Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-09-11
1997-11-11
Davis, Zinna Northington
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D21373
Patent
active
056866186
DESCRIPTION:
BRIEF SUMMARY
CROSS-REFERENCES TO RELATED APPLICATIONS
This application is derived, pursuant to 35 U.S.C. 371, from PCT/EP94/03988, filed Dec. 12, 1994.
The present invention relates to a process for preparing 3-amino-2-chloro-4-alkyl-or 4-aryl-pyridines, particularly for preparing 3-amino-2-chloro-4-C.sub.1-3 -alkylpyridines, or, in particular, for preparing 3-amino-2-chloro-4-methylpyridine, which can be used on an industrial scale.
The above-mentioned alkylpyridines are important starting compounds for the particular mention should be made of Nevirapin which is effective against HIV infections.
From the prior art there are various possible methods for synthesising 3-amino-2-chloro-4-methylpyridine, for example by catalytic hydrogenation of 2-chloro-3-nitro-4-methyl-pyridine. However, 3-amino-2-chloro-4-methylpyridine is not available in large amounts since it is not possible to chlorinate 3-amino-4-methylpyridine with chlorine on an industrial scale.
According to the invention, a two-step synthesis is proposed, preferably without isolation of the product of the first step, in which the starting compound used is a corresponding 2,6-dichloro-3-amino-4-alkyl or 4-aryl-pyridine, preferably 2,6-dichloro-3-amino-4-methylpyridine. Alternatively, the pyridine derivatives of general formula III may be prepared, again starting from the 3-amino-pyridines of general formula II. The following synthetic scheme illustrates the course of the synthesis: ##STR1##
A pyridine derivative of general formula I wherein preferably methyl, or ##STR2## R.sup.1 denotes hydrogen, C.sub.1-4 -alkyl (optionally substituted by halogen or hydroxy), nitro, cyano, hydroxy, C.sub.1-4 -alkoxy, C.sub.1-4 -alkoxy-C.sub.1-4 -alkyl, C.sub.1-4 -alkylsulphonyl, halogen, C.sub.1-4 -hydroxyalkyl-sulphonyl, COOC.sub.1-4 -alkyl, COOC.sub.1-4 -alkylphenyl, cyclopropyl, SH, S-C.sub.1-4 -alkyl; via catalytic dehalogenation to give a derivative of general formula II wherein R is as hereinbefore defined followed by selective chlorination in the 2-position, into a pyridine derivative of general formula III wherein R is as hereinbefore defined.
The alkyl groups used (including those which are constituents of other groups) may be methyl, ethyl, propyl, isopropyl, n-propyl, n-butyl, isobutyl, sec.-butyl and tert.-butyl, unless otherwise specified.
Cycloalkyl generally denotes a saturated cyclic C.sub.3-6 -hydrocarbon group which may optionally be substituted with one or several halogen atoms, a hydroxy group, an alkyl group, preferably methyl, which may be identical or different. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl. Phenyl groups may, for example, be substituted with one or more lower alkyl groups, alkoxy groups, nitro groups, amino groups and/or one or more halogen atoms (which may be identical or different).
The aryl groups may be optionally substituted phenyl or naphthyl groups.
A substituted phenyl group may also, for example, carry one or more of the substituents listed below: C.sub.1-6 -alkyl, C.sub.1-6 -alkoxy, halogen, amino, alkylamino, dialkylamino, CF.sub.3, C.sub.3-6 -cycloalkyl, cyano, NO.sub.2, COH, COOH, COOC.sub.1-4 -alkyl, cyclopropyl, hydroxy and hydroxymethyl.
Examples of substituted phenyl are as follows: 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-fluorophenyl, 2,3-dichlorophenyl, 2-methylphenyl, 4-methylphenyl, 3-ethylphenyl, 4-propylphenyl, 4-isopropylphenyl, 4-butylphenyl, 4-tert-butylphenyl, 4-isobutylphenyl, 4-pentylphenyl, 2,4-dimethylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethyl-phenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 3-ethoxyphenyl, 2-propoxyphenyl, 4-butoxyphenyl, 2,4-dimethoxyphenyl and 3,4,5-trimethoxyphenyl.
Alkoxy generally denotes a straight-chained or branched C.sub.1-4 -hydrocarbon group connected via an oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy or isobutoxy.
The number of carbon atoms specified relates to the length of the alkyl chain unless ot
REFERENCES:
patent: 5200522 (1993-04-01), Grozinger et al.
Klingsberg, Pyridine and Its Derivative, 1962, pp. 36-39.
Schickh et al., Chem. Ber., 69, 2593 (1936).
Boehringer Ingelheim KG
Davis Zinna Northington
Devlin Mary Ellen
Raymond R. P.
Stempel Alan R.
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