The condensation of cyclohexanone (I) with 4 methoxyphenylacetonitrile (II) by means of n-butyllithium in THF gives 2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl) acetonitrile (III), which is reduced with H2 over Rh/A12O3 in ethanol-ammonia yielding 1-[2-amino-1-(4 methoxyphenyl)ethyl]cyclohexanol (IV). Finally, this compound is methylated with formaldehyde and formic acid in refluxing water.
A new process for the production of venlafaxine has been reported: Esterification of 2-(4-methoxyphenyl)-acetic acid (I) with ethanol and sulfuric acid gives the corresponding ethyl ester (II), which is condensed with ethyl formate by means of NaH to yield 2-formyl-3-(4-methoxyphenyl)acetic acid ethyl ester (III). Reaction of (III) with dimethylamine and K2CO3 in EtOH affords 3-(dimethylamino)-2-(4-methoxyphenyl)acrylic acid ethyl ester (IV), which is reduced with either NaBH4, LiAlH4 or H2 over Pd/C or Pt/C in ethanol to provide the corresponding propionic ester (V). Finally, this compound is cyclized with the bismagnesiane (VI) in THF. Alternatively, acrylic ester (IV) can be obtained directly by condensation of acetate (II) with dimethylformamide diethylacetal (VII) at 135 C. Alternatively, propionic ester (V) can be obtained by condensation of acetate (II) with N,N-dimethylmethylene-iminium iodide (VIII) by means of LDA in THF/heptane/ ethylbenzene.
The condensation of 2-(4-methoxyphenyl)-N,N-dimethylthioacetamide (I) with cyclohexanone (II) by means of isopropylmagnesium bromide in toluene/methyl tert-butyl ether gives 2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)-N,N-dimethylthioacetamide (III), which is finally desulfurized by means of Raney-nickel in dioxane/acetic acid.