Method for the production of esters

Details Method for the production of esters Method for the production of esters

2001-07-17

2004-04-13

Richter, Johann (Department: 1621)

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

Organic compounds

Carboxylic acid esters

C560S226000, C560S227000

Reexamination Certificate

active

06720447

ABSTRACT:

The present invention relates to a novel process for the preparation of esters of the general formula I and a process for the extraction of compounds of the formula II.
Esters of the general formula I are valuable intermediates for the resolution of amines by enzyme-catalyzed reaction with these esters.
Thus Kitaguchi et al. (J. Amer. Chem. Soc. 111, 3094-3095, 1989) describe, for example, the resolution of amines using trifluoroethyl butyrate under subtilisin catalysis. The enantioselective acylation of 2-aminobutan-1-ol using ethyl acetate under catalysis by porcine pancreas lipase (PPL) is described by Gotor et al. (J. Chem. Soc. Chem. Commun. 957-958, 1988).
Quiros et al. (Tetrahedron: Asymmetry 4, 1105-1112, 1993) describe the lipase-catalyzed synthesis of optically active amides from racemic &agr;-halo-substituted ethyl propionates and primary amines.
In U.S. Pat. No. 5,057,607, a process for the stereoselective acylation of primary amines with esters which carry an oxygen atom in the vicinity of the carbonyl carbon is described for the synthesis of &bgr;-lactams.
WO 95/08636 describes a process for the resolution of primary and secondary amines in the presence of an ester using a hydrolase.
In the enzyme-catalyzed kinetic resolution of amines described in WO 95/08636 one enantiomer is converted into the amide. For this enzymatic acylation reaction, esters are preferably used which carry an oxygen atom in the &agr;-position to the carbonyl carbon, such as, for example, methoxyacetic acid esters. The free amine is obtained from the amide formed in this reaction by cleavage with a base. In this process, in addition to the amine, the acid, for example methoxyacetic acid, is obtained in aqueous solution in the form of its salts. It is important for the economy of the process to make this acid available again for the acylation reaction, that is to convert it into its ester again, which can then be used afresh in the enzymatic acylation.
Customarily, esters of this type are formed from the acids in the presence of an alcohol and of a mineral acid as a catalyst. This ester formation takes place, however, only up to an equilibrium.
In cases in which the boiling points of the acids, alcohols and esters are above that of water, the equilibrium can be easily shifted by removing the water by means of a distillation. If the boiling points are under that of water, this method cannot be used.
In the literature, a number of methods are described in which it was attempted to gain control of the problem of the lower boiling points of the esters and alcohols. In DE 195 39 293, for example, a process for the preparation of alkyl cyanoacetates is thus described in which the water is removed by means of an azeotropic distillation. The disadvantage of this process is that a complete conversion cannot be achieved under the conditions described.
CH 527 156 likewise describes a process for the preparation of esters of high-boiling carboxylic acids. In this process, the equilibrium and thus the reaction is affected by a large excess of alcohol. It is disadvantageous that the alcohol removed by means of the distillation must be continually supplemented during the reaction.
A disadvantage in the azeotropic distillations described above is that the water of reaction cannot be completely removed and that as a result a complete conversion is not possible.
In EP-B-0 361 839, a process is described which does not have this disadvantage. EP-B-0 361 839 claims a process for the dehydration of substances and mixtures, carried out by continuous azeotropic distillation using an organic solvent which forms a virtually immiscible azeotropic mixture of minimum boiling point with water, the condensation distillate being cooled to at least a temperature at which the condensate is supersaturated with a given water content or the organic phase of the condensate is supersaturated with water, as a result of which a further separation of water is facilitated. Unfortunately, this process is not widely applicable and necessitates cooling of the condensate as a further process step.
In U.S. Pat. No. 5,202,463, a multi-stage process for the removal of the water which is formed in the esterification is described. This process therefore necessitates a high outlay in terms of apparatus.
Since none of the known processes makes possible a reaction to give the esters which is as complete as possible and can be carried out readily and simply, the object is therefore to develop an appropriate process which does not have the disadvantages of the abovementioned processes and makes possible a simple, inexpensive preparation of esters from the acids contained in aqueous solution.
We have found that this object is achieved by a process for the preparation of esters of the general formula I
from compounds of the general formula II contained in aqueous solutions
which comprises
a) extracting the compounds of the general formula II directly or after liberation from their salts in the presence of a C
1
-C
8
-alcohol and a water-immiscible solvent and
b) then esterifying with the C
1
-C
8
-alcohol in the presence of a catalyst and of an entraining agent under the conditions of an azeotropic distillation,
where the process steps (a) and (b) can be carried out separately in terms of time and space or else in a successive continuous or batchwise sequence and where the variables and substituents in the formulae I and II have the following meanings:
R
1
=F, Cl, —OH, —OC
1
-C
10
-alkyl,
R
2
=H, C
1
-C
10
-alkyl
R
3
=C
1
-C
8
-alkyl,
Q=—OH, —O
−
K
+
, where K
+
is an alkali metal cation or alkaline earth metal cation or an amine,
n=0, 1 or 2, preferably 0 or 1, particularly preferably 0.


REFERENCES:
patent: 4082788 (1978-04-01), Mims
patent: 5057607 (1991-10-01), Zmijewski
patent: 5202463 (1993-04-01), Ruszkay
patent: 5637761 (1997-06-01), Miltenberger et al.
patent: 5648529 (1997-07-01), Jones et al.
patent: 361 839 (1990-04-01), None
Derwent Abst-XP-002139633.
Derwebt Abst-XP-002139634.
J. of Chem.Soc., Iss 0022-4936—957-958, No. 14, Jul. 14,1988 Gotor et al.
J ofAmChem.Soc., 111, 1989 3904-3095, Kitaguchi et al.

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