Process for preparing optically active 1-(p-methoxybenzyl)-1,2,3

Details Process for preparing optically active 1-(p-methoxybenzyl)-1,2,3 Process for preparing optically active 1-(p-methoxybenzyl)-1,2,3

1997-12-31

1999-04-06

Davis, Zinna Northington

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C07D21720

Patent

active

058920447

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP96/02923, filed on Jul. 3, 1996.


BACKGROUND OF THE INVENTION

1. Field of the Invention
The present invention relates to a process for the preparation of 1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline of the formula ##STR2## in optically active form by asymmetric hydrogenation.
It further relates to a novel salt of 1-(p-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoline and a process for its preparation.
It also relates to a novel chiral diphosphine having a ferrocene structure and to its use for the preparation of catalysts for asymmetric hydrogenation, to the iridium-phosphine complexes obtainable from the diphosphine and also to a novel chiral amino-phosphine having a ferrocene structure as intermediate in the synthesis of the diphosphine.
2. Background Art
1-(p-Methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline (I) is an intermediate in the synthesis of the antitussive dextromethorphan and the analgesic levorphanol. The targeted preparation of the effective enantiomer of dextromethorphan requires I in the (S)-(-)-configuration, and the synthesis of levorphanol requires I in the (R)-(+)-configuration. A classical process for obtaining these stereoisomers is racemate resolution, which, in this case, is also possible without the use of optically active ancillary reagents (DE-A 34 36 179). The main disadvantage of almost all racemate resolutions is that at least half of the substance used has to be disposed of as waste in the form of the "undesired" enantiomer unless, exceptionally, it too is required in comparable quantities. In the present case, racemization is also possible, meaning that the undesired enantiomer can be recycled as racemate and there are in theory no losses (O. Schnider et al., Helv. Chim. Acta 1954, 37, 710; A. Brossi, O. Schnider, Helv. Chim. Acta 1956, 39, 1376; HU 170 924). This method is, however, rather involved.
A significantly better strategy is the targeted synthesis through a stereoselective reaction, starting from a prochiral precursor. It is known that N-acyl-1-benzylidene-1,2,3,4,5,6,7,8-octahydroisoquinolines can be stereoselectively ("asymmetrically") hydrogenated at the exocyclic double bond using chiral ruthenium-phosphine complexes (JP-A 05/092 958). This process does, however, have the disadvantage that an N-acylated product is obtained whose acyl group has to be cleaved off again in a further synthesis step. Furthermore, the benzylidene compounds are for their part formed as E/Z-isomer mixtures, of which in each case only the Z-isomer can be used for the stereoselective hydrogenation.


BROAD DESCRIPTION OF THE INVENTION

The object of the present invention was, therefore, to provide a straightforward process which produces the title compound directly in good optical purity.
According to the invention, the object is achieved by the process of the invention.
It has been found that by using optically active iridium-phosphine complexes as catalysts, 1-(p-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoline of the formula ##STR3## or a salt thereof can be directly hydrogenated asymmetrically to give the S- or R-enantiomers of the title compound. The nature and configuration of the catalyst determine which enantiomer is formed in preference and how high the optical yield is. The optically active iridium-phosphine complexes which may be used are, in principle, any chiral complexes of iridium in low oxidation state which have polydentate chiral phosphines as ligands, are able to coordinate with hydrogen and are catalytically active. For the hydrogenation, it is possible to use both neutral and cationic iridium-phosphine complexes as catalysts. These catalysts can also be produced in situ. In this case, the active catalyst is formed directly in the hydrogenation reaction by ligand-exchange from a precursor complex of iridium, the corresponding chiral ligand and hydrogen. The precursor complex used can, for example, be a complex of the general C.sub.4-12 -diene. In this case, a neutral complex is obtained. If, on the BF.sub.4.sup.-,

REFERENCES:
O. Schnider et al., Helv. Chim. Acta, 37, (1954), 710.
A. Brossi and O. Schnider, Helv. Chim. Acta, 39, (1956), 1376.
T. Morimoto et al., Tetrahedron Lett., 30, (1989), 735.
T. Hayashi et al., Bull. Chem. Soc. Jpn., vol. 53, No. 4, (Apr. 1980), 1138 to 1151 (Hayashi et al. II).
T. Hayashi et al. J. Of Organometallic Chemistry, vol. 413, No. 1 to 3, (Aug. 7, '91), 295 to 302, (Hayashi et al. I).

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