Preparation of alkali metal salts of L-ascorbic acid

Details Preparation of alkali metal salts of L-ascorbic acid Preparation of alkali metal salts of L-ascorbic acid

2000-10-17

2001-08-14

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

06274744

ABSTRACT:

The present invention relates to a continuous process for preparing alkali metal salts of L-ascorbic acid 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 an acid catalyst and rearranging the resultant 2-keto-L-gulonic acid C
1
-C
10
-alkyl ester in the presence of an alkali metal C
1
-C
10
-alkoxide.
For the preparation of L-ascorbic acid, a multiplicity of process variants have been described in the past. An overview may be found, inter alia, in Crawford et al., Adv. Carbohydrate Chem. 37 (1980) 79 and in Ullmann's Encyclopedia of Industrial Chemistry, Vol. A27 (1996) 551-557.
In principle, two process variants have established themselves for the large-scale synthesis of vitamin C—one acid- and one base-catalyzed rearrangement of 2-keto-L-gulonic acid to form L-ascorbic acid or L-ascorbates.
Although the acid-catalyzed lactonization of 2-keto-L-gulonic acid is a simple batch process, it is associated with a high equipment requirement for catalyst removal and isolation of the product of value. The base-catalyzed lactonization is also a classical multistage process which includes the preparation of an ester of 2-keto-L-gulonic acid, the lactonization to the ascorbic acid salt and liberation of the ascorbic acid under acid conditions.
For both synthesis routes, a multiplicity of patents or patent applications are known.
Thus, U.S. Pat. No. 2,185,383 describes reacting 2-keto-L-gulonic acid with concentrated hydrochloric acid and acetic acid as solvent.
Japanese laid-open application 58-177986 describes a process which includes the addition of ethanol and acetone to the sodium salt of 2-keto-L-gulonic acid, neutralization with hydrochloric acid, separating off the sodium chloride which is precipitated out by filtration and then holding the reaction mixture at temperatures in the range from 25° C. to 75° C., as a result of which L-ascorbic acid is obtained.
Japanese published application 48-15931 describes reacting 2-keto-L-gulonic acid with a mineral acid in an inert solvent in the presence of a surface-active substance.
WO 87/00839 claims a process in which a slurry of 2-keto-L-gulonic acid is reacted in an inert organic solvent in the presence of a surface-active compound under acid catalysis to give L-ascorbic acid.
DE-A-195 47 073 describes a process for preparing L-ascorbic acid by reacting 2-keto-L-gulonic acid with aqueous mineral acid in a solvent mixture containing an inert organic solvent, an aliphatic ketone and an acid chloride.
WO 99/07691 describes reacting 2-keto-L-gulonic acid with concentrated hydrochloric acid at from 40 to 80° C.
EP-A-0 671 405 discloses a process for preparing 2-keto-L-gulonic acid methyl ester or ethyl ester by esterifying 2-keto-L-gulonic acid with methanol or ethanol in the presence of an acidic ion exchanger. In addition, it may be read in this application that the abovementioned esters can be subjected to an alkaline rearrangement (lactonization) to give ascorbic acid or a salt thereof.
U.S. Pat. No. 5,391,770 describes esterifying 2-keto-L-gulonic acid, with subsequent base-catalyzed lactonization of the resultant ester to give salts of L-ascorbic acid and liberation of ascorbic acid by addition of a strong acid.
Japanese published application 22 113/75 describes esterifying 2-keto-L-gulonic acid with butanol and the subsequent acid-catalyzed lactonization in benzene as solvent.
The acid-catalyzed lactonization generally requires long reaction times and therefore large apparatus volumes, the use of an inert solvent and a complex catalyst separation.
More favorable space-time yields are achieved in the base-catalyzed lactonization by more rapid rearrangement of the ester. However, with this synthesis route, complete esterification of the 2-keto-L-gulonic acid must be ensured and anhydrous reaction conditions maintained to avoid saponification reactions. This is not always achieved satisfactorily in general, despite the use of a stirred-tank cascade and complex dehydration of the esterification alcohol.
The base-catalyzed lactonization, for example with NaHCO
3
or NaOH in methanol, generally gives unreacted 2-keto-L-gulonic acid as an unwanted byproduct in the sodium ascorbate. In addition, when, for example, sodium hydroxide solution is used in methanol, the high water content leads to unwanted discolored byproducts and to a reduction in yield owing to the high solubility of sodium ascorbate in water.
To date, only continuous processes for esterifying 2-keto-L-gulonic acid have been described (see EP-A-0 671 405). In contrast, lactonization according to the prior art to date is a classical batch process.
It is an object of the present invention, therefore, to provide a process for preparing alkali metal salts of L-ascorbic acid which does not have the abovementioned disadvantages.
We have found that this object is achieved by a process for preparing alkali metal salts of L-ascorbic acid comprising the following steps:
a) esterifying 2-keto-L-gulonic acid or diacetone-2-keto-L-gulonic acid with a C
1
-C
10
-alcohol in the presence of an acid catalyst,
b) rearranging the 2-keto-L-gulonic acid C
1
-C
10
-alkyl ester formed in the presence of an alkali metal C
1
-C
10
-alkoxide,
which comprises carrying out each of the process steps a) and b) continuously.
Alkali metal salts of L-ascorbic acid preferably meant are sodium, potassium and lithium salts, particularly preferably sodium salts.
Suitable C
1
-C
10
-alcohols for esterifying 2-keto-L-gulonic acid or diacetone-2-keto-L-gulonic acid in process step a) are in principle all C
1
-C
10
-alcohols, advantageously saturated, branched or unbranched alkyl alcohols having a carbon number greater than or equal to 3, preferably alcohols having an alkyl residue of from 3 to 10 carbons, for example n-propanol, isopropanol, 1-butanol, 2-butanol, 2-methyl-l-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, 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 from 1 to 10 fold, preferably from 2 to 8 fold, particularly preferably from 3 to 6 fold, molar excess, based on the 2-keto-L-gulonic acid or diacetone-2-keto-L-gulonic acid used.
In the course of the esterification reaction, the water not only entrained as solvent but also additionally formed during the esterification can be removed from the reaction space via the gas phase as a lower-boiling azeotrope.
If necessary, after the condensation, phase separation (alcohol/water) can be carried out with recycling of the esterification alcohol. Generally in this case complete dehydration of the recycled alcohol, for example by membrane processes or by distillation, is not necessary, since according to the invention complete dehydration is carried out in the reaction space, for example in the counter-current process.
During the esterification of 2-keto-L-gulonic acid with C
1
-C
3
-alcohols, owing to the low boiling points of these alcohols, unwanted losses of alcohols and thus yield losses can occur during the removal of water by distillation. By appropriate supplementation of the alcohol losses during the reaction, the esterification rate may be increased again.
By adding an acid catalyst, the esterification reaction is catalyzed in a manner known per se. The catalyst is used here in amounts of from 0.001 to 0.2 mol, preferably in amounts of from 0.005 to 0.1 mol, particularly preferably from 0.005 to 0.05 mol, per mol of 2-keto-L-gulonic acid or diacetone-2-keto-L-gulonic acid.
Esterification catalysts which can be used are generally all homogeneous or heterogeneous acid catalysts which are known per se.
Preferably, the esterification is carried out in the presence of an acid homogeneous or

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