tert-Butyl 6-(bromomethyl)-1H-indazole-1-carboxylate synthesis

Yield:1126424-54-1 38%

Reaction Conditions:

Stage #1: tert-butyl 6-(hydroxymethyl)-1H-indazole-1-carboxylatewith pyridine;sulfurous dibromide in chloroform at 0 - 70; for 0.666667 h;
Stage #2: with sodium hydrogencarbonate in chloroform;water;ethyl acetate;

Steps:

17.F

Step F - Synthesis of Compound 17 G; 17F 17G; A solution of alcohol 17F (160 mg; 0.644 mmol) in dry chloroform (12 mL) was placed in an ice-water bath and treated with pyridine (4.0 eq, 0.208 mL, d 0.978) and a solution of thionyl bromide (1.2 eq, 0.060 mL, d 2.683) in 1 mL of chloroform. The ice-water bath was removed and the reaction mixture was stirred at room temp for 30 min. TLC (30 % ethyl acetate in hexanes) showed about 40 % conversion and more thionyl bromide was added (0.2 eq). The mixture was heated to 70 °C for 10 min. Upon cooling the mixture was diluted with ethyl acetate (30 mL) and washed with aqueous saturated sodium bicarbonate (5 mL), aqueous sodium hydrogen sulfate (5 mL) and brine (5 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in rotavap. The residue was purified on a Biotage 25-S silica gel column (gradient: 0 to 40 % ethyl acetate in hexanes) to give the product 17G (76 mg; 38 %) as a colorless oil along with unreacted starting material (25 mg; 24 %). ¹H- NMR (CDCl₃; 400 MHz): δ 8.23 (IH, s), 8.14 (IH, s), 7.72 (IH, d, J = 8.54 Hz), 7.32 (IH, dd, J = 1.22, 8.54 Hz), 5.21 (IH, d, J = 12.20 Hz), 5.09 (IH, d, J = 12.20 Hz), 1.71 (9H, s).

References:

WO2009/32125,2009,A1 Location in patent:Page/Page column 113