Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1991-06-12
1994-02-22
Ivy, C. Warren
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
562501, C07D31906
Patent
active
052888789
DESCRIPTION:
BRIEF SUMMARY
The invention relates to a novel process for the preparation of (1S,2S,3R,5R)-2-[(3S)-2-halo-3-hydroxy-1-alken(ynyl)]-3-trialkylsilyloxy-7 ,7-(2,2-dimethyltrimethylenedioxy)bicyclo[3.3.0]octane compounds by reduction of 15-ketocarbacyclin intermediates (PG nomenclature) with diisobutyl aluminum 2,6-di-tert-butyl-4-methylphenoxide.
The reduction of the 15-keto group to the 15.alpha.-hydroxy group at an intermediate stage of the synthesis plays an important part in the syntheses of the pharmacologically active carbacyclin analogs ##STR3## and, respectively, "Eptaloprost" ##STR4## Reduction with technically readily accessible reagents, such as sodium borohydride, leads to a mixture with the undesirable 15.alpha.-hydroxy epimer. The two epimers must be separated from each other by chromatography. (For economical reasons, the 15.alpha.-hydroxy epimer must be reoxidized and again reduced and separated into the 15-epimers, and so forth.)
The amount of adsorbent and solvent quantity required for separation is the higher, the more 15.alpha.-hydroxy epimer must be segregated. In accordance with the methods known heretofore, working with simple hydride reagents, a relatively high expenditure is necessary for preparing the 15.alpha.-hydroxy epimers. Therefore, the problem to be solved resides in further improving the chemical reduction of the 15-keto group in the sythesis of carbacyclin analogs with respect to the yield of 15.alpha.-hydroxy epimer.
The invention relates to a process for preparing (1S,2S,3R,5R)-2-[(3S)-2-halo-3-hydroxy-1-alken(ynyl)]-3-trialkylsilyloxy-7 ,7-(2,2-dimethyltrimethylenedioxy)-bicyclo[3.3.0]octane compounds of general Formula I ##STR5## wherein X is chlorine or bromine, straight-chain or branched alkenyl of up to 6 carbon atoms, straight-chain or branched alkynyl of up to 6 carbon atoms,
R.sub.2, R.sub.3, R.sub.4 can be in each case identical or different and can mean C.sub.1 -C.sub.4 -alkyl and phenyl optionally substituted by C.sub.1 -C.sub.4 -alkyl groups, wherein the 13,14-double bond has the trans configuration with respect to the C chain, ##STR6## wherein X, R.sub.1, R.sub.2, R.sub.3, R.sub.4 have the meanings given above, with a reagent produced from diisobutyl aluminum hydride and 2,6-di-tert-butyl-4-methylphenol.
The thus-prepared optical isomers exhibit the same relative stereochemical configuration as the corresponding prostacyclin from mammalian tissue, or, in case of an intermediate product, the stereochemical configuration that would be displayed by a prostacyclin-like product having the same relative stereochemical configuration as prostacyclin from mammalian tissue.
A primary problem in the synthesis of carbacyclins, prostaglandins and prostacyclins is presented by the stereoselective introduction of functional groups. The stereochemical control at C15 in the conformationally movable side chain causes special problems.
It is therefore very often desirable to produce the 15.alpha.-hydroxy epimer with preference over the 15.beta.-hydroxy epimer since this stereochemical arrangement remains preserved during the subsequent conversions into prostacyclin-type compounds in accordance with conventional methods. Consequently, compounds are obtained with the identical configuration at C15 as PGF2.alpha. with the desirable pharmacological properties.
Heretofore, the 15-hydroxy group has been prepared by reduction of the 15-ketone, using as the reducing agents NaBH.sub.4, NaBH.sub.4 /CeCl.sub.3, Zn(BH.sub.4).sub.2.
The aforementioned reducing agents, however, exhibit the drawback that they yield mixtures of 15-hydroxy epimers. Other reducing agents, such as "S-Binal-H", do provide a high stereoselectivity in favor of the 15.alpha.-hydroxy epimer, but are more expensive, can be utilized only at low temperatures (-100.degree. to -110.degree. C.), and in addition must be employed in a high excess.
Occasionally, stereoselectivity of the reduction is linked to the type of blocking group at C11. For example, a 15.alpha./15.beta. proportion of 92:8 was achieved with a p-phenylphenylcarbamoyl g
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Corey et al. "Total Synthesis of C.sub.22 -Prostanoids in the E and F Series Based on Docosahexaenoic Acid" J. Am. Chem. Soc. 1984, 106, 3875-3876.
Harre Michael
Westermann Jurgen
Ivy C. Warren
Owens A. A.
Schering Aktiengesellschaft
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