Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-08-31
1997-11-04
Shah, Mukund J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
540553, 544330, 548951, 564 27, C07D23350, C07D22900, C07D24300, C07D23902
Patent
active
056841566
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention relates to a novel method of preparing clonidine derivatives. In particular, the present invention relates to a method for producing clonidine derivatives which is shorter, less expensive and safer than the previously known methods. The present invention also relates to new thiourea complexes found as intermediates in the novel method of preparing clonidine derivatives, and the discovery that these new thiourea complexes can be directly cyclized.
Clonidine derivatives have been known for many years. Timmermans et al., Recueil des Travaux Chimiques des Pays-Bas, volume 97, page 51 (1978), first reported the synthesis of 4-nitroclonidine. Later, Rouot, et al., Bulletin de la Societe Chimique de France, page 520, (1979), used the same methodology to synthesize 4-nitroclonidine and reported reduction of this compound to 4-aminoclonidine (apraclonidine) using Fe/HCl. Van Dort et al., Journal of Medicinal Chemistry, volume 30, page 1241 (1987) also reported the synthesis of 4-aminoclonidine by the same route.
The methods of Timmermans et al. and Rouot et al., were found to be unworkable for large scale syntheses, so alternate methods were developed. These methods are described in detail in U.S. Pat. No. 4,515,800 (Cavero et al.) and U.S. Pat. No. 4,517,199 (York). The methods described in these patents are long and complicated, involving several steps of protection, deprotection and purification. In addition, the reagents used in these syntheses are hazardous, extremely corrosive to the equipment involved, and represent a disposal problem.
SUMMARY OF THE INVENTION
A novel process for preparing certain clonidine derivatives has now been unexpectedly discovered which is shorter, less expensive and safer than the previously known methods.
More specifically, the present novel process for preparing clonidine derivatives involves the discovery of a new thiourea complex which will undergo direct cyclization to produce a nitroaryl iminoheterocycle. Previous literature references have taught that displacement reactions on unactivated thioureas are difficult if not impossible. Therefore, previous references have provided for the activation of the thiocarbonyl group of thioureas, via three alternative methods: (a) s-alkylation; (b) oxidation at sulfur to an amidino sulfinic or sulfonic acid; or (c) heavy metal catalysis (lead, copper or mercury salts). See for example Van Dort et al., Journal of Medicinal Chemistry., volume 30, page 1241 (1987), and Belgian Patent No. 872 581 (1979). The present invention avoids the need for such thiourea activations, and more simply, provides a process whereby direct cyclization of the novel thiourea complex to the nitroaryl iminoheterocycle is obtained.
In particular, the present invention makes use of a novel process for direct cyclization of an nitroaryl-.omega.-amino thiourea by addition of a base, preferably an alkyl-.alpha.,.omega.-diamine or metal hydroxide in a solvent at reflux: ##STR1##
DETAILED DESCRIPTION OF THE INVENTION
The novel process of the present invention comprises six steps, which are outlined below: ##STR2## wherein: Ar is an aryl group, preferably phenyl or naphthyl, which is either unsubstituted or substituted with one or more groups, such as Cl, F, Br, I, C.sub.1 to C.sub.4 alkyl, aryl, C.sub.1 to C.sub.4 alkoxy or arylalkoxy;
In Step 1, a substituted or unsubstituted o- or p-nitroarylamine is converted to the corresponding nitroarylisothiocyanate by the addition of thiophosgene in a solvent such as toluene or water at reflux.
Step 2 involves the conversion of the nitroarylisothiocyanate to the corresponding .omega.-aminoalkylnitroarylthiourea, alkyl-.alpha.,.omega.-diamine solvate. This conversion is accomplished by slowly adding the isothiocyanate to an alkyl-.alpha.,.omega.-diamine in a solvent at or below more temperature. The product of Step 2, the .omega.-aminoalkyl nitroarylthiourea, alkyl-.alpha.,.omega.-diamine solvate (II), is a newly discovered complex. ##STR3##
In Step 3, the novel product compl
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Dean William D.
Deason Michael E.
Pierce David R.
Coleman Brenda
Mayo Michael C.
Shah Mukund J.
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