Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
1999-12-08
2002-10-15
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C560S125000, C560S128000, C518S721000
Reexamination Certificate
active
06465689
ABSTRACT:
BACKGROUND OF THE INVENTION
U.S. Pat. No. 5,091,567, hereby incorporated by reference, covers a process for the preparation of gabapentin (1-aminomethyl-1-cyclohexane-acetic acid)
which medicament is useful, for example, in the treatment of epilepsy. The process is illustrated by the scheme:
The instant invention provides a stereoselective synthesis for the ring-substituted analogs of gabapentin and to gabapentin itself. The advantages of the instant syntheses are: control of stereochemistry and no resolution is required at the end of the synthesis.
SUMMARY OF THE INVENTION
The invention encompasses a novel synthetic route for the preparation of substituted gabapentin analogues. The route enables the synthesis of certain single stereoisomers of individual alkylated gabapentin derivatives with a high degree of stereochemical purity.
The invention is outlined in the general route shown below. The first step involves conversion of a substituted cyclohexanone to an (&agr;,&bgr;-unsaturated ester via use of a trialkylphosphonoacetate or an (alkoxycarbonylmethyl)triphenyl-phosphonium halide and a base, such as sodium hydride, potassium hydride, lithium- or sodium- or potassium-hexamethyldisilazide, butyllithium or potassium t-butoxide in a solvent such as tetrahydrofuran, dimethylformamide, diethylether, or dimethylsulfoxide at a suitable temperature in the range from −78° C. to 100° C.
The second step involves reaction of the &agr;,&bgr;-unsaturated ester with nitromethane and a suitable base such as tetrabutylammonium fluoride, tetra-methylguanidine, 1,5-diazabicyclo[4,3,0]non-5-ene, 1,8-diazabicyclo[5,4,0]undec-7-ene, a sodium or potassium alkoxide, sodium hydride or potassium fluoride in a solvent such as tetrahydrofuran, diethylether, dimethylformamide, dimethylsulphoxide, benzene, toluene, dichloromethane, chloroform, or tetrachloromethane at a suitable temperature in the range from −20° C. to 100° C.
The third step involves catalytic hydrogenation of the nitro moiety using a catalyst such as Raney nickel, palladium on charcoal or rhodium catalyst or other nickel or palladium containing catalyst in a solvent such as methanol, ethanol, isopropanol, ethyl acetate, acetic acid, 1,4-dioxane, chloroform or diethyl ether at a suitable temperature in the range from 20° C. to 80° C.
The final step involves a hydrolysis using hydrochloric acid and may also utilize a cosolvent such tetrahydrofuran or 1,4-dioxane or other such inert water miscible solvent at a suitable temperature in the range from 20° C. to reflux.
REFERENCES:
patent: 5091567 (1992-02-01), Geibel et al.
patent: 0414274 (1991-02-01), None
patent: 9729101 (1997-08-01), None
patent: 9733859 (1997-09-01), None
Bryans Justin Stephen
Morrell Andrew Ian
Ashbrook Charles W.
Killos Paul J.
Warner-Lambert & Company
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