Process for the preparation of L-ascorbic acid

Details Process for the preparation of L-ascorbic acid Process for the preparation of L-ascorbic acid

2000-04-20

2001-03-06

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

06197977

ABSTRACT:

The invention relates to a process for the preparation of L-ascorbic acid, in which a melt of C
3
-C
10
-alkyl 2-keto-L-gulonate is lactonized under acidic conditions.
In the past, a large number of process variants for the preparation of L-ascorbic acid have been published. A review 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
15
reaction of 2-keto-L-gulonic acid with an acid are known.
Thus, U.S. Pat. No. 2,185,383 describes the reaction of 2-keto-L-gulonic acid with concentrated hydrochloric acid and acetic acid as a solvent.
JP-A 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, the removal of the precipitated sodium chloride by filtration and then the maintenance of the reaction mixture at temperatures in the range from 25° C. to 75° C., by means of which L-ascorbic acid is obtained.
JP-B 48-15931 describes the reaction of 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 suspension of 2-keto-L-gulonic acid is reacted to give L-ascorbic acid under acid catalysis in an inert organic solvent in the presence of a surface-active agent.
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 is furthermore to be gathered from 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 the addition of a strong acid.
Japanese published patent specification 22113/75 describes the esterification of 2-keto-L-gulonic acid with butanol and the subsequent acid-catalyzed lactonization in benzene as a solvent.
The abovementioned embodiments of the acid-catalyzed, single-stage process variant exhibit serious weaknesses. 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. At the same time, however, the problem is thus, however, also exchanged that the 2-keto-L-gulonic acid is always present undissolved in the form of a suspension at the start and in the course of the reaction and reaction only takes place on the crystal surface. The addition of surface-active substances alters the course of the reaction only slightly. What is more, this auxiliary can only be removed from the crude product with difficulty and means additional working-up steps in order to obtain the desired purity of the L-ascorbic acid. Long reaction times and accordingly large apparatus volumes are furthermore disadvantageous.
It was therefore the object to make available a process for the preparation of L-ascorbic acid which does not have the abovementioned disadvantages.
This object was achieved by a process for the preparation of L-ascorbic acid which comprises lactonizing a melt of C
3
-C
10
-alkyl 2-keto-L-gulonate under acidic conditions.
In a preferred embodiment, the process according to the invention furthermore comprises
a) esterifying 2-keto-L-gulonic acid or 2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid in the presence of an acidic catalyst using a C
3
-C
10
-alcohol,
b) distilling off the excess C
3
-C
10
-alcohol together with the water of reaction formed and
c) then lactonizing the C
3
-C
10
-alkyl 2-keto-L-gulonate formed in the form of an anhydrous melt under acidic conditions.
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 90° C.
Advantageously, higher alkyl esters of saturated, branched or unbranched alkyl alcohols having a hydrocarbon number of greater than or equal to 3, preferably having an alkyl radical of 3 to 10 carbon atoms, are suitable for the esterification, such as, 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, 4-decanol.
Those alcohols in which L-ascorbic acid is poorly soluble are preferably employed for the esterification. Those particularly preferably suitable are C
4
-C
8
alcohols, selected from the group consisting of n-propanol, isopropanol, 1-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-pentanol, 1-hexanol and 1-octanol and 1-butanol and 1-pentanol.
The alcohol is employed here in a 2- to 10-fold, preferably 3- to 6-fold, molar excess, based on the 2-keto-L-gulonic acid or 2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid employed.
2-Keto-L-gulonic acid is preferably employed for the synthesis as a starting material. The acid can be employed here either in crystalline form, for example as a dried or centrifuge-moist monohydrate or as an anhydrous compound or as an aqueous solution, for example as a concentrated fermentation solution.
As a rule, the monohydrate of 2-keto-L-gulonic acid is obtained an crystallization from water or water-containing, organic solvents. By centrifuging off the crystal magma, moist monohydrate is accessible. This can be employed directly in the subsequent esterification reaction as a centrifuge-moist product or dried under mild conditions.
It is also possible to employ a concentrated aqueous solution of the 2-keto-L-gulonic acid directly in the esterification reaction. The excess solvent is removed before or during the esterification reaction, e.g. by extraction and phase separation or azeotropic distillation. This procedure is particularly suitable for a ketogulonic acid solution from a fermentative preparation process. After removal of the biomass by standard processes known per se, the fermentation solution, which is usually colored, can preferably be employed directly without further purification after liquid-liquid extraction. The excess solvent is then removed, as described above, before or during the esterification reaction, e.g. by phase separation or azeotropic distillation.
Anhydrous 2-keto-L-gulonic acid is obtained, inter alia, from the crystalline, optionally centrifuge-moist monohydrate using intensified drying conditions.
The drying or dehydration of the monohydrate of 2-keto-L-gulonic acid can advantageously be dispensed with in the process according to the invention, as in the subsequent activation reaction according to the invention an azeotropic dehydration is carried out anyway.
The esterification reaction is catalyzed by addition of a 0.005 to 0.1 molar, preferably of a 0.005 to 0.05 molar, amount of an acidic catalyst, in free or polymer-bound form (as strongly acidic cation exchanger) or of its ester. The description “acidic cation exchanger” is understood as meaning commercially obtainable resins, such as, for example, Lewatit® S 100 and SP 112 (Bayer) or Amberlite® 18 and IRA 120 or Amberlyst® 15 or Duolite® C 20, C 26 and

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