Reaktion #1904022

Reaktionsgleichung

3-formyl-1H-indazole-6 carboxylic acid

1,2-phenylenediamine

sulfur

water

→

3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid

Ausbeute 90.0%

Lösungsmittel

DMF

Reaktionsbedingungen

Aufarbeitung

1. 1
   TemperaturThis mixture was then heated
2. 2
   Temperaturto reflux for 6 hours
3. 3
   TemperaturAfter cooling
4. 4
   Sonstigethe brown precipitate which formed
5. 5
   Filtrationwas filtered
6. 6
   Sonstigecollected

Vorschrift

To a solution of 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid (208 mg, 0.7 mmol) in dry dimethylformamide (6 mL) was added 4-aminophenol (82 mg, 0.7 mmol) followed by HATU (312 mg, 0.8 mmol) and then triethylamine (20 drops) was added. The reaction was stirred overnight at room temperature. LC/MS showed desired product as major component. The solvent was removed by vacuum. The residue remaining was taken up in water and ethyl acetate. The layers were separated and the organic layer was concentrated under vacuum. The residue was dissolved in methanol (10 mL) and half of this solution was purified by HPLC using a gradient of 5% acetonitrile/water to 55% acetonitrile/water over 60 minutes with 0.1% trifluoroacetic acid in the water. The tide compound was isolated as a solid (20 mg). 1H NMR (methanol-d4) δ 6.87 (2H, d, 8.8 Hz), 7.55 (2H, d, 8.7 Hz), 7.61 (2H, m), 7.87 (2H, br s), 8.00 (1H, d, 8.4 Hz), 8.35 (1H, s), 8.52 (1H, d, 8.6 Hz). MS (APCI pos) 370.1. The starting material was prepared as follows: To 1H-indole-6-carboxylic acid (2.0 g, 12.42 mmol) in water (100 mL) was added NaNO2 (856 g, 124.2 mmol). To this suspension was then slowly added dropwise via addition fuel 6N HCL (16 mL). The resulting slurry was allowed to stir at room temperature overnight The solid precipitate was filtered and washed with water (50 mL) to provide 2.35 g (100%) of 3-formyl-1H-indazole-5-carboxylic acid. 1H NMR (DMSO-d6) δ 14.46 (1H, s), 10.21 (1H, s), 8.26 (1H, s), 8.20 (1H, d, J=8.5 Hz), 7.90 (1H, d, J=8.3 Hz). MS (APCI positive) 205 (methyl ester). To 3-formyl-1H-indazole-6 carboxylic acid (2.35 g, 12.42 mmol) in DMF (60 mL) was added 1,2-phenylenediamine (12.42 mmol, 1.34 g) and sulfur powder (1.1 eq, 13.66 mmol). This mixture was then heated to reflux for 6 hours. The reaction was followed by TLC and LC-MS. After cooling, water (50 mL) was added to the reaction and the brown precipitate which formed was filtered and collected to provide 3.1 g (90%) of 3-(1H-benzoimidazol-2-yl)-1H-indazole-6-carboxylic acid. 1H NMR (DMSO-d6) δ 14.01 (1H, s), 8.58 (1H, d, J=8.5 Hz), 8.24 (1H, s), 7.87 (1H, d, l=8.7 Hz), 7.64 (2H, m), 7.25 (2H, m). MS (APCI positive) 279.

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