Process for the continuous production of basic cyclic optically

Details Process for the continuous production of basic cyclic optically Process for the continuous production of basic cyclic optically

1998-03-24

2000-07-25

Raymond, Richard L.

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

Organic compounds

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

540544, 540575, 540608, 544172, 546245, 548215, 548535, 5483345, C07D24104

Patent

active

060938234

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE APPLICATION

This invention relates to a novel process for the production of basic, cyclic and optically active .alpha.-amino acids of the general formula I ##STR1## in which n, m may mutually independently be 0, 1, 2 or 3, heteroatoms may in turn be substituted with H, (C.sub.1 -C.sub.6) alkyl, benzyl, formyl, COR.sup.2, or CO.sub.2 R.sup.3, benzyl, which may optionally be substituted with hydroxy, fluorine, chlorine, bromine or an NO.sub.2 group in position 2, 3 or 4, CO.sub.2 R.sup.3, -phenyl or NO.sub.2 -benzyl, NO.sub.2 -benzyl and
Chiral .alpha.-amino acids of the general formula I are, inter alia, important building blocks for the pharmaceuticals industry. Thus, for example, the non-proteinogenic piperazinecarboxylic acid in (S) configuration of the formula II ##STR2## is an intermediate compound of the HIV proteinase inhibitor L-735,525 (Tetrahedron Lett. 1994, 35, 673-676) of the formula III. ##STR3##


DISCUSSION OF THE PRIOR ART

As is generally known to the person skilled in the art (J. Jacques, Enantiomers, Racemates & Resolutions, Wiley, N.Y., 1981), racemic compounds of the general formula I may be transformed into the diastereomeric salt pairs thereof in various solvents with optically active acids and separated by fractional crystallisation.
Synthesis of the chiral amino acid of the formula II is described, for example, in Helv. Chim. Acta 1960, 888-896 starting from aromatic, heterocyclic pyrazinecarboxylic acid. A key stage in the synthesis is the resolution of the racemic (R,S)-piperazinecarboxylic acid via diastereomeric salt pairs with the assistance of optically active (S)-camphorsulphonic acid [(S)-CSA] to yield the (S,S)-salt pair of the formula IV at a yield of only approx. 50% [relative to the diastereomeric pair (an exact yield could not be found in the above-stated literature reference)], i.e. at a total yield of approx. 25%. ##STR4##
Apart from the moderate yields in conventional racemate resolution, an optical antipode is generally also obtained as a waste product on completion of a synthesis sequence, such that this method must be considered uneconomic or even unusable for industrial processes.
It is furthermore known that chiral .alpha.-amino acids may be racemised by adding catalytic quantities of aldehydes (Tetrahedron Lett. 1983, 24, 4457-4460), aldehydes and metal ions under alkaline conditions (JP 42-13445), and by heating in water under pressure (U.S. Pat. No. 3,213,106), in strong bases or acids (A. Neubergerin, M. L. Anson, J. T. Edsall, Advances in Protein Chemistry, Academic Press, New York 1948, 4, page 339) and in aliphatic carboxylic acids (Chem. Pharm. Bull. 1970, 18, 1788-1793). Disadvantages frequently associated with these stated racemisation methods are an excessively low rate of racemisation or the introduced .alpha.-amino acids undergo partial decomposition under the reaction conditions.
The object of the present invention is accordingly to provide a racemate resolution method for basic, cyclic, racemic amino acids which avoids the stated disadvantages and allows the corresponding optical antipodes to be obtained with the assistance of chiral acids at yields of above 50%, wherein attention should primarily be directed towards straightforward industrial implementation.


SUMMARY OF THE INVENTION

This object is achieved according to the invention by formula V ##STR5## in which n, m, X, Y and R.sup.1 have the above-stated meanings and Rac indicates that the adjacent carbon atom is racemic, formula VI ##STR6## in which n, m, X, Y, R.sup.1 and Rac have the above-stated meanings and p states the molar ratio of the chiral acid to the .alpha.-amino acid, wherein p is dependent upon the number of basic centres and may be a number from 1 to 6, and ##STR7## in which n, m, X, Y, R.sup.1, * and p have the above-stated meanings, from the mother liquor and auxiliary acid used for resolving the racemate before subsequently making up the mother liquor ##STR8## in which n, m, X, Y, Rac and R.sup.1 have the above-stated meanings and, from the resultant diaste

REFERENCES:
Felder et al., Helvetica Chimica Acta, vol. 43, No. 117, pp. 888-896, 1960.

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