Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2000-11-20
2002-06-04
Barts, Samuel (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S424000, C564S303000, C564S304000, C564S438000
Reexamination Certificate
active
06399829
ABSTRACT:
BACKGROUND OF THE INVENTION
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:
The cis form of Tramadol, as that phrase is used herein, includes the S,R and the R,S isomers which are shown by the following two structures:
Methods of manufacture begin with a Grignard reaction which results in a mixture of cis and trans isomers. These are then separated by methods taught in the prior art. U.S. Pat. No. 5,652,589 teaches a method of heating the mixture under reflux with a mixture of anhydrous dioxane and water for one hour while stirring and filtering. The filter residue obtained includes the trans form of the hydrochloride of Tramadol. The filtrate is a mixture of about 20-30% cis form and 70-80% trans form. This filtrate can be further separated by cooling to yield crystals which are then pulverized and stirred with dichloromethane at room temperature. The cis isomer is not dissolved whereas the trans isomer goes into solution. This solution is filtered. The filtrate yields substantially pure trans isomer. The filter residue is dissolved in methanol and crystallized by adding ether. The resulting crystals are substantially pure cis isomer of Tramadol.
U.S. Pat. No. 5,414,129, which is incorporated herein by reference, teaches a process for the improved purification and separation of the cis and trans isomers of Tramadol. This '129 patent lists the many problems with using dioxane in the preparation of a compound which is to be used as part of a drug. Included in this list are the following: dioxane has been listed as a category I carcinogen by OSHA (Kirk & Othmer, 3rd edition vol. 9, page 386) and it causes CNS depression and necrosis of the liver and kidneys (Kirk & Othmer, 3rd edition vol. 13, page 267). Therefore, the presence of dioxane as a residue is monitored and a limit of several parts per billion has been set. The '129 patent teaches a method which avoids the use of dioxane. Tramadol is first synthesized via a Grignard reaction to yield a mixture of cis and trans forms plus Grignard reaction side products. This mix of products is combined with a solution of hydrochloric acid in a low molecular weight alcohol or with gaseous hydrogen chloride in the presence of an organic solvent selected from medium molecular weight alcohols, ketones, esters and ethers or aromatic ethers, to effect the selective precipitation of the trans isomer (Tramadol). The '129 patent states that alternative solvents to dioxane which will effectively separate the cis and trans isomers were very hard to find, but those listed in the patent were found to be usable.
BRIEF SUMMARY OF THE INVENTION
In accordance with the present invention, a method is provided for forming a product comprising (R*,R*)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol (Tramadol) by a process selected from the group consisting of 1) synthesizing Tramadol in a sequence of steps including a Grignard reaction in the presence of an additive wherein the presence of said additive results in a higher trans:cis ratio of Tramadol than is obtained in the absence of said additive, 2) synthesizing a hydrochloride of Tramadol without increasing a ratio of trans:cis by performing a step consisting essentially of adding HCl to Tramadol base in the presence of toluene, and 3) synthesizing a hydrochloride of Tramadol while increasing a ratio of trans:cis by converting trans and cis forms of Tramadol to hydrochloride forms and recrystallizing said hydrochloride forms from a nitrile solvent.
REFERENCES:
patent: 3652589 (1972-03-01), Flick et al.
patent: 5414129 (1995-05-01), Cherkez et al.
patent: 0778262 (1997-11-01), None
Grayson Neile A.
Halvachs Robert E.
Jarvi Esa T.
Barts Samuel
Mallinckrodt Inc.
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