5-FLUORO-3-HYDROXY (1H)INDAZOLE synthesis

Yield:885519-12-0 52%

Reaction Conditions:

Stage #1: 2-amino-5-fluorobenzoic acidwith hydrogenchloride;sodium nitrite in water at 0 - 3; for 0.333333 h;
Stage #2: with sulfur dioxide in water at 0 - 20;

Steps:

52-53.i

A 3 litre beaker was charged with 2-amino-5-fluoro-benzoic acid (64 mmol, 10 g), 100 ml H₂O and 110 ml concentrated HCl and the suspension was cooled to 0° C. in an ice/aceton bath. A solution of natrium nitrite (64 mmol, 4.44 g) in 68 ml H₂O was added dropwise to the mixture while the temperature was maintained at below 3° C. After the addition was complete the brown solution was added in portions over 20 minutes, under a stream of sulfurdioxide, to a solution of 760 ml H₂O saturated with sulfurdioxide cooled at 0-5° C. with an ice-bath. After the addition was complete the ice-bath was removed and the solution was allowed to warm to room temperature while the stream of sulfurdioxide was maintained. After 1 hour the supply of sulfurdioxide was discontinued and the solution was allowed to stand at room temperature overnight. To the dark yellow solution which was obtained was added 620 ml concentrated HCl and after cooling the mixture a yellow precipitate separates which was collected on a cooled buchner funnel. The solid was suspended in a solution of 2 ml concentrated HCl and 200 ml H₂O and the mixture was heated to reflux. After a time the solid dissolves and a clear solution was obtained. After 1.5 hours of reflux a orange/brown solid has crystallized and the mixture was allowed to cool to room temperature and was concentrated to about 50 ml in vacuo. The solid was collected and dried in the air to afford 5-fluoro-1,2-dihydro-indazol-3-one (5.05 g, 52%)

References:

US2006/122189,2006,A1 Location in patent:Page/Page column 29