Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
2001-12-19
2003-12-09
Richter, Johann (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C568S600000, C568S678000, C568S691000, C568S814000, C568S830000, C568S862000, C568S866000
Reexamination Certificate
active
06660890
ABSTRACT:
This application is a 371 application of PCT/EP99/08446 filed Nov. 4, 1999.
The invention relates to a process for the production of optically active &agr;-hydroxyacetals by means of heterogeneous and enantioselective hydrogenation of prochiral &agr;-ketoacetals with platinum as the catalyst and in the presence of a chiral aromatic nitrogen base with at least one basic nitrogen atom adjacent to stereogenic carbon atoms, for example cinchona alkaloids and derivatives thereof.
Optically active &agr;-hydroxyacetals are valuable intermediates in the production of natural compounds [B. T. Cho et al. in Tetrahedron: Asymmetry Vol. 5, No. 7 (1994), pages 1147 to 1150], pharmaceutical active ingredients and pesticides. Cho et al. also describe the asymmetric reduction of &agr;-ketoacetals in homogeneous phase with stoichiometric quantities of a special asymmetric borohydride, namely potassium-9-O-(1,2-isopropylidene-5-deoxy-&agr;-D-xylofuranosyl)-9-boratabicyclo[3.3.1]nonane. H. Takahashi et al. describes in Chemistry Letters (1987), pages 855 to 858 the asymmetric hydrogenation of &agr;-ketopropionic acid methyl ester and 1,1-dimethoxypropan-2-one with chiral rhodium/diphosphine complexes, whereby the optical yields of 1,1dimethoxypropan-2-ol are significantly lower than those of &agr;-hydroxypropionic acid methyl ester. Furthermore, enzymatic reduction processes are known, see for example J. Peters et al. in Tetrahedron: Asymmetry Vol.4, No. 7 (1993), pages 1683 to 1692, and C.-H. Wong et al., J. Am. Chem. Soc. 1985, 107, pages 4028 to 4031. For economic reasons, the above-described processes are not suitable for processes on an industrial scale, primarily because of the high costs in the production of catalysts, which, in addition, can only be separated from the homogeneous reaction mixtures with difficulty and also cannot be reused. In enzymatic or microbial processes, often only low concentrations of substrate may be used, and the necessary reaction control requires complicated reaction equipment.
As long ago as 1979, Orito et al. described that optically active &agr;-hydroxycarboxylates were obtainable in good optical yields by means of hydrogenation of &agr;-ketocarboxylates with 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 studies have shown [see H. U. Blaser et al. in Catalysis Today 37 (1997), pages 441 to 461] that the catalytic hydrogenation system has high substrate specificity. Even the use of &agr;-diketones instead of the &agr;-keto-carboxylates (optical yield, ee up to 95%) leads to considerably lower optical yields (ee only 39 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, pages 1053). The effect is even more marked when using &agr;-ketomethylethers, 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).
It has now surprisingly been found that the carbonyl group in &agr;-ketoacetals can be enantio-selectively catalytically hydrogenated with high selectivity and a high yield, with a simultaneously high optical yield (ee to over 95%) even with high concentrations of substrate and even without solvents, if the reaction is carried out in the presence of platinum as the catalyst and in the presence of a soluble or immobilised cinchona alkaloid or derivatives thereof. The catalyst activity is excellent and the catalyst can be simply separated by filtration processes and optionally reused after purification and reactivation. The process is therefore suitable for usage on an industrial scale. This hydrogenation possibility is even more surprising, as &agr;-ketoketals cannot be hydrogenated by this process.
The object of the invention is thus a process for the heterogeneous and enantioselective hydrogenation of prochiral organic &agr;-keto compounds with platinum as the catalyst in the presence of a soluble or immobilised chiral aromatic nitrogen base with at least one basic nitrogen atom adjacent to the stereogenic carbon atoms, which is characterised in that prochiral &agr;-ketoacetals are hydrogenated to optically active &agr;-hydroxyacetals.
Being adjacent to stereogenic carbon atoms may mean, for example, that the basic nitrogen atom is in &bgr;- and more preferably in &agr;-position to at least one stereogenic carbon atom.
The prochiral &agr;-ketoacetals in question may be saturated or unsaturated, open-chained or cyclic compounds, which contain preferably 5 to 30, most preferably 5 to 20 carbon atoms, which are unsubstituted or substituted by radicals that are stable under the hydrogenation conditions. The carbon chain may be interrupted by hetero atoms preferably from the group —O—, ═N— and —NR′—, wherein R′ is H, C
1
-C
8
-alkyl, preferably C
1
-C
4
-alkyl, C
5
- or C
6
-cycloalkyl, C
6
-C
10
-aryl, for example phenyl or naphthyl, phenyl or phenylethyl.
The &agr;-ketoacetals preferably correspond to formula I
wherein R
1
, R
2
and R
3
, independently of one another, signify a monovalent, saturated or unsaturated, aliphatic radical with 1 to 12 carbon atoms, a saturated or unsaturated cyclo-aliphatic radical with 3 to 8 carbon atoms, a saturated or unsaturated heterocycloaliphatic radical with 3 to 8 ring members and one or two hetero atoms from the group O, N and NR′, a saturated or unsaturated cycloaliphatic-aliphatic radical with 4 to 12 carbon atoms, a saturated or unsaturated heterocycloaliphatic-aliphatic radical with 3 to 12 carbon atoms and one or two hetero atoms from the group O, N and NR′, an aromatic radical with 6 to 10 carbon atoms, a heteroaromatic radical with 4 to 9 carbon atoms and one or two hetero atoms from the group O and N, an aromatic-aliphatic radical with 7 to 12 carbon atoms or a heteroaromatic-aliphatic radical with 5 to 11 carbon atoms and one or two hetero atoms from the group O and N, whereby R′ is H, C
1
-C
8
-alkyl, preferably C
1
-C
4
-alkyl, C
5
- or C
6
-cyclo-alkyl, C
6
-C
10
-aryl, for example phenyl or naphthyl, phenyl or phenylethyl, R
1
and R
2
together are C
1
-C
6
-alkylene or C
3
-C
8
-1,2-cycloalkylene; or C
2
-C
4
-alkylene or C
3
-C
8
-cycloalkylene which are condensed with 1,2-phenylene, and R
3
has the above-mentioned significances,
R
2
and R
3
together signify C
1
-C
6
-alkylene, C
1
-C
8
-alkylidene, C
3
-C
8
-1,2-cycloalkylene, C
3
-C
8
-cycloalkylidene, benzylidene, 1,2-phenylene, 1,2-pyridynylene, 1,2-naphthylene; or C
3
-C
4
-alkylene or C
3
-C
8
-1,2-cycloalkylene which are condensed with 1,2-cycloalkylene or with 1,2-phenylene, and R
1
has the above-mentioned significances,
and R
1
, R
2
and R
3
are unsubstituted or substituted by one or more identical or different radicals selected from the group C
1
-C
4
-alkyl, C
2
-C
4
-alkenyl, C
1
-C
4
-alkoxy, C
1
-C
4
-halogen-alkyl, C
1
-C
4
-hydroxyalkyl, C
1
-C
4
-alkoxymethyl or -ethyl, C
1
-C
4
-halogenalkoxy, cyclohexyl, cyclohexyloxy, cyclohexylmethyl, cyclohexylmethyloxy, phenyl, phenyloxy, benzyl, benzyloxy, phenylethyl, phenylethyloxy, halogen, —OH, —OR
4
, —OC(O)—R
4
, —NH
2
, —NHR
4
, —NR
4
R
5
, —NH—C(O)—R
4
, —NR
4
—C(O)—R
4
, —CO
2
R
4
, —CO
2
—NH
2
, —CO
2
—NHR
4
, —CO
2
—NR
4
R
5
, wherein
R
4
and R
5
, independently of one another, signify C
1
-C
4
-alkyl, cyclohexyl, cyclohexylmethyl, phenyl or benzyl.
The heterocyclic radicals are bonded by a ring carbon atom to the oxygen atoms or the carbon atom of the carbonyl group in formula I.
Preferred substituents are methyl, ethyl, n- and i-propyl, n- and t-butyl, vinyl, allyl, methyloxy, ethyloxy, n- and i-propyloxy, n- and t-butyloxy, trifluoromethyl, trichloromethyl, &bgr;-hydroxyethyl, methoxy- or ethoxymethyl or -ethyl, trifluoromethoxy, cyclohexyl, cyclohexyloxy, cyclohexylmethyl, cyclohexylmethyloxy
Richter Johann
Solvias AG
Wenderoth , Lind & Ponack, L.L.P.
Witherspoon Sikarl A.
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