Substituted cyclopentene derivatives and method for preparing th

Details Substituted cyclopentene derivatives and method for preparing th Substituted cyclopentene derivatives and method for preparing th

1997-09-02

1999-02-23

Geist, Gary

Organic compounds -- part of the class 532-570 series

Organic compounds

Oxygen containing

568380, C07C 47597

Patent

active

058746340

DESCRIPTION:

BRIEF SUMMARY
This is the US National Stage Application of PCT/JP96/00422 filed Feb. 23, 1996 now WO 96/26891 published Sep. 6, 1996.


TECHNICAL FIELD

This invention relates to substituted cyclopentene derivatives and a method for preparing the same and more particularly, to novel intermediates useful for the production of prostaglandins (to be abbreviated as PG, hereinafter) useful as various drugs, especially PGE.sub.2 and 6-keto-PGE.sub.1.


BACKGROUND ART

Since PGs exhibit various important physiological actions in minor amounts, active research works have been made thereon for the intended application to drugs. With respect to the extension of PG analogues, it has been attempted in various ways to extend .alpha. and .OMEGA.-chains attached to the five-membered ring moiety. One method capable of free choice of .alpha. and .OMEGA.-chains and efficient introduction is a two-component connecting method. More particularly, direct synthesis is possible by 1,4-addition of a zinc reagent of .alpha.-chain to an enone as shown by Scheme 1 (see H. Tsujiyama, N. Ono, S. Okamoto, F. Sato, Tetrahedron Lett., 31, 4481 (1990)). ##STR2##
In the synthesis of an intermediate having a double bond in its .alpha.-chain, however, it is synthesized by introducing an .alpha.-chain into an enone using a vinyl lithium reagent and then effecting functional group conversion as shown by Scheme 2. ##STR3##
The reason is as follows. It is impossible to form an organic zinc reagent of an .alpha.-chain because reaction conditions are severe and the stereo-chemistry of olefin is not maintained. An .alpha.-chain is synthesized as an alcohol-protected one because a lithium reagent having an ester group cannot be synthesized. Many stages are thus necessary (see S. Okamoto, Y. Kobayashi, H. Kato, K. Hori, T. Takahashi, J. Tsuji, F. Sato, J. Org. Chem., 53, 5590 (1988)).
Also the route developed by E. J. Corey et al. (Scheme 3) entails much decomposition and hence, low yields since Jones oxidation under severe conditions is utilized. It is industrially inadequate since a heavy metal (Cr) is used (see YAMAMOTO Shozo et al., "Prostaglandins and Related Physiologically Active Compounds", Kodansha, 1981). ##STR4##
Further, a silyl substituted derivative of formula (VIII) which can be readily synthesized according to the present invention as will be described later is useful in the synthesis of a 6-keto-prostaglandin which now draws attention as a ulcer drug. In the past, an intermediate of this 6-keto-PG has been synthesized through the following route. This technique, however, is not satisfactory as a practical production process since only a racemic modification is obtained and further optical resolution is needed to obtain an optically active substance (see M. Brawner Floyd, Synthetic Communications, 4 (6), 317-323 (1974)). ##STR5##


DISCLOSURE OF THE INVENTION

Therefore, an object of the present invention is to provide a substituted cyclopentene derivative which is an intermediate for producing PGE.sub.2, 6-keto-PGE.sub.1 and analogues in a more advantageous manner and a method for preparing the same.
Making extensive investigations for attaining the above object, the inventor has found that a novel halogenated substituted cyclopentene derivative of formula (I) can be obtained by reacting a compound of formula (II) with a halide of formula (III) or a hydrate thereof in the presence or absence of a Lewis acid as shown below by reaction scheme A; that a novel substituted cyclopentene derivative of formula (V) can be obtained by reacting this novel halogenated substituted cyclopentene derivative of formula (I) with a novel compound of formula (IV) as shown below by reaction scheme B; that a novel epoxy radical-containing substituted cyclopentene derivative of formula (VII) is obtained by oxidizing a compound of formula (VI) embraced in the novel substituted cyclopentene derivative of formula (V) using an oxidizing agent such as peroxides as shown below by reaction scheme C; that a substituted cyclopentene derivative of formula (IX) can be obtained by a

REFERENCES:
patent: 4367340 (1983-01-01), Rickards
patent: 4703127 (1987-10-01), Rickards
Tsujiyama et al, Tetrahedron Letters, 31, 4481, 1990.
Okamoto et al, J. Org.Chem.,53,5590, 1988.
Floyd et al, Synthetic Communications, 4(6),317-323, 1974.
Rikagaku Jiten, 3rd Edition, Issued by Iwanami Shoten, (1979), pp. 138, 677-678.

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