Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Patent
1999-12-27
2000-09-12
Barts, Samuel
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
564424, 564442, 564437, C07B 5700
Patent
active
061180254
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a method for preparing optically active .alpha.-substituted benzyl alcohols from the corresponding ketones.
The optically active .alpha.-substituted benzyl alcohols are key intermediates in the synthesis of numerous pharmaceutical products, especially in the preparation of phenylethanolamines active on .beta.-adrenergic receptors.
One of the synthetic approaches for these products is the asymmetric reduction of ketones with the aid of chiral catalysts. Such chiral catalysts are, for example, described in Organometallics, 15: 24401-2449, 1996; in Synlett, April 1995, 358-360; in EP-A-0 253 700 and in EP-A-0 443 923.
These documents describe classes of Group VIII metal complexes, especially rhodium complexes, which contain, inter alia, chiral ligands; more particularly, these documents describe complexes wherein the components are bound to the metal atom via "covalent" bonds.
It has now been discovered that "ionic"-type rhodium complexes are very efficient catalysts in the preparation of optically active .alpha.-substituted benzyl alcohols.
Thus, the present invention relates to a method of preparing an optically active alcohol of formula (I): ##STR1## in which the carbon atom indicated by the symbol * can have the (R) or (S) configuration and X represents a non-substituted amino group or a mono- or di-(C.sub.1 -C.sub.4)alkylamino group, which are optionally salified, characterised in that: ##STR2## in which X is as defined above, is subjected to a catalytic hydrogenation in the presence of a rhodium complex of formula (III): (IV): ##STR3## wherein the carbon atom indicated by the symbol * can have the (R) or (S) configuration, R and R' represent a cyclohexyl or a cyclopentyl, (1,5-COD) represents 1,5 cyclooctadiene and A represents a sterically hindered and little-coordinating monovalent anion; and
The term "(C.sub.1 -C.sub.4)alkyl" designates a linear or branched alkyl residue containing 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl.
The term "sterically hindered and little-coordinating monovalent monovalent anion" according to the present invention designates an anion such as perchlorate, tetrafluoroborate, tetraphenylborate or hexafluorophosphate. A particularly preferred anion is tetrafluoroborate.
The non-substituted amino groups or mono- or di-(C.sub.1 -C.sub.4)-alkylamino groups can be salified for example with a molecule of hydrochloric acid.
According to a preferred aspect, the present invention relates to a method for preparing an optically active alcohol of formula (I'): ##STR4## in which X' represents a non-substituted amino group or dimethylamino group, which are salified with a molecule of hydrochloric acid, characterised in that: ##STR5## in which X' is as defined above, is subjected to a catalytic hydrogenation in the presence of a rhodium complex of formula (III'):
The absolute configuration of the alcohols of formula (I) is determined by the configuration of the aminophosphine-phosphinite which is used. When an aminophosphine-phosphinite of (S) configuration is used, the alcohols of (S) configuration are obtained selectively, and when an aminophosphine-phosphinite of (R) configuration is employed, the alcohols of (R) configuration are obtained.
The asymmetric hydrogenation according to the present invention is conducted in a protic solvent such as, for example, an alcohol, such as methanol or ethanol.
The reaction temperature is generally between -30.degree. C. and the reflux of the reaction solvent, preferably between 20.degree. C. and 50.degree. C.
The hydrogenation of the present invention can be carried out at atmospheric pressure or under pressure; advantageously, the reaction is conducted at a pressure of hydrogen between 1 and 80 bar, especially between 20 and 50 bar.
The amount of catalyst to be used is between 0.005 and 2% by mole with respect to the starting ketone, preferably between 0.1 and 1%, advantageously about 0.5%.
The reaction times, even if they vary as a function of other parameter
REFERENCES:
patent: 5128488 (1992-07-01), Mortreux et al.
T. Hayashi et al., "Asymmetric Synthesis of 2-Amino-1-Arylethanols by Catalytic Asymmetric Hydrogenation", Tetrahedron Letters, 1979, 5, 425-428.
M. Nogradi, "Stereoselective Synthesis", VCH (Weinheim DE), 1987, pp. 53-89, XP0020208705, 89.
A. Roucoux et al., "Amidophosphine-Phosphinites: Synthesis and Use in Rhodium-Based Asymmetric Hydrogenation of Activated Keto Compounds . . . ", Organometallics, 1996, 15, 2440-2449.
A. Roucoux et al., "Highly Efficient Asymmetric Hydrogenation of Activated and Unactivated Ketones Catalyzed by Rhodium(I) Aminophosphine . . . ", Synlett, Apr. 1995, 358-360.
Agbossou Francine
Devocelle Marc
Dormoy Jean-Robert
Mortreux Andre
Alexander Michael D.
Barts Samuel
Sanofi-Synthelabo
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