A process for the enantioselective synthesis of an (S)- or
(R)-1-[2-dimethylamino)-1-(methoxyphenyl)ethyl]cyclohexanol and analogues
or salt thereof are described. The method involves the steps of (a)
reacting an (S) or (R) 4-benzyloxazolidinone with a mixed anhydride of a
methyoxyphenylacetic acid under conditions which form a oxazolidinone,
(4S)- or (4R)-4-benzyl-3-[methyoxyphenyl]acetyl]-oxazolidin-2-one, (b)
treating the (4S)- or
(4R)-4-benzyl-3-[(methoxyphenyl)acetyl]-1,3-oxazolidin-2-one with an
aprotic amine base and titanium chloride in a chlorinated solvent under
conditions which permit formation of the corresponding anion, (c) mixing
the corresponding anion with titanium chloride and cylcohexanone under
conditions which permit an aldol reaction to form the corresponding (4S)-
or (4R)-4-benzyl-3-[(2R)-2-(1-hydroxycyclohexyl)-2-(methoxyphenyl)acetyl]-
-1,3-oxazolidin-2-one,(d) hydrolyzing the (4S)-- or
(4R)-4-benzyl-3-[(2R)-2-(1-hydroxycyclohexyl)-2-(methoxyphenyl)acetyl]-1,-
3-oxazolidin-2-one to form a chiral acid (2S or
2R)-(1-hydroxycyclohexyl)-methoxyphenyl)acetic acid, (e) coupling the
chiral phenylacid to a secondary amine to form an amide, and (f) reducing
the amide to form an (S) or (R)
1[2-dimethylamino)-1-(methoxyphenyl)ethyl]cyclohexanol or a salt thereof.