Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
1997-06-10
2003-09-02
Barts, Samuel (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S190000, C435S135000
Reexamination Certificate
active
06613934
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to enantiomerically enriched malonic acid monoesters substituted by a tertiary hydrocarbon radical, and their salts, and to a process for their preparation from the corresponding prochiral malonic acid diesters by enzymatic partial hydrolysis (or partial saponification).
2. Description of the Background
Enantiomerically enriched compounds are of considerable importance as synthetic units in the pharmaceutical and agrochemical sectors, and as chiral auxiliaries. Possible starting materials for enantiomerically enriched &agr;-monosubstituted or &agr;,&agr;-disubstituted malonic acid monoesters are the corresponding diesters, which contain a prochiral carbon atom with two identical carboxylic acid ester groups and two other substituents which differ from one another and from the carboxylic acid ester groups. Partial saponification to the monoester produces a center of chirality and enantioselective partial hydrolysis gives enantiomerically enriched and, in the most favorable case, practically enantiomerically pure malonic acid monoesters.
&agr;,&agr;-Disubstituted malonic acid diesters can be selectively converted to enantiomerically enriched malonic acid monoesters with the aid of porcine liver esterase (M. Schneider et al., Angew. 96 [1984], 54). This gives good enantiomeric excesses when there is a marked difference in size between the substituents. &agr;-Chymotrypsin is another useful enzyme for the enantioselective partial saponification of &agr;,&agr;-dialkylnialonic acid diesters to the corresponding &agr;,&agr;-dialkylmalonic acid monoesters (F. Björkling et al., Tetrahedron, 41 [1985], 1347).
This known enzyme-catalyzed partial hydrolysis could not be applied to &agr;-monoalkylmalonic acid diesters. T. Kitazume et al. (J. Org. Chem., 51 [1986], 1003) were not able to obtain significant enantiomeric excesses because the monoesters in question immediately racemized under the reaction or working-up conditions.
A. L. Gutman et al. (J. Org. Chem., 57 [1992], 1063) obtained benzyl methyl &agr;-methoxymalonate from dimethyl &agr;-methoxymalonate with an enantiomeric excess of 98% by transesterification with benzyl alcohol using the lipase from Candida cylindracea as the transesterification catalyst. Monomethyl &agr;-methoxymalonate could then be obtained by catalytic hydrogenation. This procedure is restricted to the methoxy compound and, as a two-stage process, is relatively expensive. Moreover, the configuration of the monoester is only stable in organic solvents.
SUMMARY OF THE INVENTION
The invention now provides enantiomerically enriched malonic acid monoesters &agr;-monosubstituted by a tertiary hydrocarbon radical, or their salts, of the general formula I:
in which R
1
, R
3
, R
4
and R
5
are identical or different hydrocarbon radicals, and wherein any two of the radicals R
3
, R
4
and R
5
may alternatively be present as a carbocyclic ring together with the quaternary carbon atom which they substitute, and M is hydrogen, one equivalent of a metal or an optionally substituted ammonium ion.
The invention further provides a process for the preparation of the enantiomerically enriched malonic acid monoesters &agr;-monosubstituted by a tertiary hydrocarbon radical, or their salts, of the above general formula I, which comprises an enzymatic partial hydrolysis of &agr;-monosubstituted malonic acid diesters of the general formula II:
in which R
1
, R
3
, R
4
and R
5
are defined as indicated for the formula I and R
2
is also a hydrocarbon radical, which can differ from R
1
.
DETAILED DESCRIPTION OF THE INVENTION
The process according to the invention produces the &agr;-monosubstituted malonic acid monoesters I and their salts with good yields and a high enantioselectivity starting from the corresponding &agr;-monosubstituted malonic acid diesters II, which are inexpensive and also readily available in industrial quantities. The tertiary hydrocarbon radical of the &agr;-monosubstituted malonic acid diester II, with its quaternary carbon atom bonded to the a carbon atom of the malonic acid diester II, obviously allows enantioselective hydrolysis of only one of the carboxylic acid ester groups. The configuration of the enantiomerically enriched &agr;-monosubstituted malonic acid monoesters is stable over a wide pH range. This is surprising because, according to the literature (T. Kitazume et al., loc. cit.), monosubstituted malonic acid diesters give racemic products on enzymatic saponification.
In the preferred &agr;-monosubstituted malonic acid monoesters I, and accordingly also in the &agr;-monosubstituted malonic acid diesters II preferred as starting materials, R
1
is a lower alkyl radical having 1 to 4 carbon atoms, especially 1 or 2 carbon atoms, or the benzyl radical and R
3
, R
4
and R
5
are identical or different and are alkyl, alkenyl, aryl, alkaryl or aralkyl radicals having up to 10 carbon atoms. If any two of the radicals R
3
, R
4
and R
5
form a carbocyclic ring with the quaternary carbon atom which they substitute, this ring preferably has a saturated hydrocarbon structure with 5 to 12 ring members, especially 5 or 6 ring members. M in the formula I is preferably hydrogen, one equivalent of an alkali metal or alkaline earth metal or an optionally alkyl-substituted ammonium ion. R
2
in the formula II has the same preferred meaning as R
1
and can differ from R
1
.
If all three substituents R
3
, R
4
and R
5
are different, the malonic acid esters have a center of chirality, so the &agr;-monosubstituted malonic acid diesters II can be obtained as racemates or pure enantiomers. Both are suitable as starting materials for the process according to the invention. In the case of racemates, the enzymatic partial hydrolysis proceeds as a kinetic resolution of the racemates, thereby influencing the magnitude of the enantiomeric excess which can be achieved by the process of the invention. The enantiomeric excess is generally from 80 to >99%, depending on the substituents R
3
, R
4
and R
5
. The &agr;-monosubstituted malonic acid diesters can be prepared from the unsubstituted malonic acid diesters in known manner by reaction with the appropriate electrophiles.
Examples of suitable malonic acid diesters II which may be mentioned are diethyl &agr;-tert-butylmalonate, dimethyl &agr;-tert-butylmalonate, dibenzyl &agr;-tert-pentylmalonate, dimethyl &agr;-tert-pentylmalonate, dimethyl &agr;-(1-methyl-1-phenylethyl)malonate, diethyl &agr;-(1-methyl-1-phenyl-n-propyl)malonate, dibutyl &agr;-(1 -ethyl-1 -phenylethyl)malonate, diethyl &agr;-(1-methylcyclohexyl)malonate and diethyl &agr;-(1,1-dimethylprop-2-enyl)malonate.
Any known enzymes which hydrolyze carboxylic acid ester groups in aqueous media can be used as catalysts for the enzymatic partial hydrolysis. Any commercially available ester-cleaving enzymes, including esterases, lipases and proteases, are suitable for this purpose. They can be used in crystalline form, in aqueous suspension or fixed to a support. Examples of suitable enzymes include porcine liver esterase, the lipase from Candida cylindracea and &agr;-chymotrypsin, already referred to above, the papain from Carica papaya and the lipase from porcine pancreas.
The process according to the invention is conveniently carried out by suspending the &agr;-monosubstituted malonic acid diester II in water, an aqueous solution or a buffer solution affording optimal pH adjustment. Examples of suitable buffers are phosphate buffer, citrate buffer and tris(hydroxymethyl)aminomethane (abbreviated to “Tris”). They are generally used in concentrations of 0.01 to 3 M and conveniently in a weight ratio of 2 to 50, relative to the &agr;-monosubstituted malonic acid diester II. The addition of a solvent, for example in amounts of up to about 40 percent by weight, based on the aqueous buffer solution, is helpful in many cases. Examples of suitable solvents are ethanol, tetrahydrofuran, dimethyl sulfoxide, N-methylpyrrolidone and acetonitrile.
The partia
Feld Marcel
Jegelka Udo
Kleemiss Wolfgang
Klotz-Berendes Bruno
Barts Samuel
Degussa - AG
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