1) Reductive amination of phenylacetone (I) with ammonium acetate and sodium cyanoborohydride (I) gives d,l-amphetamine (II), which is separated by distillation at reduced pressure from a secondary amine byproduct resulting from reaction of amphetamine with phenylacetone. Iodination of the N-acetyl-protected amine followed by acid hydrolysis yields a mixture of ortho-meta and para substituted iodoamphetamine, from which the para-isomer can be obtained by crystallization of the salt (IV) from hydrochloric acid. Reductive condensation of the primary amine salt with acetone and sodium cyanoborohydride then yields ofetamine (V). The free base is converted to the hydrochloride salt (VI) by treatment with dry HCl gas in ether. The acetate salt may be prepared by treatment of the free base with glacial acetic acid in ether, followed by addition of hexane or petroleum ether to precipitate the product.
2) A route that does not involve controlled drugs (phenylacetone or amphetamine) proceeds from p-iodophenylacetic acid (VII). The starting material can be made in low yield by iodination of phenylacetic acid or by a two-step process from p-aminophenylacetic acid by diazotization and treatment with potassium iodide. Condensation of p-iodophenylacetic acid (VII) with acetic anhydride gives p-iodophenylacetone (VIII) in variable yields, depending on the purity of the starting carboxylic acid and en the choice of base. Reductive amination with isopropylamine then gives iofetamine (V) in good yield.
3) A third sequence proceeds by condensation of p-iodobenzaldehyde (IX) with nitromethane, followed by reductive hydrolysis of the intermediate unsaturated nitrocompound, to yield p-iodophenylacetone (VIII). The final sequence is the same as in scheme 09034702a.