Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Patent
1997-07-11
1999-08-17
Ford, John M.
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C07D24106
Patent
active
059395494
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a process for preparing 1,4,5,6-tetrahydropyrazine-2-carboxamides of the general formula ##STR2## where R.sup.1 is hydrogen, a C.sub.1 -C.sub.30 -alkyl radical, a cycloaliphatic radical having 3 to 8 ring members, an aromatic radical or an araliphatic radical having 7 to 12 carbon atoms, and arylalkyl radical and R.sup.3, R.sup.4 and R.sup.5 independently of one another are each hydrogen, C.sub.1 -C.sub.6 -alkyl radicals, aryl radicals or arylalkyl radicals, or to form a mono- or polycyclic alicyclic system which may optionally be substituted by one or more C.sub.1 -C.sub.4 -alkyl groups, and R.sup.5 and R.sup.4 or R.sup.3 are each as defined above, where R.sup.7 is hydrogen or optionally substituted C.sub.1 -C.sub.6 -alkyl.
Here and below, alkyl radicals are in each case straight-chain or branched primary, secondary or tertiary alkyl groups, i.e. for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, octyl, etc.
Substituted alkyl is for example alkoxyalkyl groups or haloalkyl groups, in particular perfluoroalkyl groups such as, for example, trifluoromethyl.
Cycloaliphatic radicals are cycloalkyl groups, i.e. for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
Aryl radicals or aromatic radicals are mono- or polycyclic aromatic groups which may optionally be substituted by C.sub.1 -C.sub.4 -alkyl groups or halogens, i.e. for example phenyl, 1-naphthyl, 2-naphthyl, o-tolyl, m-tolyl, p-tolyl, xylyls, chlorophenyls, etc.
Correspondingly, arylalkyl radicals or araliphatic radicals are aryl-substituted alkyl radicals, in particular benzyl, 1-phenylethyl or 2-phenylethyl.
It is known that pyrazinecarboxylic acids and derivatives thereof such as esters and amides can be hydrogenated using heterogeneous catalysts (for example Pd/C). However, this hydrogenation usually leads to the corresponding piperazine derivative, i.e. the heteroaromatic ring becomes fully hydrogenated. Partial hydrogenation to the tetrahydropyrazine system has only been observed in exceptional cases, in which the isolation of a pure product in the case of the tetrahydropyrazinecarboxylic esters caused problems and the corresponding amide was not obtainable by this route. (E. Felder et al., Helv. Chim. Acta, 1960, 43, 888-896).
It is an object of the present invention to provide an industrial route to 1,4,5,6-tetrahydropyrazine-2-carboxamides substituted at the amide nitrogen. These previously unknown compounds are to provide alternative access to the corresponding piperazinecarboxamides, of which for example the (S)-piperazine-tert-butylcarboxamide is a building block of an active compound for the treatment of AIDS (U.S. Pat. Nos. 5,413,999, 5,527,799, 5,668,132 and 5,717,097)
According to the invention, this object is achieved by the process of of the invention and the compounds of of the invention.
It has been found that the 2-cyano-1,4,5,6-tetrahydropyrazines of the general formula ##STR3## where R.sup.1 is as defined above, react in the presence of a strong acid with compounds of the general formula ##STR4## where R.sup.2, R.sup.3, R.sup.4 and R.sup.4 are each as defined above and Q is a group which can be removed to leave a carbenium ion, in a Ritter reaction. It is probable that in this reaction a nitrilium salt is initially formed by the addition of the carbenium ion, formed from IIIa by protonation and/or from IIIb by removal of the group Q, to the cyano group, the nitrilium salt then being hydrolysed to the amide. If the reaction is carried out in the presence of a carboxylic acid of the formula ring is additionally selectively acylated, affording a product (I) where R.sup.6 .dbd.R.sup.7 --C(.dbd.O)--. Without the addition of a carboxylic acid, the corresponding compound where R.sup.6 .dbd.H is obtained. The embodiment with the addition of a carboxylic acid is preferred, since the acyl group may act as a protecting group in subsequent syntheses, permitting selective reactions at the nitrogen atom in position 4.
Particular
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Brieden Walter
Fuchs Rudolf
Roduit Jean-Paul
Ford John M.
Lonza AG
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