Tramadol Synthesis 4

From WikiSynth

Tramadol Synthesis
Type	Total Synthesis
Chemical Name	Tramadol
Systematic Name	(±)cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride
Reagents
Chemicals
Equipment
Reactions
Yield
Precautions
Primary Source	[1]

A variety of amine additives as well as one ether additive were tested in the Grignard reaction. These are set out in the following Table. The use of a few of these additives (TDA-1, 1-methylimidazole, and diglyme) were already noted in Examples 1, 2 and 3, respectively. Also shown are two examples of results from reactions run according to the literature procedure (U.S. Pat. No. 5,652,589) in which no additive was used. For the TDA-1 of Example 1, 2 equivalents of Grignard were used and the TDA-1 is the amount in the experimental. In the remaining Examples, 1.5-1.6 equivalents of Grignard were used and one mole of amine to one mole of Grignard added.

As seen in the above examples, the additive has an effect on the trans/cis ratio. The prior art examples yielded a ratio of 78/22 or 81/19. The present procedure in the presence of the additives yields ratios from a low of 82/18 to a high of 90.6/9.4. Some of the additives have only a minimal effect on the ratio (for example yielding only an 82/18 ratio), but others have a dramatic effect. For example, a product with an approximately 90/10 ratio has only about one-half the amount of the undesired cis product as compared to the prior art methods. The result of a higher ratio means that fewer crystallization steps may need to be performed.