Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1989-07-24
1990-10-02
Chan, Nicky
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
560119, C07D31772, C07D31908, C07C 6974, C07C 6732
Patent
active
049609076
DESCRIPTION:
BRIEF SUMMARY
The invention relates to a process for the preparation of bicyclo[3.3.0]octane-3,7-dione-2-carboxylic acid esters and associated monoketals.
Bicyclo[3.3.0]octane-3,7-dione-2-carboxylic acid esters are important potential intermediates for the production of carbacyclin derivatives and sesquiterpenes, heretofore obtainable only with difficulties.
The cleavage of D,L-bicyclo[3.3.0]octane-3,7-dione-2,6-dicarboxylic acid diesters of Formula II ##STR4## with sodium methylate in DMSO-methanol [according to U. Weiss et al., J. Org. Chem. 42 : 3089 (1977)] yields merely traces of D,L-bicyclo[3.3.0]octane-3,7-dione-2-carboxylic acid esters. ##STR5##
It has now been discovered surprisingly that D,L-bicyclo[3.3.0]octane-3,7-dione-2-carboxylic acid esters can be produced in yields of 50-70% by partially saponifying and decarboxylating D,L-bicyclo[3.3.0]octane-3,7-dione-2,6-dicarboxylic acid esters of Formula II in an aqueous or water-containing medium in the presence of acids.
Therefore, the invention relates to the selective cleavage of the D,L-diesters II under gentle acidic conditions to D,L-bicyclo[3.3.0]octane-3,7-dione-2-carboxylic acid esters.
The process for the production of D,L-bicyclo[3.3.0]octane-3,7-dione-2-carboxylic acid esters of Formula I ##STR6## wherein R is methyl or ethyl, and ##STR7## wherein X means ethylene, trimethylene or 2,2-dimethyltrimethylene, is characterized in that D,L-bicyclo[3.3.0]octane-3,7-dione-2,6-dicarboxylic acid esters of Formula II ##STR8## wherein R has the meanings given above, are partially saponified and decarboxylated in an aqueous or water-containing medium in the presence of acids, and are optionally selectively ketalized.
The starting compounds of Formula II are very readily obtainable by alkaline treatment of the bicyclo[3.3.0]octane-3,7-dione-2,4,6,8-tetracarboxylic acid esters III [cf. J. Org. Chem. 42 : 3089 (1977); Org. Synth. 64 : 27-37 (1985)]. ##STR9##
The acidic cleavage of the D,L-diesters of Formula II to the D,L-monoesters of Formula I is preferably performed in H.sub.2 O with water-soluble acids or acid mixtures which are to be maximally insoluble in methylene chloride, in amounts of 0.05-1 mole at a pH of 1-6, preferably 3-4, and at temperatures of 20.degree.-150.degree. C., preferably at 80.degree.-100.degree. C. During subsequent cooling to 2.degree. C., the unreacted D,L-diester II is crystallized and is thus to the largest part separated and recovered. Extraction of the filtrate with methylene chloride then results in a crude product from which pure D,L-monomethyl ester of Formula I (R=CH.sub.3, Z=O) is crystallized.
While the tetracarboxylic acid ethyl ester III (R=C.sub.2 H.sub.5), mp 107.degree. C., as well as the D,L-dicarboxylic acid ethyl ester II (R=C.sub.2 H.sub.5), mp 102.7.degree. C., are crystalline, the D,L-diketone monoethyl ester I (R=C.sub.2 H.sub.5) is oily, so that this compound can be obtained in the pure form only by chromatography, and therefore has a lesser importance as an intermediate as compared with the crystalline D,L-diketone monomethyl ester (R=CH.sub.3).
Suitable water-soluble acids for splitting off the ester group are citric acid, lactic acid, oxalic acid, acetic acid, formic acid, aspartic acid, glutamic acid, NaH.sub.2 PO.sub.4, amidosulfonic acid, etc., preferably citric acid. When using formic acid and acetic acid, added in relatively large amounts as the solvents, these acids can be very easily removed by evaporating under vacuum.
In order to shorten the reaction period, the process should, if at all possible, be conducted at temperatures of 50.degree.-90.degree. C.
Since the .beta.-keto ester systems in the D,L-diester II are weak acids (inherent acidity), II can be converted into I in water or in azeotropic mixtures with organic solvents even without the addition of carboxylic acids, but in this case at a reduced reaction rate. Thus, II (R=CH.sub.3) yields I (R=CH.sub.3), by boiling for 1.5 hours in xylene-H.sub.2 O at 120.degree.-140.degree. C., in an amount of about 41%.
The D,L-monoesters I (Z=O) can be selecti
REFERENCES:
Weiss et al., J. Org. Chem., 42, 3089 (1977).
Barco et al., Ibid., 45, 4776 (1980).
Krolikiewicz Konrad
Vorbrueggen Helmut
Chan Nicky
Schering Aktiengesellschaft
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