反应详情

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.

1. customthe ice bath is removed
2. stirringthe solution is stirred at 20°-25° for another 1.7 hr
3. customThe reaction flask is then placed in an ice-water bath
4. additionmethanol is added slowly until no further gas evolution
5. customThe solvents are then removed under reduced pressure and methanol
6. additionis again added
7. customremoved a second and third time
8. customThe residue is partitioned between dichloromethane, aqueous sodium bicarbonate and saline
9. customThe organic phase is separated
10. dry with materialdried over sodium sulfate
11. concentrationconcentrated