Preparation of optically active &agr;-hydroxyethers

Details Preparation of optically active &agr;-hydroxyethers Preparation of optically active &agr;-hydroxyethers

2002-09-04

2003-09-09

Keys, Rosalynd (Department: 1621)

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

Organic compounds

Oxygen containing

C568S660000, C568S670000, C568S678000

Reexamination Certificate

active

06617475

ABSTRACT:

The present invention relates to a process for heterogeneously, asymmetrically hydrogenating racemic &agr;-ketoethers using a platinum catalyst in the presence of a chiral aromatic nitrogen base and optionally a strong base to give enantiomeric &agr;-hydroxyethers.
Optically active &agr;-hydroxyethers are valuable intermediates for preparing tricyclic &bgr;-lactam antibiotics (Matsumoto, T. et al. THL 40 (1999) 5043) and natural compounds (Murata, K., et al., Org. Lett. 1 (1999) 1119), active pharmaceutical ingredients and pesticides. As early as 1979, Y. Orito et al. in Nippon Kagaku Kuishi 1979(8), pages 1118-1120 disclose that optically active &agr;-hydroxycarboxylic esters are obtainable in good optical yields by hydrogenating &agr;-ketocarboxylic esters using platinum metal catalysts in the presence of a cinchona alkaloid. The influence of solvents and other reaction conditions in this hydrogenation is described by H. U. Blaser et al. in J. of Mol. Cat. 68 (1991), pages 215 to 222. Further investigations have shown (see H. U. Blaser et al. in Catalysis Today 37 (1997), pages 441 to 461) that the catalytic hydrogenation system has a high substrate specificity. Even the use of &agr;-diketones instead of the &agr;-ketocarboxylic esters (optical yield ee up to 95%) leads to considerably reduced optical yields (ee only 38 to 50%, see also W. A. H. Vermeer et al. in J. Chem. Soc., Chem. Comm., 1993, pages 1053 to 1054 and M. Studer et al. in J. Chem. Soc., Chem. Comm., 1998, page 1053). When an unsubstituted methyl &agr;-ketoether such as methoxyacetone is used, the effect is even more pronounced and an optical yield of only about 12% ee is obtained (H. U. Blaser et al. in Heterogeneous Catalysis and Fine Chemicals, Elsevier Science Publishers B. V., Amsterdam, 1998, pages 153 to 163). WO 01/00545 discloses that, in contrast, &agr;-ketoacetals in this hydrogenation deliver excellent chemical and optical yields.
The targeted preparation of substituted enantiomeric &agr;-hydroxyethers from prochiral &agr;-ketoethers by heterogeneous hydrogenation using platinum catalysts in the presence of a chiral nitrogen base has hitherto not been described. It has now been found that, surprisingly, this type of hydrogenation selectively hydrogenates only one diastereomer to virtual completion and accordingly very high chemical and optical yields are achievable, especially because the reactants and adducts are easily separable owing to their differing physical properties.
It is known that &agr;-ketoethers can be racemized using soluble strong bases. Although soluble bases accelerate the reaction, they lead to a completely racemized product. It was found that, surprisingly, the yield of the desired diastereomer could be greatly increased when a strong heterogeneous base was added to the reaction mixture. During the hydrogenation, the undesired diastereomer is racemized and the desired diastereomer is formed and hydrogenated. In this manner, the chemical yield can be greatly increased to over 90% and more.
The invention accordingly provides a process for heterogeneously and enantioselectively hydrogenating organic &agr;-keto compounds using a platinum catalyst in the presence of a soluble or immobilized chiral aromatic nitrogen base having at least one basic nitrogen atom neighbouring at least one stereogenic carbon atom, which is characterized in that racemic &agr;-ketoethers are hydrogenated to optically active &agr;-hydroxyethers.
Neighbouring stereogenic carbon atoms means that the nitrogen atom is not bonded to the stereogenic carbon atom, but instead that the basic nitrogen atom is in the &bgr;- and more preferably in the &agr;-position to at least one stereogenic carbon atom.
The racemic &agr;-ketoethers may be saturated or unsaturated, open-chain or cyclic compounds which preferably have 5 to 50, more preferably 5 to 30, carbon atoms and are unsubstituted or substituted by one or more radicals which are stable under the hydrogenation conditions. The carbon chain may be interrupted by heteroatoms, preferably from the group of —O—, ═N— and —NR′— and/or —C(O)—, —C(NR′)—, —C(O)—O—, —C(O)—NR′— where R′ is H, C
1
-C
8
-alkyl, C
5
- or C
6
-cycloalkyl or C
6
-C
10
-aryl, for example phenyl or naphthyl, or phenylmethyl or phenylethyl.
Examples of useful inert substituents include alkyl, alkenyl, alkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxy, cycloalkyl, cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy, aryl, aryloxy, aralkyl, aralkoxy, halogen, —OH, —OR
4
, —OC(O)R
4
, —NH—C(O)—R
4
, —NR
4
—C(O)—R
4
, —CO
2
R
4
, —CO
2
—NH
2
, —CO
2
—NHR
4
, and —CO
2
—NR
4
R
5
where R
4
and R
5
are each independently C
1
-C
4
-alkyl, cyclohexyl, cyclohexylmethyl, phenyl or benzyl.
The &agr;-ketoethers are preferably of the formula I,
where R
1
, R
2
and R
3
are each independently a monovalent, saturated or unsaturated aliphatic radical having 1 to 12 carbon atoms, a saturated or unsaturated cycloaliphatic radical having 3 to 8 carbon atoms, a saturated or unsaturated heterocycloaliphatic radical having 3 to 8 ring members and one or two heteroatoms from the group of O, N and NR′, a saturated or unsaturated cycloaliphatic-aliphatic radical having 4 to 12 carbon atoms, a saturated or unsaturated heterocycloaliphatic-aliphatic radical having 3 to 12 carbon atoms and one or two heteroatoms from the group of O, N and NR′, an aromatic radical having 6 to 10 carbon atoms, a heteroaromatic radical having 4 to 9 carbon atoms and one or two heteroatoms from the group of O and N, an aromatic-aliphatic radical having 7 to 12 carbon atoms or a heteroaromatic-aliphatic radical having 5 to 11 carbon atoms and one or two heteroatoms from the group of O and N where R′ is H, C
1
-C
8
-alkyl, preferably C
1
-C
4
-alkyl, C
5
- or C
6
-cycloalkyl or C
6
-C
10
-aryl, for example phenyl or naphthyl, phenyl or phenylethyl, R
1
and R
2
together or R
1
and R
3
together form a direct bond, C
1
-C
6
-alkylene, C
3
-C
8
-cycloalkyl-1,2-ene, C
3
-C
8
-cycloalkyl-C
1
-C
4
-alkylene, C
2
-C
7
-heterocycloalkyl-1,2-ene or C
2
-C
7
-heterocycloalkyl-C
1
-C
4
-alkylene having one or two heteroatoms from the group of O and N, C
6
-C
10
-aryl-C
1
-C
4
-alkylene, C
5
-C
9
-heteroaryl-C
1
-C
4
-alkylene having one or two heteroatoms from the group of O and N; or C
2
-C
10
-alkylene, C
3
-C
8
-cycloalkylene or C
2
-C
7
-heterocycloalkylene having one or two heteroatoms from the group of O and N, each of which is fused to C
3
-C
8
-cycloalkyl-1,2-ene, C
2
-C
7
-heterocycloalkyl-1,2-ene having one or two heteroatoms from the group of O and N, C
6
-C
10
-aryl-1,2-ene or C
5
-C
9
-heteroaryl-1,2-ene having one or two heteroatoms from the group of O and N, and R
3
and R
2
respectively are each as defined above,
R
2
and R
3
together are C
1
-C
6
-alkylene, C
1
-C
8
-alkylidene, C
3
-C
8
-cycloalkylidene, benzylidene, C
3
-C
8
-cycloalkyl-1,2-ene, C
3
-C
8
-cycloalkyl-C
1
-C
4
-alkylene, C
2
-C
7
-heterocycloalkyl-1,2-ene or C
2
-C
7
-heterocycloalkyl-C
1
-C
4
-alkylene having one or two heteroatoms from the group of O and N, C
6
-C
10
-aryl-C
1
-C
4
-alkylene, C
5
-C
9
-heteroaryl-C
1
-C
4
-alkylene having one or two heteroatoms from the group of O and N; or C
2
-C
10
-alkylene, C
3
-C
8
-cycloalkylene or C
2
-C
7
-heterocycloalkylene having one or two heteroatoms from the group of O and N, each of which is fused to C
3
-C
8
-cycloalkyl-1,2-ene, C
2
-C
7
-heterocycloalkyl-1,2-ene having one or two heteroatoms from the group of O and N, C
6
-C
10
-aryl-1,2-ene or C
5
-C
9
-heteroaryl-1,2-ene having one or two heteroatoms from the group of O and N, and R
1
is as defined above, and R
1
, R
2
and R
3
are each unsubstituted or substituted by one or more, identical or different radicals selected from the group of C
1
-C
4
-alkyl, C
2
-C
4
-alkenyl, C
1
-C
4
-alkoxy, C
1
-C
4
-haloalkyl, C
1
-C
4
-hydroxyalkyl, C
1
-C
4
-alkoxymethyl or -ethyl, C
1
-C
4
-haloalkoxy, cyclohexyl, cyclohexyloxy, cyclohexylmethyl, cyclohexylmethyloxy, phenyl, phenyloxy, benzyl, benzyloxy, phenylethyl, phenyleth

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