Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-11-07
2003-09-09
Owens, Amelia (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06617463
ABSTRACT:
This application is a 371 of PCT/EP01/04961 filed May 3, 2001.
The invention relates to a process for the preparation of L-ascorbic acid, in which free 2-keto-L-gulonic acid or C
3
-C
10
-alkyl 2-keto-L-gulonate is lactonized under acidic conditions in the presence of a water-miscible solvent and where this solvent in situ forms a solvent in which the ascorbic acid formed is poorly soluble.
A large number of process variants for the preparation of L-ascorbic acid have been published in the past. A general survey is found, inter alia, in Crawford et al., Adv. Carbohydrate Chem. 37, 79 (1980) and in Ullmann's Encyclopedia of Industrial Chemistry, Vol. A27, 551-557 (1996).
A number of processes for the preparation of ascorbic acid by reaction of 2-keto-L-gulonic acid with an acid are known.
Thus the reaction of 2-keto-L-gulonic acid with concentrated hydrochloric acid and acetic acid as a solvent is described in U.S. Pat. No. 2,185,383.
JP-AS 58-177986 describes a process which comprises the addition of ethanol and acetone to the sodium salt of 2-keto-L-gulonic acid, neutralization with hydrochloric acid, separation of the precipitated sodium chloride by filtration and subsequently the keeping of the reaction mixture at temperatures in the range from 25° C. to 75° C., whereby L-ascorbic acid is obtained.
The reaction of 2-keto-L-gulonic acid with a mineral acid in an inert solvent in the presence of a surface-active substance is described in JP-B 48-15931.
WO 87/00839 claims a process in which a suspension of 2-keto-L-gulonic acid in an inert organic solvent is reacted in the presence of a surface-active agent with acid catalysis to give L-ascorbic acid.
DE-A-195 47 073 describes a process for the preparation of L-ascorbic acid by reaction of 2-keto-L-gulonic acid with aqueous mineral acid in a solvent mixture comprising an inert organic solvent, an aliphatic ketone and an acid chloride.
WO 99/07691 describes the reaction of 2-keto-L-gulonic acid with concentrated hydrochloric acid at temperatures between 40 and 80° C.
EP-A-0 671 405 discloses a process for the preparation of methyl or ethyl 2-keto-L-gulonate by esterification of 2-keto-L-gulonic acid with methanol or ethanol in the presence of an acidic ion exchanger. It furthermore says in this application that the abovementioned esters can be subjected to an alkaline rearrangement (lactonization) to give ascorbic acid or to give a salt thereof.
U.S. Pat. No. 5,391,770 describes the esterification of 2-keto-L-gulonic acid with subsequent base-catalyzed lactonization of the esters formed to give salts of L-ascorbic acid and liberation of the ascorbic acid by addition of a strong acid.
Japanese Published Patent Specification 22 113/75 describes the esterification of 2-keto-L-gulonic acid with butanol and subsequent acid-catalyzed lactonization in benzene as solvent.
The abovementioned embodiment of the acid-catalyzed rearrangement of 2-keto-L-gulonic acid is economically less attractive on account of its long reaction time and possible secondary reactions of the ascorbic acid formed. Thus as a rule the use of an inert solvent is unavoidable in order to suppress the secondary reactions of the ascorbic acid with aqueous hydrochloric acid. In particular, the complete removal of the catalyst hydrogen chloride necessitates a great technical outlay, which is usually accompanied by the use of a specific solvent. Nevertheless, this procedure is very widely employed industrially. In the acid-catalyzed lactonization of 2-keto-L-gulonic acid, its ester or its isopropylidene-protected form, it is advised to use certain solvents for known reasons. Suitable solvents employed for this batchwise rearrangement in solution advantageously are nonpolar halogenated or nonhalogenated hydrocarbons, such as carbon tetrachloride, chloroform, dichloroethane, 1,2-trichloroethylene, perchloroethylene or aromatic hydrocarbons, such as toluene, chlorobenzene, benzene or xylene. Cyclic carbonates, such as propylene carbonate, can also be used to good effect. These inert solvents lead to working-up problems in the subsequent purification of the reaction product ascorbic acid, as they frequently form azeotropes which are only separable with high expenditure by distillation and can only be completely removed from the valuable product with difficulty by evaporation of stripping. These distillations are associated with loss of product and pollution of the environment. Solvents which are not recovered must additionally be added to the process again in pure form.
A further difficulty is that the 2-keto-L-gulonic acid is always present at the start and in the course of the reaction undissolved in the form of a suspension and a reaction only takes place on the crystal surface. The addition of surface-active substances changes the course of a reaction only a little. What is more, this auxiliary can only be removed from the crude product laboriously and means additional purification steps in order to achieve the desired purity of the L-ascorbic acid. Long reaction times and accordingly large apparatus volumes are furthermore disadvantageous.
The side reactions of the ascorbic acid with the acid catalyst occurring in the acid-catalyzed rearrangement of 2-keto-L-gulonic acid are adequately known. There is therefore no technical process which manages without the use of a technically expensive preliminary purification, e.g. by means of an active carbon purification before the high purification of the ascorbic acid. The service life of this carbon filter is different, depending on the process variant. Usually, however, it lowers the efficiency of the entire process.
Continuous lactonizations of 2-keto-L-gulonic acid and diacetone-2-keto-L-gulonic acid are described in U.S. Pat. No. 2,462,251; DE 29 39052; GB 601789 and GB 1222322. A disadvantage in these processes is that the catalyst recovery, in particular the concentration of the aqueous catalyst solution, is expensive and thus economically disadvantageous.
The continuous lactonization of 2-keto-L-gulonic acid in the presence of aqueous hydrochloric acid at temperatures above 80° C. and addition of lower alcohols after the enolization is described in DE 2939052. By quenching the hot reaction mixture with butanol, rapid cooling and substantial separation of the catalyst as an azeotrope is brought about. The recycling of the hydrochloric acid can only be carried out using a complicated and expensive process concept, as described above.
It is the object of the present invention to make available a process for the preparation of L-ascorbic acid which does not have the abovementioned disadvantages.
We have found that this object is achieved by a process for the preparation of L-ascorbic acid, which comprises lactonizing 2-keto-L-gulonic acid or a melt of C
3
-C
6
-alkyl 2-keto-L-gulonate with acid catalysis in the presence exclusively of a solvent or solvent mixture which is miscible with water and in situ forms a solvent in which the ascorbic acid formed is poorly soluble.
In a preferred embodiment, the process according to the invention furthermore comprises the following steps:
a) esterification of 2-keto-L-gulonic acid or 2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid with a C
3
-C
6
-alcohol in the presence of an acidic catalyst,
b) distillation of the excess C
3
-C
6
-alcohol together with the water of reaction formed and
c) lactonization of the C
3
-C
6
-alkyl 2-keto-L-gulonate formed with acid catalysis in the presence exclusively of a solvent or solvent mixture which is miscible with water and in situ forms a solvent in which the ascorbic acid formed is poorly soluble.
In the course of the process according to the invention, 2-keto-L-gulonic acid or 2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid is first reacted to give the alkyl ester in a single-stage esterification step in the presence of an acidic catalyst. The esterification is carried out in a temperature range from −10 to 160° C., preferably from 20 to 100° C., particularly preferably in a temperature range from 40 to 95° C.
Higher alkyl esters
Böttcher Andreas
Burst Wolfram
BASF - Aktiengesellschaft
Keil & Weinkauf
Owens Amelia
LandOfFree
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