Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-05-23
1997-03-04
Higel, Floyd D.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
5483201, C07D23376, C07D23372, A61K 31415
Patent
active
056080760
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a method of preparing 5-(aminoalkyl)-hydantoins of the general formula I or the aminoalkyl-.alpha.-amino acids of the general formula II or their salts obtainable from them ##STR1## in which X stands for a C.sub.1 -C.sub.6 alkylene group which can be substituted and/or interrupted by heteroatoms such as, for instance, sulfur or oxygen (i.e., the alkylene group may be substituted by heteroatoms as demonstrated in Formula I or the heteroatom may fit in the alkylene group as shown in Formula II), with preservation of the adjacent amino function and Y stands for hydrogen or an organic group with up to 8 C atoms which can be substituted and/or interrupted by heteroatoms, such as, for instance, sulfur or oxygen, with preservation of the X and Y adjacent amino function and
In describing X as a C.sub.1 -C.sub.6 alkylene group which can be substituted and/or interrupted by heteroatoms it is meant that the alkylene group may be substituted by heteroatoms as shown immediately below in FIG. 1 or the heteroatom may fit in the alkylene group as shown immediately below in FIG. 2. ##STR2##
The synthesis of amino acids via the corresponding hydantoins is a known method of procedure. Thus, for example, .alpha.-amino acids can be cyclized with cyanate or cyanohydrins with ammonium hydrogen carbonate to the corresponding hydantoin (5-substituted imidazolidine-2,4-dione). The hydantoins can basically be split by means of chemical hydrolysis into the D,L amino acids, by means of enzymatic hydrolysis selectively into the D- or L-amino acids. Corresponding methods are known, for example, from DE 39 17 057 C and EP 0,377,083 A. In particular, the stereospecific splitting of the hydantoins is especially interesting since the D-antipodes of natural amino acids can be prepared as a result thereof. As is known from Ch. Syldatk et al. Adv. Biochem. Eng. 44, 29-75, 40 (1990), the corresponding preparation of amino acids with charged side chains poses problems. Thus, A. Moller et al., Enzyme Microb. Techol. 10, also found a broad hydantoinase and carbamoylase activity in the bacterium Arthrobacter crystallopaites AM2; however, hydantoins with charged side chains, including among others the hydantoins of lysine and ornithine, were not converted. On the other hand, the conversion of basic hydantoins is sporadically suggested (DE 39 17 057 C) and described (S. Takahashi et al., J. Ferment. Technol. 56, 492-8 (1978) and 57, 328 (1979); however, in the latter instance the conversion takes place only up to the carbamoyl-D-lysine. It basically turned out that, if at all, only the derivatives unprotected on the amino function are received as substrates during the enzymatic conversion. Thus, for example, corresponding amides such as 5-(4'-(N-carbobenzoxyamino)-butyl)-hydantoin are not converted with Agrobacterium radiobacter whereas the correspondingly unprotected 5-(4'-aminobutyl)-hydantoin is recognized as substrate. This has the consequence that correspondingly protected aminoalkylhydantoins must be unprotected in a complicated manner before an enzymatic conversion. The protective groups to be used thereby belong to the state of the art (Barton/011 is "Comprehensive Organic Chemistry" vol. 5 p. 333, Pergamon Press, Oxford, 1979; Chem. Abstr. 110 (1989) 135715x; Chem. Abstr. 190 (1988) 6967m).
Examples are also known (Angew. Chem. 103 (1991) 704-706) for preparing certain amino acids such as D-citrulline from L-amino acids with the same C number, such as for example L-ornithine. For this, 2 equivalents cyanate are reacted with L-ornithine and the .alpha.,.omega.-bisureido compound is acidicly changed into citrulline hydantoin, which can be converted enzymatically to D-citrulline. However, the suggested synthesis pathway does not function with amino acids containing an amino function.
The present invention address the problem of creating a method of preparing .alpha.-amino acids or 5-substituted hydantoins with basic side chain in which the protection of the amino function in the side chain necessary during the f
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Drauz, et al: "Chemoenzymatische Synthese von N-Carbamoyl-D-4-thialysin and N-Carbamoyl-D-homo-5-thialysin" (1992).
Drauz, et al: "Chemoenzymatische syntheses of omega-ureido D-amino acids" (1991).
Sobczyk, et al: "13C NMR spectra of hydantoins and 3-phanyl-2-thiohydantoins of amino acids", Polish Journal of Chemistry, vol. 54, No. 9, 1980.
Bommarius Andreas
Drauz Karlheinz
Kottenhahn Matthias
Degussa - Aktiengesellschaft
Higel Floyd D.
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