7-fluoro-1H-indazole-3-carboxylic acid synthesis
- Product Name:7-fluoro-1H-indazole-3-carboxylic acid
- CAS Number:959236-59-0
- Molecular formula:C8H5FN2O2
- Molecular Weight:180.14
317-20-4
959236-59-0
The general procedure for the synthesis of 7-fluoro-1H-indazole-3-carboxylic acid from 7-fluoroindolomanedione was carried out as follows: with reference to the methodology reported by Johnson, B.L. and Rogers, J.D. in Syn. Commun. 2005, 35, 2681-2684. First, 5.28 g of 7-fluoroindigo was suspended in 30 mL of water under stirring conditions, followed by the addition of a solution of 1.30 g NaOH dissolved in 10 mL of water. Stirring was continued until all solids were completely dissolved to form a deep red solution, which was subsequently cooled in an ice water bath. Next, a pre-cooled (ice bath) solution of 2.21 g NaNO2 dissolved in 10 mL of water was slowly added. The mixed solution was slowly added dropwise to the pre-cooled (ice bath) aqueous sulfuric acid solution (3.4 mL of H2SO4 dissolved in 60 mL of water), with ice being added during the process to maintain the temperature at approximately 0°C. After stirring for about 10 minutes, the dark red diazo solution was slowly added to a pre-cooled (0°C, ice bath) solution of 18 g SnCl2-2H2O dissolved in 30 mL of concentrated HCl, and ice was continued to be added to maintain the temperature at about 0°C. After the reaction mixture was stirred for about 1 h, filtration was performed and the resulting residue was dissolved in 60 mL of 1N NaOH and washed with ether (2 x 50 mL). The yellow-brown solution obtained was cooled in an ice bath and acidified with concentrated HCl to pH 3 (detected using litmus paper), at which point a dark yellow precipitate precipitated. The precipitate was collected by filtration, washed with water and dried in an oven overnight to give 3.69 g (47% yield) of 7-fluoro-1H-indazole-3-carboxylic acid as an orange solid. The product was characterized by 1H NMR (400 MHz, DMSO-d6): δ 14.35 (br s, 1H), 13.22 (br s, 1H), 7.89-7.87 (m, 1H), 7.26-7.21 (m, 2H). m/z MS (ESI) m/z 181 (M + H)+.
317-20-4
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959236-59-0
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Yield: 47%
Reaction Conditions:
Stage #1:7-fluoro-1H-indole-2,3-dione with sodium hydroxide;sodium nitrite in waterCooling with ice;
Stage #2: with sulfuric acid in water at 0; for 0.166667 h;
Stage #3: with hydrogenchloride;tin(II) chloride dihdyrate in water at 0; for 1 h;
Steps:
10.1
This compound was prepared following the procedure of Johnson, B. L.; Rodgers, J. D. Syn. Comm. 2005, 35, 2681-2684. A suspension of 5.28 g 7-fluoroisatin in 30 mL of water was added 1.30 g NaOH, in 10 mL water with stirring. The resulting dark red solution was stirred until all of the solids dissolved and was then cooled in an ice water bath. The solution was then slowly added a cooled (ice bath) solution of 2.21 g NaNO2 in 10 mL water. These combined solutions were then added slowly to cooled (ice bath) to solution of aqueous sulfuric acid (3.4 mL H2SO4 in 60 mL water). Ice was added to maintain a temperature of approximately 0° C. After stirring for approximately 10 minutes, this dark red diazonium solution was added slowly to a chilled (0° C., ice bath) solution of 18 g SnCl22H2O in 30 mL concentrated HCl. Ice was again added to maintain a temperature of approximately 0° C. After stirring for approximately 1 hour, the reaction was filtered and the resulting residue was dissolved in 1 N NaOH (60 mL), washed with ether (2×50 mL). The resulting yellow-brown solution was cooled in an ice bath and acidified to a pH3 (litmus paper) with concentrated HCl, which resulted in the formation of a dark yellow precipitate. The precipitate was collected by filtration, washed with water, and dried over night in an oven to give 3.69 g (47%) of 7-fluoro-1H-indazole-3-carboxylic acid as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ 14.35 (br s, 1H), 13.22 (br s, 1H), 7.89-7.87 (m, 1H), 7.26-7.21 (m, 2H). MS (ESI) m/z 181 (M+H)+.
References:
Pfizer Inc. US2011/28447, 2011, A1 Location in patent:Page/Page column 40