Improved synthesis and purification of (R*,R*)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol (Tramadol) hydrochloride.

Abstract

Tramadol was prepd. by (1) a sequence including a Grignard reaction in the presence of an additive resulting in a higher trans:cis ratio of product than is obtained in the absence of the additive (2) synthesizing a hydrochloride of Tramadol without increasing the trans/cis ratio by addn. of HCl to Tramadol base in the presence of PhMe, and (3) synthesizing a hydrochloride of Tramadol while increasing the trans/cis ratio by converting the trans and cis forms to hydrochloride forms and recrystn. of the hydrochloride forms from MeCN. Thus, 3-bromoanisole in THF was added to Mg in THF over 25 min.; tris[2-(2-methoxyethoxy)ethyl]amine and 2-dimethylaminocyclohexane in tBuOMe were added followed by 1.5 h reflux to give 72% of a product comprising 89% trans-Tramadol. The product was converted to the hydrochloride and recrystd. from MeCN to give 99.99% trans-Tramadol hydrochloride. [on SciFinder(R)]