Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1991-01-02
1993-04-13
Dentz, Bernard
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
A61K30793
Patent
active
052024474
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to a manufacturing process of PGI.sub.2 derivatives having m-phenylene structure, i.e., a compound represented by the formula [VII]: ##STR2## (wherein R.sub.2 represents methyl or ethyl; R.sub.3 and R.sub.4 represent hydrogen atom or methyl) which is useful as an anti-thrombus agent.
BACKGROUND ART
As a process for manufacturing m-phenylene type PGI.sub.2 derivatives which have an .alpha.-side chain containing 4 carbon atoms, processes shown in Charts 1 and 2 (disclosed in Japanese Laid Open Patent Application (Kokai) Nos. 36477/81 and 124778/83, respectively) and shown in the literature ("Advances in Prostaglandin, Thromboxane and Leukotriene Research", vol.15, p.279) are known. ##STR3##
However, the conventional manufacturing processes described above have a variety of drawbacks which are disadvantageous in the industrial production in large scale, i.e., in that the reproducibility is poor, a large number of steps need to employ column chromatography, the stereoselectivity and the regiospecificity are poor, reactions which are carried out at low temperature are necessary, operation is troublesome, yield is low and so on.
DISCLOSURE OF THE INVENTION
Accordingly, the object of the present invention is to provide a novel manufacturing process of PGI.sub.2 derivatives having m-phenylene structure which is excellent in the stereoselectivity, the regiospecificity, ease of operation and reproducibility.
The present inventors investigated intensively to find a novel process for synthesizing m-phenylene PGI.sub.2 derivatives to accomplish this invention.
The present invention relates to a process for manufacturing 5,6,7-trinor-4,8-inter-m-phenylene PGI.sub.2 derivatives represented by the formula [VII] as shown in Step A.
PGI.sub.2 derivatives obtained by the method of the present invention are named based on the rules of nomenclature for prostaglandins and prostacycline analogues which is defined by N. A. Nelson et al. [N. A. Nelson, J. Med. Chem., 17, 911 (1974), and R. A. Johson, D. R. Morton, N. A. Nelson, Prostaglandins, 15, 787 (1978)]. The fundamental compound which has inter-m-phenylene structure in place of exo-enol ether structure of PGI.sub.2 is represented by the following formula. The position numbers are assigned as shown in the following formula, and the compound is named 5,6,7-trinor-4,8-inter-m-phenylene PGI.sub.2. ##STR4## In accordance with this nomenclature, the compound represented by the following formula is named 16-methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI.sub.2. ##STR5## If this compound is named in accordance with the formal rule of nomenclature, it is named as a butyric acid derivative. In this case, the moiety of the condensed rings is named based on the 1H-cyclopenta[b]benzofuran of the formula: ##STR6## Thus, it is named 4-[2-endo-hydroxy-1-exo-(3-hydroxy-4-methyl-6,7-tetradehydro-1-octenyl)-3a ,8b-cis-2,3,3a,8b-tetrahydro-1H-5-cyclopenta[b]benzofuranyl] butyric acid. In the present specification, the structural formula of the compound is shown to represent only one of the optical isomers. However, it is intended that these structural formulae include the d-, l- and dl-optical isomers and indication of the absolute configuration, i.e., the indication of R- and S- is omitted in the naming.
BEST MODE FOR CARRYING OUT THE INVENTION
The method of the present invention may be carried out in accordance with the following process shown in Step A. ##STR7##
Each of the steps will now be described in detail.
Step A-1 is a process in which the dibromide (Compound 1) is converted to transdiacetate by so-called Prins reaction and then the reaction product is hydrolyzed to give a diol (Compound 2). Usually, Prins reaction is carried out by heating the dibromide and formalin or a compound equivalent to formalin in acetic acid solvent in the presence of an acid. Examples of the compound equivalent to formalin include peraformaldehyde and 1,3,5-trioxane. As a catalyst, sulfuric acid, chlorosulfonic acid, trichloroacetic acid, tri
REFERENCES:
Ohno et al. II, Adv. in Prostaglandin, Thromboxane and Leukotriene Res., vol. 15, Raven Press, N.Y., pp. 279-281 (1985).
Hosono Yutaka
Kawai Koji
Nagase Hiroshi
Ohno Kiyotaka
Wakita Hisanori
Dentz Bernard
Miller Austin R.
Toray Industries Inc.
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