Organic compounds -- part of the class 532-570 series – Organic compounds – Sulfonic acids or salts thereof
Patent
1998-09-18
2000-05-30
Gerstl, Robert
Organic compounds -- part of the class 532-570 series
Organic compounds
Sulfonic acids or salts thereof
C07C45500
Patent
active
060692693
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a new process for the preparation of (11 60.13E.15S)-11,15-dihydroxy-9-oxoprost-13-en-1-oic-acid (prostaglandin E1/PGE.sub.1) of formula (I) starting from the compound of formula (II). FIGS. 1A and 1B illustrate formulas (I)-(VIII).
Endogen PGE.sub.1 plays a significant regulating role in the living organism and it can be used advantageously for the treatment and prevention of diseases of cardiovascular origin.
Biosynthetic PGE1 is formed from dihomo-.gamma.-linolenic acid (Prostaglandin 20, 187, 1980). Several total synthesis of PGE1 has been performed (J. Chem. Soc. Chem. Comm. 304, 1972, J. Chem. Soc. Chem. Comm. 180, 1973, J. Am. Chem. Soc. 94, 3643, 1972: J. Am. Chem. Soc. 95, 1676, 1973, J. Org. Chem. 37, 2921, 1972), the but their industrial realization is very cumbersome. Another possible approach is the regioselective saturation of the cis double bonds of the prostanoid structure of the formula (III) containing cis and trans double bonds. Hydrogenation of 5(Z).11.alpha.,13E,15(S)-11,15-dihydroxy-9-oxoprosta-5,13-diene-1-oic-acid (PGE.sub.2) of formula (IV) in ethyl acetate yields only 6% of PGE.sub.1 of formula (I) (J. Biol. Chem. 239, 4091 1964).
By the application of homogen catalysis at room temperature in case of Wilson type catalyst PGE.sub.1 of formula (1) is formed in 72% yield in a 2:3 mixture of benzene and acetone from PGE.sub.2 of formula (IV). This reaction is accompanied by formation in significant amounts of the compound of formula (VI) by the elimination of water and of dihydro-PGE.sub.1 of formula (V) (J. Labelled Compd. Radiopharm. 14, 515, 1978 and J. Org. Chem 38, 951, 1973). By examining, the hydrogenation of PGE.sub.2 of formula (IV) in the presence of ethyl acetate, acetone, benzene, chloroform, methanol and dioxane, catalysts such as palladium on barium sulfate and carbon, platinum on carbon, and nickel and copper on calcium carbonate and Lindlar catalyst, the formed quantity of PGE.sub.1 of formula (I) did not exceed 70% and was accompanied by significant amounts of starting PGE.sub.2 of formula (IV), dihydro-PGE.sub.1 of formula (V) and other prostaglandin derivatives (J. Labelled. Compd. Radiopharm. 27, 1243, 1989) Similar difficulties are encountered if the derivative, containing hydroxyl groups in positions 11 and 15 of PGE.sub.2 of formula (IV) is used as the starting material (J. Labelled Compd. Radiopharm. 27, 1243, 1989). Hydrogenation of PGF.sub.2a of formula (II) protected by tetrahydropiranyl groups (U.S. Pat. No. 4,085,139; U.S. Pat. No. 4,122,282; J. Am. Chem. SOC. 92, 2586, 1970), and PGF.sub.2a derivatives containing other protective groups (J. Am. Chem. Soc. 93, 7319, 1971) has been caried out in ethyl acetate at room temperature and in methanol in the presence of the palladium on carbon catalyst at -20.degree. C. but beside the expected compound of formula (VII) significant quantity of the dihydro derivative of formula (VIII) has also been formed. It is very difficult to separate chromatographically (J. Am. Chem. Soc. 92, 2586, 1970) the non-hydrogenated starting material (e.g. compound of formula (II)) and the reduction products (e.g. compounds of formula (VII) and VIII)).
Thus there remains a need in the art for a regioselective, simple catalytic reduction process for the preparation of PGE1. The present invention is directed to such a regioselective catalytic hydrogenation of the double bond in the 5,6 position selected from the two double bonds, existing in the compound of formula (II), forming a diastomeric mixture in the given case. We intended to achieve such a selectivity beside a minimum of 97% conversion that the purity of the formed compound of formula (VII) should allow its further use without chromatographic purification.
We reached the above goal by an unexpected observation which is the base of our new process. Compound of the formula (II) containing two double bonds can be saturated in positions 5 and 6 with good regioselectivity and appropriate reaction speed in the following way:
The compound of formula (II) is hy
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Dalmadi Gyula
Hajdu Felix
Hermecz Istvan
Mozsolits Karoly
Szabo Tibor
Chinoin Gyogyszer es Vegyeszeti
Gerstl Robert
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