Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
2001-02-01
2001-10-30
Padmanabhan, Sreeni (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C568S338000, C568S366000, C549S512000, C549S513000
Reexamination Certificate
active
06310257
ABSTRACT:
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
2
and 6-keto-PGE
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 &agr; and &ohgr;-chains attached to the five-membered ring moiety. One method capable of free choice of &agr; and &ohgr;-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 &agr;-chain to an enone as shown by Scheme 1 (see H. Tsujiyama, N. Ono, S. Okamoto, F. Sato, Tetrahedron Lett., 31, 4481 (1990)).
In the synthesis of an intermediate having a double bond in its &agr;-chain, however, it is synthesized by introducing an &agr;-chain into an enone using a vinyl lithium reagent and then effecting functional group conversion as shown by Scheme 2.
The reason is as follows. It is impossible to form an organic zinc reagent of an &agr;-chain because reaction conditions are severe and the stereo-chemistry of olefin is not maintained. An &agr;-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).
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)).
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
2
, 6-keto-PGE
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 acidolysis of a compound of formula (VIII) which is a substituted cyclopentene derivative of formula (VII) wherein R is a substituted silyl radical as shown below by reaction scheme D; and that PGs can be advantageously prepared from these substituted cyclopentene derivatives. The present invention is predicated on these findings.
More particularly, among PG synthesis methods, a method represented by “Scheme 5” and known as a two-component method has the advantages of easy reaction control due to the-use of an intermediate having an &agr;-chain and more versatility of &ohgr;-chain introduction. The present invention enables synthesis of the following compounds (8b), (10d), etc. in accordance with this method and effective preparation of PGE
2
analogues or 6-keto-PGE
1
analogues from these compounds as shown by “Scheme 6” and “Scheme 7.”
In fact, synthesis of PGs themselves and intermediates (8b), (11d), (13e), (16d), and (10c) is completed as will be shown in Examples and Reference Examples later, with which the invention is acknowledged useful.
Accordingly, the present invention provides (1) to (8) as described below.
(1) A halogenated substituted cyclopentene derivative of the formula (I):
wherein R is a hydrogen atom, alkyl radical having 1 to 6 carbon atoms, alkenyl radical having 2 to 6 carbon atoms, alkynyl radical having 2 to 6 carbon atoms, cycloalkyl radical having 3 to 8 carbon atoms, aralkyl radical having 7 to 19 carbon atoms, aryl radical having 6 to 12 carbon atoms, alkoxy radical having 1 to 6 carbon atoms, alkenyloxy radical having 2 to 6 carbon atoms, alkylthio radical having 1 to 6 carbon atoms or alkenylthio radical having 2 to 6 carbon atoms; X
1
is (&agr;-OZ
a
, &bgr;-H) or (&agr;-H, &bgr;-OZ
a
), X
3
is (&agr;-OZ
d
, &bgr;-H), (&agr;-H, &bgr;-OZ
d
) or oxygen atom, each of Z
a
and Z
d
, which may be the same or different, is a hydrogen atom or a protective radical for a hydroxyl radical; and W is a halogen atom.
(2) A method for preparing a halogenated substituted cyclopentene derivative of the formula (I):
wherein R, X
1
, X
3
, and W are as defined below,
said method comprising the step of reacting a substituted cyclopentane derivative of the formula (II):
wherein R is a hydrogen atom, alkyl radical having 1 to 6 carbon atoms, alkenyl radical having 2 to 6 carbon atoms, alkynyl radical having 2 to 6 carbon atoms, cycloalkyl radical having 3 to 8 carbon atoms, aralkyl radical having 7 to 19 carbon atoms, aryl radical having 6 to 12 carbon atoms, alkoxy radical having 1 to 6 carbon atoms, alkenyloxy radical having 2 to 6 carbon atoms, alkylthio radical having 1 to 6 carbon atoms or alkenylthio radical having 2 to 6 carbon atoms; X
1
is (&agr;-OZ
a
, &bgr;-H) or (&agr;-H, OZ
a
), X
3
is (&agr;-OZ
d
, &bgr;-H) , (&agr;-H, &bgr;-OZ
d
) or oxygen atom, Y is (&agr;-OZ
c
, &bgr;-H) or (&agr;-H, &bgr;-OZ
c
), and each of Z
a
, Z
c
and Z
d
, which may be the same or different, is a hydrogen atom or a protective radical for a hydroxyl radical, with a halide of the formula (III):
M
1
W
h
(III)
wherein M
1
is a metal atom selected from the group consisting of an alkali metal, alkaline earth metal, first transition metal, Al, Zr, and Ce, or quaternary ammonium, w is a halogen atom, and h representative of the valence of said metal or quaternary ammonium is an integer of 1 to 4, or a hydrate thereof in the presence or absence of a Lewis acid.
(3) A method for preparing a substituted cyclopentene derivative of the formula (V):
wherein R, X
1
, X
3
, U, R
5
, R
6
, R
7
, R
8
, X
2
, m, n, p, q, and Z
1
are as defined below,
said method characterized by comprising the step of reacting a halogenated substituted cyclopentene derivative of the formula (I):
wherein R is a hydrogen atom, alkyl radical having 1 to 6 carbon atoms, alkenyl radical having 2 to 6 carbon atoms, alkynyl radical having 2 to 6 carbon atoms, cycloalkyl radical having 3 to 8 carbon atoms, aralkyl radical having 7 to 19 carbon atoms, aryl radical having 6 to 12 carbon atoms, alkoxy radical having 1 to 6 carbon atoms, alkenyloxy radical having 2 to 6 carbon atoms, alkylthio radical having 1 to 6 carbon atoms or alkenylthio radical having 2 to 6 carbon atoms; X
Nissan Chemical Industries, LTD
Padmanabhan Sreeni
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