Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Patent
1989-03-17
1990-03-27
Shippen, Michael L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C07C 67343
Patent
active
049122517
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The invention relates to a new process for the production of symmetrical bicyclo[3.3.0]octanedione dicarboxylic acid diesters. Optically active 6a-carba-prostacyclin and especially some compounds derived from it have a therapeutic use as stable analogs of the natural prostacyclin (PGI.sub.2) [R. C. Nickolsen, M. H. Town, H. Vorbrueggen: Prostacyclin-Analogs, Medicinal Research Reviews, Vol. 5, No. 1, pp. 1-53 (1985)]. The syntheses specified in this recent survey are long and lead partly only to racemic carbacyclins. The syntheses, which lead to carbacyclins in the absolute configuration corresponding to the natural PGI.sub.2, are especially expensive. The reason for this is that easily accessible suitable initial materials are achiral and the optical activity must be introduced in the course of the synthesis only in intermediate stages suitable for this purpose.
It is known that symmetrical prochiral dicarboxylic acid diesters of prostacyclin and carbacyclin intermediate stages can be saponified and decarboxylated enantioselectively to the monocarboxylic acid esters in very good yields, if enzymes, especially alpha-chymotrypsin, are used for this purpose (DE 36 38 760.6). ##STR1##
Symmetrical diester I used as initial material for this process is produced, according to literature methods, from 4-acetoxy-2-cyclopenten-1-one and acetone dicarboxylic acid ester [V. Osterthun and E. Winterfeldt, Chem. Ber. 11, 146 (1977) M. Harre, P. Raddatz, R. Walenta and E. Winterfeld, Angew, Chem. 94, 496 (1982)]. In both publications the acetoxy group in the 4-acetoxy-2-cyclopenten-1-one is stressed as the leaving group necessary for the reaction. But the production of 4-acetoxy-2-cyclopenten-1-one proves to be especially expensive and, in addition, uneconomical. Up to now no economical synthesis has been found for this purpose and it has been necessary to resort to the expensive initial materials 4-bromo-2-cyclo-penten-1-one and silver racemate.
SUMMARY OF THE INVENTION
It has now been found that the above-named prochiral, symmetrical dicarboxylic acid diesters I can be produced in very good yields from the easily available 4-hydroxy-2-cyclopenten-1-one [P. G. Baraldi et al., Synthesis 1986, 781; K. Ogura et al., Tetr. Lett. 1976, 759] or 4-tert-butoxy-2-cyclopenten-1-one or 4-cumyloxy-2-cyclopenten-1-one [S. Takano et al., Chem. Pharm. Bull. 34 (8), 3445 (1986); S. Takano et al., Heterocycles 16, 605 (1981)] and acetone dicarboxylic acid esters.
The invention is suitable for the economical production of symmetrical prochiral diesters of general formula I.
Therefore the invention relates to a process for the production of symmetrical bicyclo[3.3.0]octane dicarboxylic acid diesters of general formula I, ##STR2## in which R.sub.1 represents a straight-chain or branched-chain alkyl group with 1-10 C atoms, characterized in that a 4-hydroxy or 4-alkoxy-2-cyclopenten-1-one of general formula III ##STR3## in which R.sub.2 can be a hydrogen atom or a straight-chain or branched-chain alkyl group with 1-10 C atoms, which optionally can be substituted by a phenyl group, is reacted with acetone dicarboxylic acid diesters of formula IV, ##STR4## in which R.sub.1 has the above-mentioned meaning, in the presence of a base.
Potassium carbonate, sodium carbonate or a tertiary amine such as diisopropylethylamine can, for example, be used as a base for the above process. The reaction is performed at -60.degree. C. to +60.degree. C., preferably 0.degree. to 40.degree. C. Methanol, ethanol, isopropanol, methylene chloride, tetrahydrofuran, among others, can be used as solvents or as solvent mixtures.
The radical methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isohepty, n-octyl, isooctyl, n-nonyl, n-decyl among others are suitable as straight-chain or branched-chain alkyl radical with 1-10 C atoms. The alkyl radicals with 1-6 C atoms are preferred, which can be substituted by a phenyl radical. There can be mentioned, e.g., benzyl, p
Schering Aktiengesellschaft
Shippen Michael L.
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