Asymmetric hydrogenation of &bgr;-keto esters

Details Asymmetric hydrogenation of &bgr;-keto esters Asymmetric hydrogenation of &bgr;-keto esters

1999-09-29

2002-03-19

Geist, Gary (Department: 1623)

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

Organic compounds

Carboxylic acid esters

C560S105000, C560S126000, C560S127000, C560S128000, C560S145000, C560S165000, C560S180000, C556S016000, C556S018000, C556S021000, C556S023000

Reexamination Certificate

active

06359165

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a process for preparing enantiomerically pure &bgr;-hydroxy esters by hydrogenation in the presence of ruthenium catalysts.
2. Description of the Related Art
The catalytic hydrogenation of ketones and &bgr;-keto esters with Ru-diphosphine complexes is known (e.g. Burk et al., J. Am. Chem. Soc. 1995, 117, 4423; A. Mortreux et al., Tetrahedron: Asymmetry, 7(2), 379-82, 1996; Noyori et al., Angew. Chem., Int. Ed. Engl., 36(3), 285-288, 1997; WO 9713763 A1).
The catalytic transfer hydrogenation of ketones with formic acid/triethylamine complex as reducing agent and ruthenium catalysts is also known (P. Knochel et al., Tetrahedron Lett., 37(45), 8165-8168, 1996; Sammakia et al., J. Org. Chem., 62(18), 6104-6105, 1997 (isopropanol as reducing agent)).
A common feature of all these methods is that the ligands and catalysts used are very awkward to prepare. In the transfer hydrogenations, furthermore, it is not the inexpensive hydrogen which is used but isopropanol or formic acid/tertiary amines instead. When the latter is used in the reaction it makes workup more difficult and automatically produces acetone or carbon dioxide.
In addition, the amounts of catalyst employed in these reactions are generally very large; this makes the prior art processes uneconomic.
BRIEF SUMMARY OF THE INVENTION
It is an object of the present invention to discover a process for hydrogenating keto esters which operates with hydrogen as reducing agent, uses a catalyst which is easy to prepare, permits a high substrate:catalyst ratio, and operates with high enantioselectivity.
DETAILED DESCRIPTION OF THE INVENTION
We have found that this object is achieved by a process for preparing enantiomerically pure &bgr;-hydroxy esters by reacting &bgr;-keto esters with hydrogen in the presence of catalysts of the formula LRuX
2
where
X is halogen, acetate, allyl, methallyl, 2-phenylallyl, per-chlorate, trifluoroacetate, tetrafluoroborate, hexafluoroan-timonate, hexafluorophosphate, hexafluoroarsenate, trichlo-roacetate,
L is a bidentate phospholane of the formula I
 where
B=is a bridging link with 1-5 carbon atoms between the two phosphorus atoms,
R
1
=H, C
1
-C
6
-alkyl, aryl, alkylaryl or SiR
2
3
,
R
2
=alkyl or aryl,
m=0 or 1,
R
3
=H or OR
4
, and
R
4
=R
1
,
with the proviso that if m=1 then R
3
=H and if m=0 then R
3
≠H.
Preferred bridging links B are those where
Particular preference is given to bridging links B where n=1 or 2 or r=0.
The preparation of the bidentate phospholane ligands L is described in patent applications DE 19725796.8 and DE 19824121.6 and in the experimental section of this specification.
The preparation starts from the sugar mannitol, which is available in enantiomerically pure form from natural sources.
The catalytically active ruthenium complexes LRuX
2
can be prepared by conventional reaction (e.g. Uson, Inorg. Chim. Acta 73, 275 (1983), EP-A 0158875, EP-A 437690) with ruthenium complexes containing labile ligands (e.g. [RuCl
2
(COD)]
n
, p-cymene-ruthenium chloride dimer).
The hydrogenation of the invention is generally conducted at a temperature from −20 to 150° C., preferably from 0 to 100° C. and, with particular preference, from 15 to 40° C.
For the hydrogenation process of the invention the hydrogen pressure can be varied within a wide range between 0.1 and 300 bar. Very good results are obtained within a pressure range from 1 to 100 bar, preferably from 1 to 50 bar.
The reaction is preferably conducted in a solvent which comprises an alkanol.
Preferred solvents for the hydrogenations are C
1
-C
4
-alkanols, especially MeOH. In the case of poorly soluble substrates suitability extends to solvent mixtures, such as methanol and CH
2
Cl
2
, THF, toluene, or else water.
It is particularly preferred to use the alkanol on which the &bgr;-keto ester substrate is based, since this prevents unwanted transesterifications.
The catalyst is commonly employed in amounts of from 1:10 to 1:1,000,000, preferably from 1:1000 to 1:100,000 (w/w), based on the hydrogenation substrate.
The reaction can be improved in terms of both yield and selectivity by adding an acid, especially a strong acid, such as mineral acids or trifluoro- or trichloroacetic acids.
In this case the acid is generally added in an amount of 0.5-2 mol equivalents, based on catalyst.


REFERENCES:
patent: 6013833 (2000-01-01), Gewald et al.
patent: 6214763 (2001-04-01), Dobbs et al.
patent: 6225487 (2001-05-01), Guram
patent: 863125 (1998-09-01), None
patent: 92/19630 (1992-11-01), None
patent: 97/13763 (1997-04-01), None
Burk et al.,J. Am. Chem. Soc., 1995, 117, 4423-4424.
Haack et al.,Angew. Chem. Int. Ed. Engl., 1997, 36(3), 285-288.
Roucoux et al.,Tetrahedron Asymmetry, 7(2), 379-382, 1996.
Puntener et al.,Tetrahedron Letters, 37(45), 8165-8168, 1996.
Sammakia et al.,J. Org. Chem., 1997, 62, 6104-6105.

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