The reaction mixture was heated at reflux for 24 h and was allowed to cool to room temperature. The reaction mixture was washed with a saturated, aqueous solution of sodium bicarbonate, dried over sodium sulfate, and concentrated. Methanol (100 mL) and 6 N hydrochloric acid (100 mL) were added to the residue and the mixture was maintained for 18 h at rt. The volatiles were removed under reduced pressure and the residue was triturated with ethyl acetate (100 mL). The product was isolated by filtration, washed with ethyl acetate (20 mL), and dried, thus providing methyl 1H-indazole-7-carboxylate hydrochloride in 68percent yield.'H NMR (500 MHz, Me2SO-d6) 8 13.3 (bs, 1H), 8.26 (d, 1H), 8.12 (d, 1H), 8.25 (dd, 1H), 7.27 (t, 1H), 3.97 (s, 3H); MS (APCI) m/z 177 (M++1). A solution of the indazole (33.0 mmol) in methanol (100 mL) at 0 °C was treated with an 29percent aqueous solution of potassium hydroxide (20 mL). The reaction mixture was allowed to warm to rt and was maintained for 18 h. The pH of the solution was adjusted to 5.5 by the addition of concentrated hydrochloric acid and the volatiles were removed under reduced pressure. The residue was partitioned between brine (100 mL) and ethyl acetate (200 mL) and the aqueous layer was extracted with additional warm ethyl acetate (200 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated. The residue was triturated with ethyl acetate (30 mL) and the solids were isolated by filtration, thus providing the acid in 94percent yield.To a stirred solution of 1 H-To a stirred solution of tert-butyl (S)-4-amino-6-bromospiro[chromane-2, 4'- piperidine]-1 '-carboxylate (1 .51 g, 3.80 mmol) and 1 H-To a stirred solution of ethyl (S)-4'-amino-6'-bromo-3', 4'-dihydrospiro[piperidine- 4, 2'-pyrano[2, 3-c]pyridine]-1 -carboxylate (4.5 g , 11 .1 mmol) and 1 H-To a stirred solution of methyl (S)-4'-amino-6'-methoxy-3', 4'- dihydrospiro[piperidine-4, 2'-pyrano[3, 2-b]pyridine]-1 -carboxylate (70 mg, 0.227 mmol), 1 H-To a stirring solution of (S)-ethyl 4'-amino-6'-methoxy-3', 4'-dihydrospiro[piperidine- 4, 2'-pyrano[3, 2-b]pyridine]-1 -carboxylate (4.5 g, 12.6 mmol) and 1 H-1 /-/-lndazole-7-carboxylic acid (100 mg, 0.62 mmol) was suspended in anhydrous DCM (10 mL). DIPEA (430 muIota_, 2.47 mmol) was added followed by HATU (281 mg, 0.74 mmol) and the reaction was stirred at rt for 20 min. Dimethylamine hydrochloride (100 mg, 1 .23 mmol) was added and the reaction stirred at rt O/N. Additional dimethylamine (0948) hydrochloride (100 mg, 1 .23 mmol), DI PEA (1 mL, 5.74 mmol) and HATU (281 mg, 0.74 mmol) were added and the reaction stirred for a further 18 h. The reaction was diluted with DCM and washed with water and saturated aqueous sodium hydrogen carbonate. The organic fraction was dried and concentrated in vacuo. Initial purification by column chromatography (Biotage Isolera Four, 10 g, KP-Sil column, eluting with isohexane to EtOAc) afforded impure title compound. Final purification by preparative H PLC (acidic conditions) afforded the title compound as a white solid, (43 mg, 0.23 mmol, 37percent). (0949) An alternative procedure can be employed using 1 /-/-To a mixture of

Molecular Weight:162.15
XLogP3:1.1
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:162.042927438
Monoisotopic Mass:162.042927438
Topological Polar Surface Area:66
Heavy Atom Count:12
Complexity:196
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes