Ethylene Glycol → (-)-4-[4-[2-(Isochroman-1-yl)ethyl]piperazin-1-yl]benzamide

Participants

Reaction Steps

Borane-methyl sulfide (10.5 ml) in THF is added to an ice-cooled solution of (-)-(isochroman-1-yl)acetic acid (LXI, EXAMPLE 45--Step 3, 7.08 g, 36.8 mmol). After stirring for 20 min at 0°, the ice bath is removed and the solution is stirred at 20-25° for another 1.7 hr. The reaction flask is then placed in an ice-water bath and methanol is added slowly until no further gas evolution occurs. The solvents are then removed under reduced pressure and methanol is again added and removed a second and third time. The residue is partitioned between dichloromethane, aqueous sodium bicarbonate and saline. The organic phase is separated, dried over sodium sulfate and concentrated to give (-)-2-(isochroman-1-yl)ethanol (LXXIX). This material is added to dimethylaminopyridine (0.22 g, 1.8 mmol), diisopropylethylamine (16.0 ml, 92 mmol) and THF (60 ml). The mixture is cooled in an ice-water bath and methanesulfonyl chloride (3.4 ml, 44.2 mmol) is added dropwise over several minutes. After stirring for 55 min at 0°, 4-(piperazin-1-yl)benzamide (IV, EXAMPLE 47 Step 1, 9.06 g, 44.2 mmol) and ethylene glycol (60 ml) are added. The mixture is heated at 80° overnight and then water is added and the resulting solid is collected and washed with water and toluene. After drying, the solid is passed through silica gel using methanol/dichloromethane (4/96) to give (-)-4-[4-[2-(isochroman-1-yl)ethyl]piperazin-1-yl]benzamide, MS (m/z) 365; IR (mineral oil) 1610, 1239, 1643, 1112, 1622 cm-1.

Provenance & Evidence