Process for the catalytic enantioselective reduction of ketones

Details Process for the catalytic enantioselective reduction of ketones Process for the catalytic enantioselective reduction of ketones

1999-07-13

2001-01-30

Vollano, Jean F. (Department: 1621)

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

Organic compounds

Oxygen containing

Reexamination Certificate

active

06180837

ABSTRACT:

FIELD OF THE INVENTION
The invention involves a procedure for the catalytic enantioselective reduction of ketones to chiral alcohols.
DISCUSSION OF THE PRIOR ART
Chiral alcohols are, for example, important intermediates in the pharmaceutical industry. There is therefore a great interest in procedures which make these compounds available in high optical purity. In conjunction therewith, catalytic procedures are particularly advantageous since with the use of small quantities of the generally expensive chiral auxiliaries, a multiple of the chiral product can be produced.
A procedure of this type is, for example, the oxazaborolidine-catalyzed reduction of ketones to chiral alcohols with boranes, for example, borane dimethylsulfide complex, or borane tetrahydrofuran complex (see for example, Wallbaum, S. and Martens, J., in
Tetrahedron Asymmetry
3 1992, 1475-1504). The reaction is set forth in FIG.
1
. This method provides chiral alcohols in good to very good yield and enantiomeric excess (enantiomeric excess=ee). In this manner a series of pharmaceutically relevant compounds can be produced.
In general, for the achievement of an optimal enantiomeric excess, between about 5 to 10 mol/% of the catalyst (relative to the ketone) is needed. A minimization of the catalyst expenses can therefore make a crucial contribution to the cost advantage of the procedure.
Many attempts have been undertaken to raise the cycling number (mols of product per mol of spent catalyst). Thus for example, the oxazaborolidines utilized as catalysts were immobilized on insoluble carriers. These heterogeneous oxazaborolidines were obtained by coupling the utilized chiral amino alcohol ligands to a cross-linked polystyrene resin with boric acid groups (Franot, et al., in
Tetrahedron Asymmetry
6, 1995, 2755-2766). The thus obtained heterogeneous catalyst can be filtered off after the reaction and charged anew. Already during carrying out of the third reaction cycle, the enantiomeric excess achieved, drops under 80% so that further provision of the catalyst is no longer meaningful. Therefore by this means, the cyclic number can only be negligibly raised from 10 (corresponding to 10 mol % catalyst) up to 20 to 30.
SUMMARY OF THE INVENTION
The purpose of the present invention was to solve the technical problem of making a procedure available which enables the effective exploitation of the chiral catalyst.
This problem is solved by the present invention in that the catalytic enantioselective reduction of ketones to chiral alcohols with a molecular weight increased catalyst is carried out in a membrane reactor. By means of this procedure in accordance with the present invention, one is surprisingly able to raise the cycling number by a factor of 10 to 120 moreover without loss of the enantioselectivity of the charged catalyst. Moreover, this procedure delivers the chiral alcohols in enantiomeric excess of 90% ee. The retention, as well as the separation of the soluble catalyst by the membrane such as for example, an ultra or nanofiltration membrane, has furthermore the advantage that the reaction can be carried out in a homogeneous solution without material transportation limitations.
As catalyst, the charging of a chiral oxazaborolidine is particularly advantageous. As catalysts however, there may also be utilized transition metal compounds such as for example titanates, which then, via the chiral ligands, for example diol-ligands, can be coupled to the compound utilized for molecular weight increase.
The preferred oxazaborolidine of the present invention has two possible positions for molecular weight enlargement. A coupling of this substance to the compound utilized in molecular weight increase can occur either via an amino alcohol or a boron acid. Preferably the oxazaborolidine in accordance with the present invention, is coupled to the molecular weight increasing compound via the chiral amino alcohol.


REFERENCES:
patent: 3883580 (1975-05-01), Solodar
Francot et al A polymer-bound Oxazaborolidine Catalyst: Enantioselective Borane Reductions of ketones' Tetrahedral Asymmetry, vol. 6 No. 11 pp. 2755-2766 (found in the PCT report), Nov. 1995.
CA:124:144896 abs of React. Funct. Polymer by Caze 26 (1-3) pp. 85-94, 1995.
CA:125:81151 abs of Recl Trav Chim Pays-Bas by Kruse 115(4) pp. 239-243, 1996.
CA:124:311470 abs of Biochem Eng 3, Int Sym 3rd by Kruse pp. 181-3, 1995.

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