Organic compounds -- part of the class 532-570 series – Organic compounds – Heavy metal containing
Reexamination Certificate
2001-10-03
2003-11-18
Nazario-Gonzalez, Porfirio (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heavy metal containing
C556S045000, C556S051000, C556S113000, C556S116000, C556S118000, C556S130000, C556S135000, C556S136000, C556S150000, C514S492000, C514S494000, C514S499000, C514S501000, C514S502000, C252S183130, C564S443000
Reexamination Certificate
active
06649783
ABSTRACT:
1. FIELD OF THE INVENTION
The present invention relates to compositions comprising (±)-2-((dimethylamino)methyl)cyclohexanone, a transition-metal salt, and an organic solvent and to methods for preparing (±)-cis-2-((dimethylamino)methyl)-1-(aryl)cyclohexanols, in particular, (±)-cis-2-((dimethylamino)methyl)-1-(3-methoxyphenyl) cyclohexanol.
2. BACKGROUND OF THE INVENTION
Tramadol, whose chemical name is (±)-cis-2-((dimethylamino)methyl)-1-(3-methoxyphenyl)cyclohexanol, is a non-addictive, non-opioid analgesic agent useful for the management of moderate to moderately severe pain. Tramadol does not cause side effects associated with opioid analgesic agents (R. B. Reffa, J. Pharmacol. Exp. Ther., 267, 331, (1993)). Tramadol hydrochloride compositions are sold under several trade names, including TRAMAL, ULTRAM, CRISPIN, and TRAMUNDIN.
Tramadol is racemic and consists of the following two enantiomers: (1R,2R)-2-((dimethylamino)methyl)-1-(3-methoxyphenyl)cyclohexanol (IIIb) and (1S,2S)-2-((dimethylamino)methyl)-1-(3-methoxyphenyl)cyclohexanol (IIIa). The chemical structures of these enantiomers are depicted below:
(±)-Trans-2-((dimethylamino)methyl)-1-(3-methoxyphenyl)cyclohexanol, tramadol's corresponding trans isomer, is also racemic and consists of the following two enantiomers: (1S,2R)-2-((dimethylamino)methyl)-1-(3-methoxyphenyl)cyclohexanol (IIIc) and (1R,2S)-2-((dimethylamino)methyl)-1-(3-methoxyphenyl)cyclohexanol (IIId). The chemical structures of these enantiomers are depicted below:
Tramadol may be formed from a Grignard reaction of (±)-2-((dimethylamino)methyl)cyclohexanone and 3-methoxyphenylmagnesium bromide (U.S. Pat. No. 3,652,589 to Flick et al. and British Patent No. 997,399). But the product of this reaction is a mixture of tramadol and its corresponding trans isomer in a ratio of only about 78:22 to 82:18. Tramadol is significantly more analgesically active than its corresponding trans isomer (E. Frankus et al., Arzneim.-Forsch., 28(1A), 114 (1978)). Accordingly, tramadol is preferably separated from its corresponding trans isomer prior to administration.
The following paragraphs relate to processes for obtaining tramadol:
U.S. Pat. No. 3,652,589 to Flick et al. and British Patent No. 997,399 describe separating tramadol from its corresponding trans isomer by forming their corresponding hydrochloride salts and selectively crystallizing tramadol hydrochloride from moist dioxane. Dioxane, however, has many undesirable properties. For example, dioxane has recently been listed as a Category I carcinogen by OSHA (Kirk & Othmer, 3
rd
Ed., Vol. 9, p. 3861), is known to cause central nervous system (CNS) depression and liver necrosis (ibid., Vol. 13, p. 2671), is flammable, and tends to form hazardous peroxides (ibid., Vol 17, p. 48).
U.S. Pat. No. 5,414,129 to Cherkez et al. discloses a selective precipitation of tramadol hydrochloride by treating a mixture of tramadol and its corresponding trans isomer with a solution of hydrochloric acid and 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.
U.S. Pat. No. 5,672,755 to Lerman et al. and EP 0 778 262 disclose separating a mixture of tramadol and its corresponding trans isomer by reacting the mixture in a solvent at elevated temperature under acidic conditions. Under these conditions, tramadol's corresponding trans isomer is selectively dehydrated, and tramadol is precipitated as a salt.
U.S. Pat. No. 5,847,620 to Lerman et al. and EP 0 831 082 disclose separating a mixture of tramadol and its corresponding trans isomer by combining the mixture with an electrophilic reagent that selectively reacts with the hydroxyl group of tramadol's corresponding trans isomer and precipitating the unreacted tramadol from the reaction mixture.
U.S. Pat. No. 5,877,351 to Anderson discloses separating a mixture of tramadol and its corresponding trans isomer by adding aqueous HBr to the mixture. Here, tramadol hydrobromide selectively precipitates, while the hydrobromide of its corresponding trans isomer remains in solution.
U.S. Pat. No. 6,169,205 to Cabri et al. and EP 0 940 385 discloses a process for separating a mixture of tramadol and its corresponding trans isomer by selectively precipitating tramadol from a solution of water and a water-miscible organic solvent, such as acetone, dimethylformamide, ethanol, methanol, or tetrahydrofuran.
WO 99/36389 discloses a process for separating a mixture of tramadol and its corresponding trans isomer by diluting the mixture with a solvent and adding water to the resulting solution, forming hydrates of tramadol and its corresponding trans isomer. The hydrate of tramadol is then selectively precipitated.
WO 99/36390 discloses a process for separating a mixture of tramadol and its corresponding trans isomer by diluting the mixture with a solvent and contacting the resulting solution with hydrobromic or hydroiodic acid. The hydrobromic or hydroiodic salt of tramadol is then selectively precipitated.
WO 99/03820 discloses a process for separating a mixture of the monohydrate of tramadol and its corresponding trans isomer by selectively crystallizing tramadol monohydrate from ethyl acetate.
Conventional processes for preparing tramadol, which involve synthesizing a mixture of tramadol and its corresponding trans isomer via a Grignard reaction and selectively precipitating tramadol from the mixture, have disadvantages. In particular, about half of the reaction-mixture product, tramadol's corresponding trans isomer, is substantially less analgesically active then tramadol. Accordingly, a Grignard-reaction method that produces a high ratio of tramadol to its corresponding trans isomer is highly desirable.
WO 99/61405 discloses a process for preparing tramadol by reacting (±)-2-((dimethylamino)methyl)-1-(3-methoxyphenyl)cyclohexanone with 3-methoxyphenyl magnesium bromide in the presence of an amine or ether additive. The presence of the amine or ether additive allegedly increases the ratio of tramadol to its corresponding trans isomer.
There remains a need for methods for preparing tramadol having a high ratio of tramadol to its corresponding trans isomer.
3. SUMMARY OF THE INVENTION
The present invention is directed to a composition comprising (±)-2-((dimethylamino)methyl)cyclohexanone, a transition-metal salt and an organic solvent.
The present invention is further directed to a (±)-2-((dimethylamino)methyl)cyclohexanone:transition-metal salt complex.
The present invention is still further directed to a composition comprising the (±)-2-((dimethylamino)methyl)cyclohexanone:transition-metal salt complex and an organic solvent.
The (±)-2-((dimethylamino)methyl)cyclohexanone:transition-metal salt complex and the compositions of the invention are useful for synthesizing a (±)-cis-2-((dimethylamino)methyl)-1-(aryl)cyclohexanol and a (±)-trans-2-((dimethylamino)methyl)-1-(aryl)cyclohexanol in a ratio of at least about 85:15, wherein:
aryl is a phenyl or naphthyl group optionally substituted with one or more R
1
groups;
R
1
is selected from C
1
-C
10
straight or branched chain alkyls, —OR
2
, halogen, —CF
3
, —NH
2
, NHR
2
, NR
2
R
2
, and
each R
2
is independently a phenyl, benzyl or C
1
-C
10
straight or branched alkyl group.
The invention is also directed to a method for synthesizing a (±)-cis-2-((dimethylamino)methyl)-1-(aryl)cyclohexanol and a (±)-trans-2-((dimethylamino)methyl)-1-(aryl)cyclohexanol in a ratio of at least about 85:15, comprising the steps of:
(a) contacting (1) a composition comprising (±)-2-((dimethylamino)methyl)cyclohexanone, a transition metal-salt, and an organic solvent and (2) an aryl organometallic compound to provide a (±)-cis-2-((dimethylamino)methyl)-1-(aryl)cyclohexoxide salt and a (±)-trans-2-((dimethylamino)methyl)-1-(aryl)cyclohexoxide salt in a ratio of at least about 85:1
Kupper Robert J.
Stumpf Andreas
Euro-Celtique S.A.
Nazario-Gonzalez Porfirio
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