反应详情

Methanesulfony chloride (524 ml, 6.77 mol) is added to a cooled mixture of (-)-2-(isochroman-1-yl)ethanol (EXAMPLE 48, LXXIX, 940 g, 5.2 mol), diisopropylethylamine (1.27 l, 7.29 mol) in tetrahydrofuran (5.6 l). After 4 hr, aqueous hydrochloric acid (1N, 8 l) is added and the mixture extracted with ethyl acetate (17 l). The organic phase is washed with saturated aqueous sodium chloride (2 l) and concentrated under reduced pressure. The concentrate is dissolved in pyridine (4 l) and added to a mixture of piperazine (2.71 kg, 31.5 mol) in pyridine (6.88 l). After 21 hr, the mixture is concentrated under reduced pressure to a slurry and the solids filtered off and washed with ethyl acetate (10 l). The filtrate is concentrated under reduced pressure to an oil and azeotroped with heptane (8 l). The oil is dissolved in ethyl acetate (20 l) and washed with saturated aqueous sodium bicarbonate (2.4 l). The organic phase is concentrated under reduced pressure and the oil azeotroped with toluene (4 l) to give 1.28 kg of the title compound; HPLC retention time=7.3 min (Column=Zorbax C-8; Injection vol.=10 μl; Mobile phase=water (1100 ml)/acetonitrile (500 ml)/methanol (400 mm)/potassium phosphate, monobasic (15 g); Detector=254 nm; Flow rate =0.5 ml/min).

1. extractionthe mixture extracted with ethyl acetate (17 l)
2. washThe organic phase is washed with saturated aqueous sodium chloride (2 l)
3. concentrationconcentrated under reduced pressure
4. dissolutionThe concentrate is dissolved in pyridine (4 l)
5. waitAfter 21 hr
6. concentrationthe mixture is concentrated under reduced pressure to a slurry
7. filtrationthe solids filtered off
8. washwashed with ethyl acetate (10 l)
9. concentrationThe filtrate is concentrated under reduced pressure to an oil
10. customazeotroped with heptane (8 l)
11. dissolutionThe oil is dissolved in ethyl acetate (20 l)
12. washwashed with saturated aqueous sodium bicarbonate (2.4 l)
13. concentrationThe organic phase is concentrated under reduced pressure
14. customthe oil azeotroped with toluene (4 l)