Preparation of 2-keto-L-gulonic esters

Details Preparation of 2-keto-L-gulonic esters Preparation of 2-keto-L-gulonic esters

2000-08-14

2003-06-03

Rotman, Alan L. (Department: 1625)

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

Organic compounds

Carboxylic acid esters

C560S186000

Reexamination Certificate

active

06573400

ABSTRACT:

The present invention relates to a novel process for the preparation of 2-keto-L-gulonic esters. These esters are important intermediates for the synthesis of L-ascorbic acid (vitamin C).
The esterification of 2-keto-L-gulonic acid with a lower alcohol, in particular methanol, is known from numerous publications.
In this type of reaction, the yield is limited in principle by the equilibrium in the esterification reaction. The esterification thus benefits from an excess of alcohol or from continuous removal of the resulting water, which can be effected, for example, by azeotropic distillation.
In the conventional processes, including the Reichstein process, a long boiling time is usually chosen for achieving a high degree of esterification and hence a satisfactory yield. However, this impairs the purity, since both the 2-keto-L-gulonic acid and its methyl ester may form further byproducts under these conditions.
Various methods have been proposed for reducing the water content in the esterification. Water can be removed during the reaction by continuously distilling off the water/alcohol mixture, treating the distillate with molecular sieves and recycling the alcohol thus dried (Pol. Pat. 57042; Pol. Pat. 57573). Another possibility mentioned comprises distilling off the water/alcohol mixture continuously during the reaction and replacing it with fresh dry alcohol (EP-A-0 535 927). In both cases, a large amount of alcohol must be distilled off, with a correspondingly high energy consumption. Moreover, reaction times of up to 10 hours are necessary, with the danger of decomposition and secondary reactions.
EP-A-0 671 405 describes a process for the preparation of methyl or ethyl 2-keto-L-gulonate by esterifying 2-keto-L-gulonic acid with methanol or ethanol, respectively, in the presence of an acidic ion exchanger. The reaction is carried out in a tubular reactor filled with ion exchange resin, for an average residence time of the reactants of from 10 to 120 minutes.
EP-A-0 403 993 describes a process for the preparation of methyl 2-keto-L-gulonate, in which the esterification is carried out only partially, i.e. not until the equilibrium of the esterification reaction is reached. In an intermediate stage, unesterified 2-keto-L-gulonic acid and impurities present are precipitated by adding sodium bicarbonate or potassium bicarbonate—in an amount just sufficient essentially for neutralizing the ester solution—and are separated off.
In a process described in WO 99/03853, 2-keto-L-gulonic acid is converted into 2-keto-L-gulonic ester in a two-stage esterification process, the solution formed after the first esterification step being at least partly evaporated down to remove the resulting water of reaction, and the residue formed being subjected to a second esterification process.
WO 97/43433 and U.S. Pat. No. 5,391,770 describe the synthesis of butyl 2-keto-L-gulonate by refluxing 2-keto-L-gulonic acid in butanol for several hours in the presence of p-toluenesulfonic acid and then crystallizing out the desired product by cooling the reaction mixture.
DE-A-198 29 809 relates to a process for the preparation of esters from alcohol and carboxylic acid by means of a catalyst and isolation of the ester in a rectification column provided with internals.
For diacetone-2-keto-L-gulonic acid (DAK), the reaction product of the classical Reichstein process [Reichstein and Grüssner, Helv. Chim. Acta 17, (1934), 311], U.S. Pat. No. 2,491,933 mentions an esterification with elimination of acetone. The acetone formed is removed as a low boiler via the top of the distillation column.
The abovementioned esterification methods are moreover suitable only to a limited extent for a continuous procedure. Methods for a continuous procedure have been described only for the methyl and the ethyl ester of 2-keto-L-gulonic acid. Even under optimized conditions, average residence times of more than 10 minutes are required in all these reactions. In addition, an excessively high residual water content is still measured in the reaction mixture. In some subsequent reactions of the ester, for example for a vitamin C synthesis, this is generally not desired.
It is an object of the present invention to provide a process for the preparation of 2-keto-L-gulonic esters which does not have the abovementioned disadvantages.
We have found that this object is achieved by a process for the preparation of C
1
-C
10
-alkyl 2-keto-L-gulonates by esterifying 2-keto-L-gulonic acid or diacetone-2-keto-L-gulonic acid with a C
1
-C
10
-alcohol in the presence of a acidic catalyst, wherein the esterification is carried out in a liquid film on a hot surface with simultaneous removal of water.
In the above definition of the subject of the invention, the term “liquid film” includes the thin liquid or flowable films or layers formed by the reaction mixture and having a thickness of from 0.05 to 10 mm, preferably from 0.05 to 5 mm, particularly preferably from 0.1 to 2 mm. Such thin layers are produced, for example, by allowing the liquid reaction mixture to trickle down, by the action of centrifugal force or by especially designed wipers on the heated surfaces. Typical apparatuses for producing such thin layers include falling-film or downflow evaporators, Sambay and Luwa thin-film evaporators [evaporators in which thin liquid films are produced by means of rotating wiper blades or rollers], rotary evaporators and thin-film rectification columns [e.g. packed columns and film columns, rectifiers having rotating inserts (spray columns)]. A more detailed description of the reactors mentioned here is to be found in Ullmanns Encyklopädie der technischen Chemie, 4th Edition, Volume 2 (1972), pages 516, 533-537 and 652-660 and in Volume 3 (1973), pages 386-388.
In principle all C
1
-C
10
-alcohols are suitable for the esterification, advantageously saturated, branched or straight-chain alkyl alcohols having 3 or more carbons, preferably alcohols having an alkyl radical of 3 to 10 carbons atoms, for example n-propanol, isopropanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-pentanol, 2-pentanol, 3-pentanol, 1-hexanol, 2-hexanol, 1-heptanol, 2-heptanol, 1-octanol, 2-octanol, 3-octanol, 1-nonanol, 2-nonanol, 1-decanol, 2-decanol and 4-decanol, particularly preferably C
3
-C
8
-alcohols selected from the group consisting of n-propanol, isopropanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-pentanol, 1-hexanol and 1-octanol. Very particularly preferred alcohols are n-butanol and n-pentanol.
The alcohol is used in a 2- to 10-fold, preferably 3- to 8-fold, preferably 4- to 6-fold molar excess, based on the particularly 2-keto-L-gulonic acid or diacetone-2-keto-L-gulonic acid used.
In the course of the esterification reaction, both the water present as solvent and the water additionally formed in the esterification can be removed from the reaction space as a lower-boiling azeotropic mixture via the gas phase.
If required, phase separation (alcohol/water) can be carried out after the condensation, with recycling of the esterification alcohol. However, complete dewatering of the recycled alcohol, for example by membrane methods or by distillation, is as a rule not necessary since, according to the invention, complete dewatering takes place in the reaction space.
In the esterification of 2-keto-L-gulonic acid with C
1
-C
3
-alcohols, undesired losses of alcohols and hence lower yields may occur in the removal of water by distillation, owing to the low boiling points of these alcohols. The esterification rate can be increased again by appropriately replenishing the alcohol losses during the reaction.
By adding an acidic catalyst, the esterification reaction is catalyzed in a manner known per se. The catalyst is used in amounts of from 0.001 to 0.2, preferably from 0.005 to 0.1, particularly preferably from 0.005 to 0.05, mol per mole of 2-keto-L-gulonic acid or diacetone-2-keto-gulonic acid.
As a rule, all homogeneous or heterogeneous acidic catalysts known per se may be used as

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