Sodium Hydroxide → Manifaxine

To a chilled suspension of (2S,3S,5R)-2-(3,5-difluorophenyl)-3 5-dimethyl-2-morpholinol hydrochloride (Example 2) (10.0 g, 0.036 mole) in a mixture of water (100 ml) and diethyl ether (100 ml) was added sodium hydroxide as a 50% aqueous solution until the mixture was basic. The layers were separated and the aqueous layer extracted with diethyl ether. The combined extracts were dried (potassium carbonate). filtered and concentrated under reduced pressure to give (2S,3S,5R)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol (8 7g) A mixture of this base (8.7g. 0.036 mole) and methyl iodide (7.7g. 0.054 mole) in acetonitrile (50ml) was placed in a Wheaton pressure bottle and warmed in a water bath on a steam bath for 48 h. Further methyl iodide (7.7g, 0.054 mole) was then added and the mixture warmed for an additional five days. The reaction mixture was then concentrated under reduced pressure and the residue partitioned between diethyl ether and sodium hydroxide (lN aq.). The ether phase was dried (sodium sulphate). filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate: ethanol (95:5) as eluent to give (2S,3S,5R)-2-(3,5-difluorophenyl)-3,4,5,trimethyl-2-morpholinol This was dissolved in diethyl ether and a solution of 1.OM hydrogen chloride in diethyl ether added. The resulting salt was filtered washed with diethyl ether and recrystallised from acetonitrile: diethyl ether mixtures to give the title compound as a white solid. M.P 212°-214° C. eff. [α]D20 =+50.35° (c=0.727, 95% ethanol).