Synthesis and purification of (r,r)-2-[ (dimethylamino) methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride

• Main Authors: Jarvi, Esa T, Grayson, Neile A, Halvachs, Robert E
• Format: Patent
• Language: English
• Published: 04.06.2002

The compound (R*,R*)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol hydrochloride is a nonaddictive analgesic and is also known as Tramadol. This compound is manufactured by Gruenenthal GmbH of Germany and is sold under tradenames Tramal and Crispin. Methods for the synthesis of Tramadol are described in U.S. Pat. No. 3,652,589 which is incorporated herein by reference. This synthesis leads to a mixture of trans and cis forms of the compound, herein referred to as the trans and cis forms of Tramadol (although the name Tramadol, when used alone, generally refers to substantially pure trans form of the compound). There is some confusion within the literature as to what should be called cis and what should be called trans. For purposes of this disclosure, what is referred to herein as the trans form of Tramadol includes the R,R and S,S isomers as shown by the following two structures: (R*,R*)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol (Tramadol) is synthesized in 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. The Grignard reaction between 3 bromoanisole and the appropriate Mannich base in the presence of an amine or ether additive gives the amine product in an improved trans/cis ratio. The base is converted to its hydrochloride and recrystallized from a low molecular weight nitrile such as acetonitrile until a greater than 98% trans/cis ratio is obtained. Recrystallization from isopropanol gives (R*,R*)2-[(dimethylamino)methyl]-1-(3-metboxyphenyl)cyclohexanol hydrochloride free of the nitrile solvent. A hydrochloride of Tramadol can be synthesized without increasing a ratio of trans:cis by including a step in which HCl is added to Tramadol base in the presence of toluene.