Water → AFN-1252 tosylate monohydrate

Participants

Reaction Conditions

Reaction Steps

A 22-L three-necked round-bottomed flask with a mechanical stirrer, a thermocouple, a reflux condenser and a nitrogen inlet was flushed with N2. The flask was charged with DCM (12 L, 16 v) and (E)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide (0.75 kg, 1.999 mol, 1.0 eq.). To the suspension, MeOH (1 L, 1.33 eq) was added and resulting suspension was heated to IT=35-40° C. When IT=35° C., a solution of TsOH.H2O (0.38 kg, 1.999 mol. 1 eq.) in methanol (0.5 L, 0.67 v) was added over 10 min while maintaining IT=35-40° C. After the addition was complete a clear solution was formed which was then filtered through 0.45 μm filter paper. The filtrate was divided in to two halves and transferred into two 22-L three-necked round-bottomed flasks with a mechanical stirrer, a thermocouple, a reflux condenser and a nitrogen inlet. Each solution was stirred at IT=35-40° C. and water (32 g, 2 mol, 1 eq.) was added. The clear solutions were then diluted with heptane (6 L, 8 v) over 15 min while maintaining IT=35-40° C. The resulting suspensions were allowed cooled to IT=20-25° C. over 3 h and allowed to stir at the same temperature for 18 h. The solid was collected by filtration using a Buchnner funnel with a cloth filter and 20-L glass receiver under vacuum. The solids were washed with heptane (3×2.7 v). The damp solid was dried under vacuum at 30-35° C. with a slow N2 bleed for 72 h to a constant weight to give 1.06 kg of the desired product as a white solid. The material was analyzed and the results indicated 98.3% area HPLC purity with 7.7 ppm Pd. This material was used for ball milling.

Provenance & Evidence