Phenylhydrazine → 4-Methoxybenzamide

Participants

Reaction Conditions

Reaction Steps

1-(1-Ethoxyethyl)-3-(4-methoxybenzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid (0.3 g, 0.77 mmol), O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (0.247 g, 0.77 mmol, 1 eq.), dimethylformamide (3.85 mL) and phenylhydrazine (0.151 mL, 1.54 mmol, 2 eq.) are successively introduced into a 20 mL round-bottomed flask under argon. Triethylamine (0.322 mL, 2.31 mmol, 3 eq.) is added to the reaction mixture. The mixture is stirred at a temperature in the region of 60° C. for 15 hours. The solvent is then evaporated off under vacuum and the residual oil is diluted with 15 mL of ethyl acetate and 10 mL of water. The aqueous phase is isolated and then acidified to pH 4-5, after which it is extracted with ethyl acetate (3×15 mL). The combined organic phases are dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue is purified by flash chromatography on silica gel, eluting with a 1:1 ethyl acetate/heptane mixture. The product obtained in oil form (0.310 g, 84%, Rf=0.47 (1:9 MeOH/dichloromethane)) is placed without further purification in 5 mL of tetrahydrofuran and 2.5 mL of 2.5 N hydrochloric acid. The reaction mixture is then heated at a temperature in the region of 50° C. for 2 hours and is then cooled to room temperature. 15 mL of water are then added to the mixture. A precipitate forms. The tetrahydrofuran is evaporated off and the aqueous phase is neutralized with 5 N NaOH. The precipitate formed is filtered off and then washed with water. The beige-colored solid is dried in an oven at a temperature in the region of 60° C. under vacuum. The dry solid is then dissolved in acetone and precipitated from heptane. The 5-(N′-phenylhydrazinocarbonyl)-1H-thieno[2,3-c]pyrazol-3-yl]-4-methoxybenzamide thus obtained (86 mg, 33%) has a purity of 95%. Overall yield=28%. 1H NMR (400 MHz, (CD3)2SO-d6, δ in ppm): 3.85 (s, 3H); 6.72 (broad t, J=7.5 Hz, 1H); 6.76 (broad d, J=8.0 Hz, 2H); 7.05 (broad d, J=8.0 Hz, 2H); 7.15 (broad t, J=7.5 Hz, 2H); 7.85 (broad s, 1H); 8.09 (broad d, J=8.0 Hz, 2H); 8.19 (broad s, 1H); 10.45 (broad m, 1H); 11.0 (broad m, 1H); 12.9 (broad m, 1H). LC/MS: m=407. ES m/z=408 MH+

Provenance & Evidence