Isocarbacyclin derivatives and process for production thereof

Details Isocarbacyclin derivatives and process for production thereof Isocarbacyclin derivatives and process for production thereof

1987-05-29

1988-10-11

Chan, Nicky

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

549214, 562501, C07D31904

Patent

active

047772719

DESCRIPTION:

BRIEF SUMMARY
TECHNOLOGICAL FIELD

This invention relates to isocarbacyclin derivatives represented by the following general formula (I) ##STR2##
wherein R.sup.1 represents a linear, branched or cyclic alkyl, alkenyl or alkynyl group having 5 to 10 carbon atoms, and the hydroxyl group,
The isocarbacyclin derivatives represented by general formula (I) provided by this invention can be converted to 9(O)-methano-.DELTA..sup.6(9.alpha.) -PGI.sub.1 (isocarbacyclin) and its analogs by hydrolyzing their ortho esters, and then when R.sup.2 and R.sup.3 are protective groups, removing the protective groups from the hydroxyl groups. Isocarbacyclin has strong platelet aggregation inhibiting activity. Its activity on, for example, human platelets is comparable to that of chemically unstable PGI.sub.2, and it has been gaining acceptance as a therapeutic or prophylactic agent for various cardiovascular diseases (see Japanese Laid-Open Patent Publication No. 137445/1984).


BACKGROUND TECHNOLOGY

A method starting from furfural and goes through general formulae (II) and (III) has previously been known as the most efficient method of producing isocarbacyclin [Tetrahedron Letters, 25, 5087 (1984)]. ##STR3##
In the formulae, --OZ represents a t-butyldimethylsilyloxy group (same hereinafter).
According to this method, the step of deriving the triene compound of general formula (III) from the acetoxy compound of general formula (II) requires the use of 3-butenyllithium. Hence, it has the serious defect of using a very large amount of mercuric chloride for production of 3-butenyllithium. The present inventors studied a method of avoiding the use of mercury and further extensively worked in search of a method by which isocarbacyclin and its analogs can be synthesized in less process steps. These efforts have led to the discovery that isocarbacyclin and its analogs can be synthesized in less process steps by preparing the isocarbacyclin derivatives of general formula (I) and hydrolyzing them; and consequently, to the accomplishment of the present invention.


DETAILED DESCRIPTION OF THE INVENTION

The isocarbacyclin derivatives of general formula (I) in accordance with this invention can be produced by condensing bicyclo[3.3.0]octene derivatives represented by the general formula ##STR4## wherein R.sup.1 represents a linear, branched or cyclic alkyl, alkenyl or alkynyl group having 5 to 10 carbon atoms, hydroxyl group, and methanesulfonyloxy, ##STR5##
The bicyclo[3.3.0]octene derivatives of general formula (IV) can be produced in accordance with the method described in the literature [Tetrahedron Letters, 25, 5087 (1984)].
R.sup.1 in general formula (IV) represents a linear, branched or cyclic alkyl, alkenyl or alkynyl group having 5 to 10 carbon atoms. Examples include alkyl groups such as pentyl, hexyl, 1-methylpentyl, 2-methylpentyl, 2-methylhexyl, cyclopentyl and cyclohexyl; alkenyl groups such as 1-pentenyl, 2-pentenyl, 1-hexenyl, 2-hexenyl, 2-methyl-3-pentenyl, 1-methyl-4-pentenyl, 1,4-dimethyl-3-pentenyl, 6-methyl-5-heptenyl and 2,6-dimethyl-5-heptenyl; and alkynyl groups such as 2-pentynyl, 3-pentynyl, 1-methyl-2-pentynyl and 1-methyl-3-pentynyl.
R.sup.2 and R.sup.3 represent a hydrogen atom or a protective group for the hydroxyl group. Examples of the protective group for the hydroxyl group are tri(C.sub.1 -C.sub.7)-hydrocarbon-silyl groups such as trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, dimethylphenyl and tribenzylsilyl; and groups forming an acetal linkage together with the oxygen atom of the hydroxyl group, such as methoxymethyl, 1-ethoxyethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, 2-tetrahydrofuranyl, 2-tetrahydropyranyl and 6,6-dimethyl-3-oxa-2-oxobicyclo[3.1.0]hexa-4-yl.
The lithium compound of general formula (VI) is prepared from an ortho ester compound represented by the following general formula (V) ##STR6## wherein R.sup.4 represents bromo or iodo, and, for example, a lithium naphthalene anion radical or t-butyllithium.
The ortho ester derivatives of general formula (V) can be easily synthesized by t

REFERENCES:
patent: 4215048 (1980-07-01), Chen et al.
patent: 4530925 (1985-07-01), Collington et al.

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