Process for preparing 2-piperazinecarboxylic acid derivatives

Details Process for preparing 2-piperazinecarboxylic acid derivatives Process for preparing 2-piperazinecarboxylic acid derivatives

1996-12-23

1999-01-05

Bernhardt, Emily

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

544388, 544390, C07D49804, C07D24104

Patent

active

058564853

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

1. Field of the Invention
The invention relates to a new process for preparing 2-piperazinecarboxamides of the general formula ##STR6## where R.sub.1 is a) unsubstituted or substituted alkyl or b) --OR.sub.4, where R.sub.4 is unsubstituted or substituted alkyl, is alkenyl or aryl, or c) --NR.sub.5 R.sub.6, where R.sub.5 is hydrogen or alkyl and R.sub.6 is alkyl, and R.sub.2 and R.sub.3 are identical or different and are hydrogen, unsubstituted or substituted alkyl, alkenyl or aryl, or the radical of an amino acid or an amino acid ester. The process of the invention enables both the (R) or (S) enantiomers of the 2-piperazinecarboxamides and the mixtures of the enantiomers, e.g., the racemates, to be obtained. The 2-piperazinecarboxamides are, inter alia, important intermediates for preparing orally active HIV-1 protease inhibitors European Published Patent Application No. A 541 168).
2. Background Art
In the previously known synthesis as described in European Published Patent Application No. A 541 168, the N-(t-butyl)-4-(t-butoxycarbonyl)-2(S)-piperazinecarboxamide of the formula ##STR7## is prepared, according to Example 15, starting from the 2-(S)-piperazinecarboxylic acid by conversion into the 1-Z-protected and 4-BOC-protected 2-(S)-piperazine-carboxylic acid by formation of the tert-butylamide and finally by catalytic hydrogenation to remove the Z protective group. This synthesis is very complicated and is therefore only suitable for the laboratory scale. Furthermore, Tetrahedron Letters 1994, 35, 676, discloses the preparation of the compound of the formula Ia in an overall yield of 26% starting from 2-pyrazinecarboxylic acid by further conversion into the t-butylamide, hydrogenation to give the piperazinecarboxamide, racemate resolution using camphorsulphonic acid and finally by introduction of the BOC protective group. This synthesis too is not suitable for transfer to an industrial scale.
3. Broad Description of the Invention
There was therefore the object of developing a synthesis which allows the piperazinecarboxamides to be prepared simply, in good yields and on an industrial scale.
The object was able to be achieved by means of the process of the invention.
The first stage of this process comprises the conversion of a 2-piperazinecarboxylic acid of the formula ##STR8## or a salt thereof into an N-acyl derivative of the general formula ##STR9## where R.sub.1 and R.sub.4 are as defined above.


DETAILED DESCRIPTION OF THE INVENTION

Alkyl is advantageously a straight-chain or branched, unsubstituted or substituted alkyl group having from 1 to 6 carbon atoms. Examples which may be mentioned of alkyl are methyl, ethyl, n- or i-propyl, n-, i- or t-butyl, pentyl and its isomers or hexyl and its isomers. Suitable alkenyl groups are vinyl, 1- or 2-propenyl (allyl), 1-, 2- or 3-butenyl, pentenyl and its isomers or hexenyl and its isomers. Aryl is advantageously an unsubstituted or substituted phenyl or naphthyl group. Substituents of the alkyl or alkenyl group which may be mentioned are, in particular, phenyl or halogens such as chlorine or bromine. A preferred representative of a substituted alkyl group is benzyl. Aryl substituents may be halogens such as chlorine or bromine or the specified alkyl groups. R.sub.1 is preferably --OR.sub.4, where R.sub.4 is as defined above. R.sub.4 is preferably benzyl, t-butyl or allyl.
The N-acylation to form the N-acyl derivatives of the general formula III can be carried out using acylation reagents known for blocking amino groups and under known conditions (see, for example, Houben-Weyl, Methoden der org. Chemie, 4th Edltion, Vol. 15/1, Synthese von Peptiden p. 46 ff).
For preparing the said preferred N-acyl derivatives, acylation reagents used are, for example, benzyl chloroformate for R.sub.4 =benzyl, di-t-butyl dicarbonate for R.sub.4 =t-butyl and, for example, allyl chloroformate for R.sub.4 =allyl.
In the cases where R.sub.1 is not --OR.sub.4, the acylation step can be preceded by the introduction, in accordance with the further me

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