Organic compounds -- part of the class 532-570 series – Organic compounds – Nitriles
Patent
1986-09-29
1989-06-20
Gerstl, Robert
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitriles
560121, 560231, 562503, C07C17700
Patent
active
048410918
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a novel process for producing 16-substituted prostaglandin Es. More particularly, this invention relates to a novel process for producing 16-substituted prostaglandin Es comprising allowing 4-substituted-2-cyclopentenones to react with an organocopper compound by means of conjugate addition to produce enolate intermediates, which intermediates are then allowed to react with aldehydes to give 7-hydroxy-16-substituted prostaglandin Es, which are thereafter converted into 7-organic sulfonyloxy-16-substituted prostaglandin Es and further into 16-substituted .DELTA..sup.7 -prostaglandin Es and finally into originally desired 16-substituted prostaglandin Es.
BACKGROUND OF THE ART
Naturally occurring prostaglandins (abbreviated to PG) are known as local hormones (autacoid) which have high activities from the viewpoints of biology and pharmacology. Researches have, therefore, been made to develop medicines of a new type along the lines of not only naturally occurring PG but also their derivatives of various kinds by skillfully taking advantage of the physiological characteristic features of PGs.
Of the natural PGs, PGEs are the earliest known compounds, and PGE.sub.2 has already been made into a drug to be used as an oxytocics because of its contractility on the smooth muscle of the uterus and PGE.sub.1 is used as a therapeutic drug for peripheral circulatory disorders because of its physiological activities such as suppressive effect against the platelet aggregation and antihypertensive action.
With regard to the production of these PGEs, many processes have hitherto been developed and reported, and the following will be mentioned as epochal ones to represent these processes.
(i) A process for biosynthetically producing PGE from arachidonic acid or dihomo-.gamma.-linolenic acid (see B. Samuelsson et al., Angew. Chem. Int. Ed. Engl., 4, 410 (1965)).
(ii) A process for obtaining PGE through an important intermediate Corey lactone (see E. J. Corey et al., J. Am. Chem. Soc., 92, 397 (1970)).
(iii) A process for producing PGE through an important intermediate 2-substituted-2-cyclopentenone compound (see C. J. Sih et al., J. Am. Chem. Soc., 97, 865 (1975)).
(iv) A process wherein 5,6-dehydro PGE.sub.2 or PGF.sub.2 .alpha. is selectively reduced (see E. S. Ferdinandi et al., Can. J. Chem., 49, 1070 (1971); C. H. Lin et al., Prostaglandin, 11, 377 (1976)).
Of these methods mentioned above, the process for obtaining PGE by the biosynthetic method involves problems of difficulty in obtaining the material poly-unsaturated fatty acid, very low yield from the material, and difficult isolation and purification from the by-product. While the process carried out according to chemical synthesis requires many steps of procedure before the starting material is obtained, and even when the starting material is made readily available, the process from the starting material to prostaglandin still includes many steps of procedure, thus lowering the total yield remarkably.
A report has been made with regard to a chemically synthetic process for producing PGEs based on the improvements made upon the aforementioned processes, including (i) the use of starting materials which are readily obtainable; (ii) the reaction process is short; and (iii) the total yield is high. The intended PGEs are produced by selectively removing the hydroxy group at the 7-position from 7-hydroxy PGEs, which have been obtained in high yield from protected 4-hydroxy-2-cyclopentenone in a single stage reaction, followed by the conversion of the functional group if necessary (see Noyori et al., Tetrahedron Letters, 23, 4057 (1982) and Tetrahedron Letters, 23, 5563 (1982)).
In parallel with the research and development of processes suited for practical use in synthesizing prostaglandin skeletons, many reports have also been made about the progress of researches conducted on the new applications of synthetic prostaglandins to medicaments and a number of resultant medical preparations based on the synthesized p
REFERENCES:
patent: 4237307 (1980-12-01), Wissner
Supplementary European Search Report.
Hazato Atsuo
Koga Masahiro
Kurozumi Seizi
Tanaka Toshio
Gerstl Robert
Teijin Limited
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