反应详情

温度

100 °C

A mixture of 1.9 g of sodium hydride, 12.07 g of 1-methyl-3-phenyl-4-piperidinol (mixture of isomers) of Example 1 and 70 ml of dry DMF is heated at approximately 100° C. for 1 hour under nitrogen, then cooled to room temperature. A solution of 16.45 g of 3-chlorofluorobenzene in 40 ml of DMF is added all at once, and the mixture is stirred for 18 hours at room temperature, then heated slowly so that after 4 hours the pot temperature is 68° C. After stirring for about 64 hours at room temperature, another 0.76 g of sodium hydride is added and the mixture is again heated slowly to approximately 70° C. After 2 hours the mixture is cooled and treated with 50 ml of saturated aqueous NaCl solution, then poured into a mixture of saturated aqueous NaCl solution and ether. The phases are separated and the aqueous phase is extracted with ether. The combined ether extracts was washed with water, saturated NaCl solution, and then concentrated in vacuo. The residue is partitioned between dichloromethane and water. The phases are separated and the aqueous phase is extracted with more dichloromethane. The combined dichloromethane phases are extracted with 2 N HCl solution, then washed successively with 10% aqueous NaOH solution, water, saturated aqueous NaCl solution, and dried over anhydrous Na2SO4. Concentration in vacuo affords an oil, which TLC shows to be a mixture of product isomers. This material is chromatographed on silica gel, using acetone as the initial solvent. The trans product is eluted with 25% methanol/acetone as solvent. The cis product is eluted with 25% and then 50% methanol/acetone, giving a crude free base which NMR shows to be an 8:3 mixture of cis product to 1-methyl-3-phenyl-1,2,5,6-tetrahydropyridine. The hydrochloride salt is prepared by dissolving the free base in ether and treating with HCl-saturated ether solution until the mixture is acidic to pH paper. The crude salt is filtered and washed with ether to afford a solid, m.p. s 180°, 207°-220° C. Recrystallization from acetone affords a solid of cis-4-(3-chlorophenoxy)-1-methyl-3-phenylpiperidine hydrochloride, mp s 230°, 231°-232.5° C.

1. temperaturecooled to room temperature
2. temperatureheated slowly so that after 4 hours the pot temperature
3. customis 68° C
4. stirringAfter stirring for about 64 hours at room temperature
5. temperaturethe mixture is again heated slowly to approximately 70° C
6. temperatureAfter 2 hours the mixture is cooled
7. customThe phases are separated
8. extractionthe aqueous phase is extracted with ether
9. washThe combined ether extracts was washed with water, saturated NaCl solution
10. concentrationconcentrated in vacuo
11. customThe residue is partitioned between dichloromethane and water
12. customThe phases are separated
13. extractionthe aqueous phase is extracted with more dichloromethane
14. extractionThe combined dichloromethane phases are extracted with 2 N HCl solution
15. washwashed successively with 10% aqueous NaOH solution, water, saturated aqueous NaCl solution
16. dry with materialdried over anhydrous Na2SO4
17. concentrationConcentration in vacuo
18. customaffords an oil, which TLC
19. additiona mixture of product isomers
20. customThis material is chromatographed on silica gel
21. washThe trans product is eluted with 25% methanol/acetone as solvent
22. washThe cis product is eluted with 25%
23. custom50% methanol/acetone, giving a crude free base which NMR
24. filtrationThe crude salt is filtered
25. washwashed with ether
26. customto afford a solid, m.p.
27. customs 180°, 207°-220° C
28. customRecrystallization from acetone