反应详情

A stirred solution of 7 g (0.024 mole) of 3-(3,5-dichlorophenoxy)-1-pyrrolidinecarbonyl chloride in 70 ml of tetrahydrofuran was treated with 7 g (0.05 mole) of N,N,N'-triethylethylenediamine (slight exothermic) and stirred at ambient temperature overnight. The mixture filtered to remove a small amount of precipitate. The filtrate was diluted with 200 ml of ice water, extracted with 3×100 ml of benzene and the combined extracts washed with water, dried over magnesium sulfate and concentrated in vacuo to give a pale brown oil, 8.24 g. The oil was dissolved in acetone, treated with 1.9 g of oxalic acid and heated until dissolved. A fine amorphous gel was removed by filtration and the filtrate diluted with isopropyl ether until cloudy. The salt was allowed to precipitate overnight. After 2 weeks the oil which separated from the acetone/isopropyl ether failed to crystallize. The solvents were removed by decantation and the residual oil converted back to the free base. The free base in methylene chloride was treated with 200 g of florisil and diluted with enough methylene chloride to give a stirrable slurry. After 30 minutes the slurry was filtered and the florisil washed with 2 volumes of methylene chloride. The florisil was suspended in 500 ml of methanol and transferred to a column. The column was washed with an additional 500 ml of methanol. Concentration in vacuo of the combined methanol effluents gave 7.6 g of dark oil which was chromatographed on a 100 g alumina column by eluting with a 0-5% methanol/acetonitrile gradient. The first 2 fractions were discarded and the remainder combined and concentrated to an oil (5.2 g). The oil was dissolved in ethyl ether, filtered to remove traces of alumina, concentrated in vacuo and excess solvent removed by pumping under high vacuum at 55° C. for 18 hours.

1. filtrationThe mixture filtered
2. customto remove a small amount of precipitate
3. additionThe filtrate was diluted with 200 ml of ice water
4. extractionextracted with 3×100 ml of benzene
5. washthe combined extracts washed with water
6. dry with materialdried over magnesium sulfate
7. concentrationconcentrated in vacuo
8. customto give a pale brown oil, 8.24 g
9. temperatureheated
10. dissolutionuntil dissolved
11. customA fine amorphous gel was removed by filtration
12. additionthe filtrate diluted with isopropyl ether until cloudy
13. customto precipitate overnight
14. customAfter 2 weeks the oil which separated from the acetone/isopropyl ether
15. customto crystallize
16. customThe solvents were removed by decantation
17. additionThe free base in methylene chloride was treated with 200 g of florisil
18. additiondiluted with enough methylene chloride
19. customto give a stirrable slurry
20. filtrationAfter 30 minutes the slurry was filtered
21. washthe florisil washed with 2 volumes of methylene chloride
22. washThe column was washed with an additional 500 ml of methanol
23. concentrationConcentration in vacuo of the combined methanol effluents