Process for producing 4a-aryldecahydroisoquinoline derivatives

Details Process for producing 4a-aryldecahydroisoquinoline derivatives Process for producing 4a-aryldecahydroisoquinoline derivatives

1998-04-06

1999-08-17

Davis, Zinna Northington

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C07D21704

Patent

active

059395516

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to a process for producing 4a-aryldecahydroisoquinoline derivatives. The 4a-aryldecahydroisoquinoline derivatives are useful as analgesics and/or narcotic antagonists as disclosed in Japanese Laid-open Patent Application (Kokai) No. 5-155857, and as materials for synthesizing immunosuppressive agents as disclosed in WO 839/995.


BACKGROUND ART

Known processes for producing 4a-aryl-trans-decahydroisoquinolines, especially, 6-oxo compounds, include the method of Rapoport et al. (U.S. Pat. No. 4,189,583, J. Org. Chem. 42, 1485, 1977), the method of Zimmerman et al. (J. Org. Chem. 54, 1442, 1989) and the method of Judd et al. (J. Med. Chem. 35, 48, 1992).
A key step utilized in the present invention, that is, the step of introducing an aromatic ring employs the 1,4-conjugate addition reaction to an enone compound (II) using an aromatic metal compound represented by aromatic copper compounds. A process for producing 4a-aryl-6-oxodecahydroisoquinolines utilizing a reaction similar to this reaction is known (J. Org. Chem. 39, 1118, 1974., U.S. Pat. No. 4,301,290). That is, in this process, a compound of the formula (XI) ##STR1## is reacted with a aromatic copper complex to produce a 4a-aryl-6-oxodecahydroisoquinoline of the formula (XII). ##STR2## However, the condensed ring moiety of the compound produced by this process has the cis configuration, and the trans isomers which the invention aims at producing cannot be obtained by this process.
Further, it is known that among the 4a-aryldecahydroisoquinoline compounds, the compounds having a condensed ring with cis configuration are thermodynamically stable than the compounds having a condensed ring with trans configuration.


DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a process for producing 4a-aryl-trans-6-oxodecahydroisoquinoline derivatives which are useful as analgesics and/or narcotic antagonists and as materials for synthesizing immunosuppressive agents by smaller number of steps and with high yield.
The present inventors intensively studied the process for producing 4a-aryl-6-oxodecahydroisoquinoline derivatives, especially, their trans isomers. As a result, as shown in Chart 1, 1,4-conjugate addition reaction to a compound (II) derived from a compound (I) which is a starting material was attained using an aromatic metal compound, and a novel synthesis route to 4a-aryl-trans-6-oxodecahydroisoquinoline derivatives employing this reaction a key step was discovered, thereby reaching the present invention. The present invention makes it possible to synthesize 4a-aryl-trans-6-oxodecahydroisoquinolines with shorter steps than those of known process.
That is, the present invention provides a process for producing 4a-aryl-trans-6-oxodecahydroisoquinoline derivatives comprising the steps of: ##STR3## (wherein R.sup.1 is C.sub.1 -C.sub.6 alkyl, allyl, benzyl, phenethyl or C.sub.4 -C.sub.7 cycloalkylalkyl and R.sup.2 is C.sub.1 -C.sub.4 alkyl or benzyl) with methylvinylketone to convert the compound of the formula (I) to a compound of the formula (II) ##STR4## (wherein R.sup.1 and R.sup.2 represent the same meanings as described above); prepared from a compound of the formula (III) ##STR5## (wherein R.sup.3 is hydrogen atom, C.sub.1 -C.sub.4 alkoxy or benzyloxy group, M is lithium, magnesium chloride, magnesium bromide or magnesium iodide) to Groups VIIB, VIII, IB, IIB and IIIA, to convert the compound (II) to a compound of the formula (IV) ##STR6## (wherein R.sup.1, R.sup.2 and R.sup.3 represent the same meanings as described above); compound of the formula (IV) to a compound of the formula (V) ##STR7## (wherein R.sup.1, R.sup.2 and R.sup.3 represent the same meanings as described above, R.sup.4 and R.sup.4' independently are methyl or ethyl, or R and R.sup.4' are bonded to form ethylene or trimethylene); the formula (V) to a compound of the formula (VI) ##STR8## (wherein R.sup.1, R.sup.3, R.sup.4 and R.sup.4' represent the same meanings as described above); (VII) ##STR9## (wherein R.

REFERENCES:
patent: 4189583 (1980-02-01), Gless et al.
Bartmann et al., Synthetic Communications, vol. 18, No. 7, pp. 711-715, 1988.
Judd et al., Journal of Medicinal Chemistry, vol. 35, No. 1, pp. 48-56, Jan. 10, 1992.
Cantrell et al., J. Org. Chem., vol. 54, No. 6, pp. 1442-1445, 1989.

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