6-METHOXY-1H-INDAZOLE-3-CARBOXYLIC ACID synthesis

Yield:518990-36-8 100%

Reaction Conditions:

Stage #1:6-methoxyisatin with sodium hydroxide;water at 20 - 50; for 1.5 h;
Stage #2: with sulfuric acid;sodium nitrite in water at 0; for 0.75 h;
Stage #3: with hydrogenchloride;tin(ll) chloride in water at 0; for 1.16667 h;

Steps:

3
The conversion of the substituted isatins to the corresponding indazole-3- carboxylic acids is essentially the same method as described for indazole-3-carboxylic acid: Snyder, H.R., et. al. J. Am. Chem. Soc. 1952, 74, 2009. The substituted isatin (22.1 mmol) was diluted with 1 N sodium hydroxide (24 mL) and was heated at 50 ⁰C for 30 min. The burgundy solution was allowed to cool to rt and was maintained for Ih. The reaction mixture was cooled to 0 ⁰C and was treated with a 0 ⁰C solution of sodium nitrite (22.0 mmol) in water (5.5 mL). This solution was added through a pipet submerged below the surface of a vigorously stirred solution of sulfuric acid (2.3 mL) in water (45 mL) at 0 ⁰C. The addition took 15 min and the reaction was maintained for an additional 30 min. A cold (0 ⁰C) solution of tin (II) chloride dihydrate (52.7 mmol) in concentrated hydrochloric acid (20 mL) was added to the reaction mixture over 10 min and the reaction mixture was maintained for 60 min. The precipitated solids were isolated by filtration, washed with water, and dried to give a quantitative mass balance. This material was of sufficient purity (¹H NMR and LC/MS) to use in the next step without further purification. Alternatively, the acid was recrystallized from acetic acid to provide pure material. Ethyl esters were prepared from the acids using sulfuric acid in ethanol.

References:

MEMORY PHARMACEUTICALS CORPORATION WO2007/56582, 2007, A1 Location in patent:Page/Page column 72

FullText