Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
1999-09-21
2001-03-13
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
Reexamination Certificate
active
06201147
ABSTRACT:
The invention relates to a process for the resolution of esters of arylalkylcarboxylic acids.
Lipases and esterases are distinguished by a broad substrate spectrum combined with frequently very high stereoselectivity and stability even in nonaqueous solvents. The successful use of these enzymes is documented in a number of extensive review articles (Schoffers et al., Tetrahedron, 52, 1996: 3769-3826; Kazlauskas & Bornscheuer, Biotransformations, VCH, Weinheim, Vol. 8a, 1998: 37; Schmid et al., Angew. Chem. Int. Ed. Engl., 37, 1998: 1608) and in books (F. Theil, Enzyme in der Organischen Synthese [Enzymes in Organic Synthesis], Spektrum Akademischer Verlag, Heidelberg, 1997; C. H. Wong, G. M. Whitesides, Enzymes in Synthetic Organic Chemistry, Pergamon Press, Oxford, 1994; K. Faber, Biotransformations in Organic Chemistry, A Textbook, 3rd Edition, Springer, Berlin 1997; K. Drauz, H. Waldmann, Enzyme 20 Catalysis in Organic Synthesis, A Comprehensive Handbook, Vol I+II, VCH, Weinheim, 1995).
By means of this enzyme catalysis, optically pure alcohols are readily accessible. To prepare these optically pure alcohols, transesterifications in organic solvents starting from racemic or prostereogenic precursors have been widely described. To increase the reaction rate and to shift the reaction equilibrium, it has proven very useful to employ activated esters, in particular enol esters. Frequently employed acyl donors are vinyl esters and, among these, especially vinyl acetate. The vinyl alcohol formed intermediately in the transesterification is rearranged in a keto-enol tautomerism into the readily volatile acetaldehyde, which leads to a suppression of the undesirable back reaction (see Degueil-Castaing et al., Tetrahedron Lett., 28, 1987: 953-954; Wang et al., J. Am. Chem. Soc., 110, 1988: 7200-7205; Laumen et al., J. Chem. Soc., Chem. Commun., 1988: 1459-1461).
The accessibility in the case of optically active carboxylic acids appears different. Unlike the above-described preparation of optically pure alcohols utilizing the synthesis direction of lipases or esterases in nonaqueous solvents, optically pure carboxylic acids are prepared in the hydrolysis direction, in which the corresponding esters are hydrolyzed. This is necessary, since the enzymes used only accept a very small substrate spectrum in the synthesis direction on the carboxylic acid side and the hydrolysis direction makes possible a wider substrate spectrum. A disadvantage here, however, is that water-labile compounds cannot be used under these conditions. Moreover, a partial or complete racemization of the products can occur in the aqueous medium. This leads to a decrease in the optical purity of the products.
The utilization of the synthesis direction in the preparation of chiral carboxylic acids with nonactivated esters is likewise known from the literature (see Holmberg et al., Appl. Microbiol. Biotechnol., 35, 1992: 572-578; Persichetti et al., Tetrahedron Lett., 37, 1996: 6507-6510; Ozegowski et al., Liebigs Ann. 1994: 215-217). It is affected by further disadvantages, however, in addition to the disadvantage of small substrate breadth already mentioned above. The equilibrium position during resolution in a transesterification reaction with nonactivated esters is very unfavorable and leads either to product mixtures or to very long reaction times. In order to overcome these disadvantages, the reaction for shifting the equilibrium can be carried out in the presence of a molecular sieve (Soumanou et al., J. Am. Oil Chem. Soc., 75, 1998: 703-710), at reduced pressure or with application of a vacuum (Björkling et al., J. Chem. Soc., Chem. Commun., 1989: 934-935) or as a solid-phase synthesis (McNeill et al., J. Am. Oil Chem. Soc., 67, 1990: 779-783; Cao et al., Biocatal. Biotransform., 14, 1997: 269-283), which, however, in each case leads to a technically more complicated reaction.
It is an object of the present invention to develop an access to optically active carboxylic acids, which does not have the abovementioned disadvantages and is easy to carry out.
We have found that this object is achieved by the process according to the invention for the resolution of esters of arylalkylcarboxylic acids of the general formula I
which comprises reacting compounds of the general formula I with an alcohol of the general formula R
6
—OH in the presence of a lipase or esterase to give compounds of the general formulae Ia and II
at least one of the compounds of the formulae Ia and II being present in an enantiomeric excess and the substituents and variables in the formulae I, Ia and II having the following meanings:
*=optically active center
n and m independently of one another are 0 or 1
R
1
=hydrogen or methyl
R
2
=substituted or unsubstituted, branched or unbranched C
1
-C
6
-alkyl-, C
3
-C
6
-cycloalkyl-, aryl- or hetaryl-,
R
3
, R
4
, R
5
independently of one another are hydrogen, substituted or unsubstituted, branched or unbranched C
1
-C
10
-alkyl-, C
2
-C
10
-alkenyl-, C
2
-C
10
-alkynyl-, C
1
-C
10
-alkoxy-, C
2
-C
10
-alkenyloxy-, C
2
-C
10
-alkynyloxy-, C
3
-C
10
-cycloalkyl-, C
3
-C
10
-cycloalkyloxy-, C
1
-C
4
-alkylaryl-, C
1
-C
4
-alkylhetaryl-, aryl-, hetaryl-, hydroxyl-, halogen-, cyano-, nitro- or amino-,
R
6
=substituted or unsubstituted, branched or unbranched C
1
-C
20
-alkyl-, C
1
-C
20
-alkoxy-, C
2
-C
20
-alkenyl-, C
3
-C
10
-cycloalkyl- or aryl-,
and where two adjacent substituents R
3
, R
4
and R
5
together can form a further substituted or unsubstituted aromatic, saturated or partially saturated ring having 5 to 6 atoms in the ring, which can contain one or more heteroatoms such as O, N or S.
R
2
in the compounds of the formulae I, Ia and II is substituted or unsubstituted, branched or unbranched C
1
-C
6
-alkyl-, C
3
-C
6
-cycloalkyl-, aryl- or hetaryl-.
Alkyl radicals which may be mentioned are substituted or unsubstituted branched or unbranched C
1
-C
6
-alkyl chains such as, for example, methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl or 1-ethyl-2-methylpropyl. Methyl, ethyl, n-propyl, n-butyl, i-propyl and i-butyl are preferred.
Cycloalkyl radicals in the formula which may be mentioned by way of example are substituted or unsubstituted branched or unbranched C
3
-C
6
-cycloalkyl chains having 3 to 6 carbon atoms in the ring or ring system, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-methylcyclopropyl, 1-ethylcyclopropyl or 1-propylcyclopropyl. The cycloalkyl radicals can also contain heteroatoms such as S, N and O in the ring.
Aryl which may be mentioned is substituted or unsubstituted phenyl or naphthyl. Phenyl and naphthyl are preferred.
Hetaryl radicals which may be mentioned are substituted and unsubstituted hetaryl radicals, which contain one or more nitrogen, sulfur and/or oxygen atoms in the ring or ring system.
Possible substituents of the radicals of R
2
mentioned are, for example, one or more substituents such as halogen, such as fluorine, chlorine or bromine, cyano, nitro, amino or hydroxyl. Methyl, chlorine and hydroxyl are preferred.
R
3
, R
4
, R
5
in the compounds of the formulae I, Ia and II independently of one another are hydrogen, substituted or unsubstituted, branched or unbranched C
1
-C
10
-alkyl-, C
2
-C
10
-alkenyl-, C
2
-C
10
-alkynyl-, C
1
-C
10
-alkoxy-, C
2
-C
10
-alkenyloxy-, C
2
-C
10
-alkynyloxy-, C
3
-C
10
-cycloalkyl-, C
3
-C
10
-cycloalkyloxy-, C
1
-C
4
-alkylaryl-, C
1
-C
4
-alkylhetaryl-, aryl-, hetaryl-, hydroxyl-, halogen- such as fluorine, chlorine or bromine, cyano , nitro or amino . Furthermore, two adjacent substituents R
3
, R
4
a
Bornscheuer Uwe
Henke Erik
Hong Yang
BASF - Aktiengesellschaft
Keil & Weinkauf
McKane Joseph K.
Murray Joseph
LandOfFree
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