Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing heterocyclic carbon compound having only o – n – s,...
Patent
1988-07-13
1992-04-07
Robinson, Douglas W.
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing heterocyclic carbon compound having only o, n, s,...
435123, 435280, 435939, 435911, 435254, 435255, C12P 1708, C12P 1702, C12N 114, C12N 116
Patent
active
051027933
DESCRIPTION:
BRIEF SUMMARY
The invention relates to a microbiological process for stereospecific mono-keto reduction of racemic bicyclic carbacyclin intermediate stages of the formula (.+-.)-II to the corresponding optically active 3alpha-hydroxy compounds of the formula (+)-I. ##STR1##
The radicals A, B and R in the formula mean: ##STR2## or other ketal radicals and R: C.sub.1 -C.sub.6 alkyl.
The process is characterized in that a ketone of the general formula (.+-.)-II, in which A, B and R have the meaning indicated above, is treated with microorganisms, and the resulting 3alpha-hydroxy-prostacyclin intermediate product, which in its configuration corresponds to the natural PGI.sub.2, is isolated.
In a second embodiment of the stereospecific keto reduction process according to the invention not the enantiomers of the racemic synthon (.+-.)-II correspondingly configured to the natural PGI.sub.2 but the antipodal form is reduced by microorganisms. In this case, the naturally configured keto enantiomers (+)-II, which has remained unchanged in the microbiological transformation, is used for the synthesis of prostacyclins, by reducing it either chemically (for example, with sodium boron hydride) or microbiologically to (+)-I. ##STR3##
The invention is especially suitable for microbiological stereospecific reduction of the prostacyclin intermediate products 3-7 specified below. ##STR4##
Optically active 6alpha-carbaprostacyclin and especially some compounds derived for it have, as stable analogs of the natural prostacyclin (PGI.sub.2), a high therapeutic use [R. C. Nickolson, M. H. Town, H. Vorbrueggen: Prostacyclin Analogs, Medical Research Reviews, Vol. 5, No. 1, pp. 1-53 (1985). The syntheses specified in this more recent survey are long and lead partially only to racemic carbacyclins. The syntheses, which lead to the carbacyclins in the absolute configuration corresponding to the natural PGI.sub.2, are especially costly. This is due to the fact that readily accessible, suitable initial materials are achiral and the optical activity must be introduced into the intermediate stages suitable for this purpose only in the course of the synthesis.
Several syntheses already start from optically active 7alpha-hydroxy-6beta-hydroxymethyl-2-oxa-bicyclo[3.3.0]octan-3-one derivatives. Thus the problem of the introduction of optical activity is indeed solved. But further multistage synthesis sequences must still be performed for the substitution of the 2-oxa function by a methylene group, to reach derivatives of 3alpha-hydroxy-2beta-hydroxymethyl-bicyclo[3.3.0]octan-7-one, which are suitable only for the attachment of alpha and omega chains typical, respectively, for the carbacyclin analogs.
A more recent publication describes the use of cis-bicyclo[3.3.0]octan-3,7-dione derivatives for synthesis of optically active carbacyclins. Kojima et al. describe in Chem. Pharm. Bull. 33, 2688 (1985) a process, which includes the separation of diastereomeric salts of the racemic 7,7-ethylenedioxy-3alpha-hydroxy-cis-bicyclo[3.3.0]octane-2-carboxylic acid.
This process also still requires 7 reaction steps to reach the starting material for carbacyclin analogs starting from 3-oxaglutaric esters. In addition, an unstable beta keto acid intermediate stage is passed through.
Further, for the production of optically active carbacyclin analogs, as described above, no synthesis method, which allows a simple production, is known.
The microbiological reduction according to the invention of the prostacyclin intermediate products specified above is performed with the following microorganism strains or enzymes isolated from them:
Among the different types of classes of microorganisms indicated, naturally differences of the effectiveness in the keto reduction according to the invention occur.
On 11/11/1986 the strains Rhizopus oryzae (DSM 3899) and Rhizopus arrhizus (DSM 3898) were deposited with the German Collection of Microorganism, Mascheroder Weg 1b,1)-3300 Braunschweig, West Germany.
Pharmacologically effective prostacyclins can be produced from the optically active
REFERENCES:
patent: 4004978 (1977-01-01), McMullen
Mori et al., Tetrahedon, vol. 42, No. 1, pp. 435-444 1986.
ATCC Catalogue of fungi; 1987, pp. 316-317.
Kieslich, K., Microbial Transformations, 1976, Wiley & Sons, pp. 639-640
Rose A., "The Yeasts", vol. 1, 1987, pp. 30-38.
Dahl Helmut
Petzoldt Karl
Vorbruggen Helmut
Marx Irene
Robinson Douglas W.
Schering Aktiengesellschaft
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