Novel process for manufacturing optically active carbacyclin int

Details Novel process for manufacturing optically active carbacyclin int Novel process for manufacturing optically active carbacyclin int

1988-07-13

1990-05-15

Chan, Nicky

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

549421, 549337, 549336, 549332, 556436, 562501, 568445, C07D31908, C07C17700, C07C 47575, C07F 718

Patent

active

049259563

DESCRIPTION:

BRIEF SUMMARY
The various possibilities of synthetizing carbacyclin analogs are compiled in the two following articles of an overview nature: R. C. Nickolson, M. H. Town and H. Vorbruggen, "Medicinal Research Review" 5: 1 (1985); P. A. Aristoff in "Advances in Prostaglandin, Thromboxane and Leukotriene Research" 15 (1985). Heretofore, all known synthesis methods for pure, optically active carbacyclins have been accompanied by considerable expense for the synthesis. Thus, carbacyclin syntheses have been described, for example, in DOS 2,912,409 and DOS 3,021,895 which make it possible to obtain, from the optically active "Corey lactone", a conversion into carbacyclin intermediates only under great losses in yield.
It has now been found that the diastereomeric amides of Formula II, formed from D-(-)-.alpha.-phenylglycinol and racemic cis-bicyclo[3.3.0]octane-2-carboxylic acids, surprisingly can be separated with special ease and therefore are suitable, after reductive splitting of the amide, for the production of the pure, optically active carbacyclin intermediates of Formula I.
The invention accordingly concerns a process for the manufacture of optically active cis-bicyclo-[3.3.0]octane-2-aldehydes of Formula I ##STR1## wherein R.sub.1 and R.sub.2 jointly represent the double-linkage residue --O--X--O-- where X is straight-chain or branched-chain alkylene of 1-7 carbon atoms, or straight-chain or branched-chain alkyl of 1-7 carbon atoms, and aralkyl residue of 7-10 carbon atoms, a tetrahydropyranyl residue, a trialkylsilyl residue of 1-6 carbon atoms in the alkyl, wherein alkyl can also be substituted by phenyl, a dialkylphenylsilyl residue or an alkyldiphenylsilyl residue of 1-16 carbon atoms in the alkyl, ##STR2## wherein R.sub.1, R.sub.2 and R.sub.3 have the meanings set forth above, are separated and the enantiomerically pure amide of Formula II is reduced.
If X represents a straight-chain or branched-chain alkylene residue of 1-7 carbon atoms, then the following residues are meant:
--(CH.sub.2).sub.n -- wherein n=1-7 (methylene, ethylene, tri-, tetra-, penta-, hexa- and heptamethylene), --C(CH.sub.3).sub.2 --, --CH(CH.sub.3)--, --CH((CH.sub.3)--CH.sub.2 --, --C(CH.sub.3).sub.2 --CH.sub.2 --, --CH.sub.2 --CH(CH.sub.3)--, CH.sub.2 --C(CH.sub.3).sub.2, --CH.sub.2 --CH(CH.sub.3)--CH.sub.2 --, --CH.sub.2 --C(CH.sub.3).sub.2 --CH.sub.2 --, --CH--(C.sub.2 H.sub.5)--, --C(C.sub.2 H.sub.5).sub.2 --, --CH(C.sub.2 H.sub.5)--CH.sub.2 --, --C(C.sub.2 H.sub.5).sub.2 --CH.sub.2 --, --CH.sub.2 --CH(C.sub.2 H.sub.5)--, --CH.sub.2 --C(C.sub.2 H.sub.5).sub.2 --, --CH.sub.2 --CH(C.sub.2 H.sub.5)--CH.sub.2 --, --CH.sub.2 --C(C.sub.2 H.sub.5).sub.2 --CH.sub.2 -- etc.
R, as a straight-chain or branched-chain alkyl residue of 1-7 carbon atoms, means methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl.
R.sub.3 and, respectively, R.sub.4 (in Formula IV) as saturated alkyl residues of 1-7 carbon atoms mean the alkyl residues already recited for R.
R.sub.3 and, respectively, R.sub.4 as aralkyl residues of 7-10 carbon atoms are to encompass the following residues: ##STR3##
The residues recited above for R are suitable for the "alkyl" residues in trialkyl- (of 1-6 carbon atoms in the alkyl), dialkylphenyl-, or alkyldiphenylsilyl of 1-16 carbon atoms in the alkyl.
The compounds of Formula I are especially suited as intermediates for the preparation of stable, pharmacologically effective carbacyclin derivatives (e.g. iloprost).
The amides of Formula II are prepared according to the methods known to persons skilled in the art. For example, the diastereomeric amides of Formula II can be produced by reacting the racemic carboxylic acids of Formula III ##STR4## wherein R.sub.1, R.sub.2 and R.sub.3 have the meanings indicated above, with a base, preferably triethylamine, and the isobutyl ester of chloroformic acid to obtain the intermediate anhydride, and by subsequent addition of D-(-)-.alpha.-phenylglycinol. The reaction is performed at -20.deg

REFERENCES:
patent: 3891676 (1975-06-01), Kuo et al.
Mukaiyama et al., Chem. Lett., No. 3, 1983, pp. 385-388.

Affiliated with

Also associated with

Rating

Novel process for manufacturing optically active carbacyclin int does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Novel process for manufacturing optically active carbacyclin int, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Novel process for manufacturing optically active carbacyclin int will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-622340