3-HYDROXY-4,6-DIFLUORO-(1H)INDAZOLE synthesis

Yield:887567-77-3 76%

Reaction Conditions:

with hydrazine hydrate in tetrahydrofuran;ethanol at 70; for 24 h;

Steps:

4.2.4. 3-Hydroxy-4,6-difluoro-1H-indazole (20)

In a three-neck round-bottom flask equipped with a reflux condenser, methyl 2,4,6-trifluorobenzoate (49) (0.20 g, 1.1 mmol) was dissolved in tetrahydrofuran (20 mL); then, a solution of 98% hydrazine monohydrate (0.15 g, 3.0 mmol) in ethanol (10 mL) was added dropwise. The mixture was heated at 70 °C for 24 h. After cooling at room temperature, the solution was decanted and the organic solvent evaporated under vacuum. The solid residue was washed with dichloromethane and dried to afford 20 (0.13 g, 76%) as a white solid. Mp 293.5 °C. Anal. Calcd for C₇H₄F₂N₂O: C, 49.42; H, 2.37; N, 16.47. Found: C, 49.44; H, 2.49; N, 16.27. ¹H NMR (DMSO-d₆) δ 11.8 (br s, 1H, NH), 10.9 (br s, 1H, OH), 6.71 (ddd, ³J_F4 = ³J_F6 = 10.3, ⁴J_H7 = 1.9, 1H, H5), 7.09 (dd, ³J_F6 = 9.2, ⁴J_H5 = 1.9, 1H, H7); ¹⁹F NMR (DMSO-d₆) δ -115.9 (dd, ³J_H5 = 9.6, ⁴J_F6 = 8.4, F4), -111.6 (br s, F6); ¹³C NMR (DMSO-d₆) δ 153.6 (s, C3), 98.9 (d, ²J = 20.2, C3a), 155.7 (dd, ¹J = 253.3, ³J = 16.7, C4), 94.4 (dd, ²J = 30.5, ²J = 23.3, C5), 161.8 (dd, ¹J = 242.7, ³J = 11.7, C6), 92.0 (dd, ²J = 26.1, ⁴J = 4.7, C7), 143.6 (dd, ³J = 15.1, ³J = 10.3, C7a); ¹⁵N NMR (THF-d₈, T = 207 K) δ -224.1 (N1, ¹J = 107.1), -117.9 (N2).

References:

Claramunt, Rosa M.;López, Concepción;López, Ana;Pérez-Medina, Carlos;Pérez-Torralba, Marta;Alkorta, Ibon;Elguero, José;Escames, Germaine;Acu?a-Castroviejo, Darío [European Journal of Medicinal Chemistry,2011,vol. 46,# 4,p. 1439 - 1447] Location in patent:experimental part