677304-69-7

1H-indazole-7-carboxylic Acid is an inhibitor of nitric oxide synthases.

Synthesis of 1H-indazole-7-carboxylic acid, H2L4: To 60 mL anhydrous toluene under a nitrogen atmosphere was added methyl-2-amino-3-methylbenzoate (1.8 g, 11 mmol) and KOAc (560 mg, 5.7 mmol), and the mixture heated to reflux, at which time acetic anhydride (3.2 mL, 34 mmol) was added and the mixture stirred at reflux for 10 min. Isoamyl nitrite (2.3 mL, 18 mmol) was added over 30 min and the mixture refluxed overnight. On cooling, the mixture was filtered and evaporated to dryness to give 1.6 g of a pale brown solid, which analysed for methyl 1H-indazole-7-carboxylate. This material was taken up in 40 mL THF, added to a solution of LiOH (5 g, 210 mmol) in 40 mL water, and heated at reflux for 48 h. On cooling, the mixture was concentrated on a rotary evaporator and the resulting aqueous phase filtered and adjusted to pH 4 with dilute HCl, to precipitate the product, which was filtered, washed with water and dried under vacuum. Yield 810 mg, 45%; mp 218–222 °C (decomp);
δH (500 MHz, d6-DMSO): 7.23 (t, 1H, J = 7.5 Hz, H4 ), 7.97 (dd, 1H, J = 7.5, 1.0 Hz, H3 ), 8.06 (dd, 1H, J = 7.8, 0.8 Hz, H5 ), 8.21 (s, 1H, H2 ), 13.1 (br s, 2H, H1 & H6 ); δc (125 MHz, d6-DMSO): 113.7, 120.1, 124.6, 126.5, 129.0, 134.3, 138.0, 167.0; HRMS-ESI m/z: found: 163.0503; C8H7N2O2 requires: 163.0502 [M + H+ ]; ˉνmax/cm?1 (KBr): 3316 s br, 1700 s, 1619 m, 1592 m, 1509 m, 1285 s, 1201 m, 1145 m, 1078 m, 1056 w, 943 m, 858 s, 745 s, 638 m, 601 m.

General procedure for the synthesis of 7-carboxy-1H-indazole from 1H-indazole-7-carboxylic acid methyl ester: 1H-indazole-7-carboxylic acid methyl ester (8.30 g, 33.0 mmol) was dissolved in methanol (100 mL) at 0 °C, followed by the addition of 29% aqueous potassium hydroxide solution (20 mL). The reaction mixture was gradually warmed to room temperature and stirred for 18 hours. Upon completion of the reaction, the pH of the reaction solution was adjusted to 5.5 with concentrated hydrochloric acid and the volatile solvent was subsequently removed under reduced pressure. The residue was extracted by partitioning with brine (100 mL) and ethyl acetate (200 mL), and the aqueous layer was further extracted with warmed ethyl acetate (200 mL). All organic phases were combined, dried over anhydrous sodium sulfate and concentrated. The residue was ground with ethyl acetate (30 mL) and isolated by filtration to give the solid product 7-carboxy-1H-indazole in a yield of 5.86 g and 94% yield.

[1] Patent: WO2004/29050, 2004, A1. Location in patent: Page 64;65
[2] Patent: WO2008/65508, 2008, A1. Location in patent: Page/Page column 27-28