Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-11-04
1999-11-23
Rotman, Alan L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
546127, C07D45102, C07D45110
Patent
active
059903120
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a novel process for the preparation of esters of anhydroecgonine from cocaine and derivatives thereof. Esters of anhydroecgonine are useful intermediates in the preparation of pharmaceutically active tropane derivatives.
BACKGROUND OF THE INVENTION AND PRIOR ART
Several publications describe conversions of cocaine to anhydroecgonine where the conversion is effected by heating cocaine in aqueous acid (hydrochloric or sulphuric acid) or with benzoic acid for several hours (de Jong, Recl. Trav. Chim. Pays-Bas, 56 (1937), pages 187-201 and Chem. Ber., 21 (1888), pages 3029-3045). At the time of the references cited above, the analytical methods available for the qualitative and quantitative determination of chemical compounds were limited, which makes the results obtained highly uncertain. Furthermore there is a lack of precise descriptions of how the reactions were carried out.
Several attempts to convert ecgonine or cocaine to anhydroecgonine in alkaline solutions or by heating in water, giving poor results, have also been described. In fact it seems that alkaline solutions favour isomerisation (de Jong, Recl. Trav. Chim. Pays-Bas, 56 (1937), pages 192-194.
In later references Anhydroecgonine and esters thereof have been prepared by hydrolysis of cocaine in aqueous hydrochloric acid followed by dehydration with phosphorus oxychloride (J. Amer. Chem. Soc., 82 (1960), page 4643 and EP-A1-604 355 ). Although both the hydrolysis of cocaine and the dehydration of ecgonine produces high yields, it is a serious drawback to this method that the reaction mixture becomes syrupy during the dehydration step which makes stirring almost impossible. Using SOCl.sub.2 as dehydrating agent causes similar problems.
Neither of these methods are thus suitable for large-scale production.
It has now surprisingly been found that esters of anhydroecgonine can be prepared in large-scale from cocaine or derivatives thereof using a convenient, high-yielding, one-pot synthesis.
The esters prepared according to the invention are useful intermediates in the preparation of pharmaceutically active tropane derivatives, see EP-A1-604 355).
OBJECTS OF THE INVENTION
It is an object of the invention to provide a novel method for preparing carboesters of anhydroecgonine, which is convenient, high-yielding and suitable for large-scale productions. Additional objects will be obvious to a person skilled in the art.
SUMMARY OF THE INVENTION
The invention then, inter alia comprises the following:
A process for the preparation of esters of anhydroecgonine having the formula ##STR1## any of its enantiomers or any mixture thereof, or a salt thereof, wherein R is alkyl, or optionally substituted aryl, or arylalkyl; comprising the step of reacting a compound of formula ##STR2## any of its enantiomers or any mixture thereof, or a salt thereof, wherein R.sup.1 is hydrogen, alkyl-CO--, or optionally substituted aryl-CO--, or arylalkyl-CO--; with an alcoholate RO.sup.-, M.sup.+ wherein R is as defined above and M.sup.+ is a counter ion, followed by isolation of the resulting compound either as the base or, if desired, in the form of a salt thereof; potassium ethanolate, lithium ethanolate, sodium methanolate, potassium methanolate, or lithium methanolate.
In the above definition of R and R.sup.1, alkyl means a straight-chained or branched chain of from one to six carbon atoms or cyclic alkyl of from three to seven carbon atoms, including but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; methyl, ethyl, propyl and isopropyl are preferred groups.
Aryl means an aromatic group, such as for example phenyl or napthyl which may substituted one or more times with alkyl, alkoxy, halogen, amino, nitro, cyano and trifluoromethyl for example.
Examples of salts of the compounds of formula (I) and (II) are acid addition salts including inorganic and organic acid addition salts such as the hydrochloride, hydrobromide, phosphate, nitrate, per
REFERENCES:
patent: 5506359 (1996-04-01), Madras et al.
L.G.Wadw,jr. Organic Chemistry, p. 349, Prentice Hall publishers, 1987.
Majewski, M. and Zheng, G., "Stereoselective deprotonation of tropinone and reactions of tropinone lithium enolate", Canadian Journal of Chemistry, vol. 70, pp. 2618-2626 (1992).
NeuroSearch A/S
Rotman Alan L.
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