Hydrochloric Acid → 4-(4-bromophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one

Participants

Reaction Conditions

Reaction Steps

In a 10 L 3-necked round bottom flask equipped with reflux condenser, mechanical stirrer and a stopper, a mixture of crude N-(4-bromophenyl)-2-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetyl}hydrazinecarboxamide (108.29 g, 63% purity, 167 mmol) and potassium carbonate (115 g, 833 mmol) in water (6 L) was stirred at reflux (variac heating mantle ˜130° C.) for 18 h. The variac heating was turned off and the flask was removed from the mantle and allowed to cool to ˜70° C. White solid settled to the bottom of the flask during this time. The liquid layer was siphoned into 2 L Erlenmeyer flasks using gravity and tygon tubing initially filled with water. When no more liquid could be siphoned, the remaining slurry was filtered. The filtrate was added to an Erlenmeyer flask and all the contents of these flasks were concentrated in vacuo using a large Buchi rotovap. LCMS analysis of the filtered white solid showed that it contained desired product. The filtered solid was added to the solid obtained from rotovapping. Ethyl acetate (2 L) and water (500 mL) were added to the contents of the flask and the mixture was acidified to pH˜5.5 using 6N aq HCl solution. The aqueous layer was extracted with ethyl acetate (5×500 mL). Then the aqueous layer was divided into 3 smaller portions and each was extracted with ethyl acetate (2×200 mL). The organic layers were combined, dried over magnesium sulfate and concentrated in vacuo to give a white solid. Trituration of the solid with dichloromethane (50 mL) followed by vacuum suction drying provided the title compound as a white solid (59.27 g, 74% pure, 112 mmol, 67% yield). MS(ES)+ m/e 391.1, 393.3 [M+H]+. The filtrate was concentrated in vacuo, dissolved in minimal dichloromethane and loaded directly onto a silica gel column. Purification by silica gel chromatography (Analogix IF280, 0-100% 10% MeOH in CH2Cl2/CH2Cl2 (effectively 0-10% MeOH/CH2Cl2), SF65-400 g, 60 min) provided another batch of the title compound as a white solid (9.5 g, 90% pure, 22 mmol, 13%). Impure product could be further purified by silica gel chromatography (Analogix IF280, 0-5% MeOH/CH2Cl2 over 30 min, then 5-10% MeOH/CH2Cl2 over 15 min) to afford clean desired product as a white solid. Purified material was used in subsequent reactions. MS(ES)+ m/e 391.1, 392.8 [M+H]+.

Provenance & Evidence