WO1991013068A1 - Process for the production of dipostassium ascorbate-2-sulphate - Google Patents

Abstract

For the production of dipotassium ascorbate-2-sulphate dihydrate, trimethyl amine-sulphur trioxide complex is added in molar excess to a concentrated solution of a 2-keto-L-gulonic acid ester in water or a water-methanol mixture. The pH of this reaction mixture is adjusted to a value in the range between 9.3 and 10.2 by the successive addition of potassium hydroxide solution and maintained at this value throughout the reaction. The process is particularly suitable for the economical mass production of the substance of adequate purity for use as fish food.

Description

 Process for the preparation of dipotassium ascorbate 2-sulfate

Technical field

The present invention relates to a process for the preparation of dipotassium ascorbate-2-sulfate dihydrate of the formula

HO-CH ₂ HO-CH

Dipotassium ascorbate-2-sulfate dihydrate is a derivative of Vitamin C (ascorbic acid). It is used, among other things, in fish

Metabolism formed by vitamin C as a vitamin C reserve. A lack of vitamin C leads to scurvy.

To protect fish against scurvy, vitamin C is added to the fish feed. However, vitamin C is not very stable, especially very sensitive to temperature. In the production and storage of fish feed, up to 65% of the vitamin C used is therefore broken down and lost. However, such a loss does not occur when using the much more stable dipotassium ascorbate-2-sulfate dihydrate instead of vitamin C. Dipotassium ascorbate-2-sulfate dihydrate is therefore used with great success as an additive to fish feed instead of vitamin C (B.W. Tucker, J.E. Halver, Fish Physiol. Boichem., __, 151, (1986)). Fish have the enzyme (sulfatase) required to split off the sulfate residue. This enables your organism to regenerate the pure vitamin C from the stored derivative.

State of the art

Other ascorbate 2-sulfate salts are usually prepared by means of two processes:

One of the two known methods is based on the reaction of ascorbic acid protected in positions 5 and 6 with pyridine-sulfur-trioxide complex in a dimethylformamide solution (PASieb et al., J.Chern. Soc. Perkin I, 1120 (1974)). After the sulfation reaction, this process requires the protective groups to be separated again using hydrochloric acid.

The other of the known methods is described in U.S. Patent No. 3,954,809. It is based on the sulfation of unprotected vitamin C or its salts with trimethylamine-sulfur-trioxide complex in aqueous solution in the presence of a base. The complex mentioned is used in a high molar excess (over 50%). The cleaning of the desired end product is quite complex in this process.

In both known processes, vitamin C or one of its salts serves as the starting material. These substances are available on the market (mostly in pharmaceutically pure form); However, they are much too expensive to produce dipotassium ascorbate-2-sulphate dihydrate, which should only be used as an additive to fish feed and therefore does not necessarily have to be of the highest purity. Such a production would not be economical.

Presentation of the invention

The invention as characterized in the claims is the object of specifying a process for the preparation of dipotassium ascorbate-2-sulfate dihydrate which is sufficiently pure for fish feed, which starts from a starting material which is also available on the market but is considerably cheaper and which is economically viable with a high yield is more executable than the known methods.

Accordingly, in the process according to the invention, trimethylamine-sulfur-trioxide complex in molar excess becomes a concentrated solution of a 2-keto-L-guloic acid ester (L-xylo-2-hexulosonic acid ester) of the general formula:

COOR co

HIGH

(II)

HC-OH HO-CH CH ₂ OH

a) R - H b) R - CH ₃ c) R - C ₂ H ₅

added in water or a water / methanol mixture, the pH of this reaction mixture is adjusted to a value in the range between 9.3 and 10.2 by successive addition of potassium hydroxide solution and for the duration of the reaction thereon Value held. Trimethylamine-sulfur-trioxide complex is also available on the market.

Advantageous refinements of the method according to the invention are characterized in the dependent claims.

For example, methyl ester (IIb) is preferably used as the ester. However, it can also be ethyl ester (IIc), for example.

A suitable solution of 2-keto-L-gulonic acid methyl ester (Ilb) in a water / methanol mixture can be easily and also very economically e.g. are obtained by adding sulfuric acid in a catalytic amount to a solution of the monohydrate of 2-keto-L-gulonic acid (Ha) in methanol, precipitating non-esterified acid together with sulfates after a predetermined reaction time and adding the precipitate.

Instead of 2-keto-L-gulonic acid methyl ester (Ilb), diacetone-2-keto-L-gulonic acid (2,3: 4,6-di-O-isopropylide-L-xylo-hexulofuranosonic acid) can also be used with the general formula

Me ₂ C - O

(III)

verwendet werden. Diaceton-2-Keto-L-Gulonsäure ist ein auf dem Markt sehr günstig erhältliches Zwischenprodukt der Vitamin-C Herstellung.

be used. Diacetone-2-keto-L-gulonic acid is an intermediate product of vitamin C production which is very cheaply available on the market.

In addition to the use of cheaper starting products, the economic viability of the process according to the invention is primarily due to the fact that it can be carried out in a single reaction vessel without isolation of intermediate products. When using methyl ester and its production in one of the two ways described above from 2-keto-L-gulonic acid or from diacetone-2-keto-L-gulonic acid, the procedural steps required for this can also be carried out beforehand in the same reaction vessel. Acid which has not reacted or sulfates formed are precipitated and separated off.

The main reaction path in the method according to the invention should be as shown below:

Im ersten Schritt wird der Ester in Enolform sulfatiert; erst danach erfolgt die Laktonisierung zum Ascorbat.K

In the first step, the ester is sulfated in enol form; Only then does the lactonization to ascorbate take place.

The molar excess in which the trimethylamine-sulfur-trioxide complex is added to the solution of the 2-keto-L-gulonic acid ester in water or the water / methanol mixture is preferably between 4 and 10%.

The potassium hydroxide solution added successively to adjust the pH is preferably a 10 N solution. By adjusting the pH to a value between 9.2 and 10.2, the 2-keto group is kept in the enol form.

The temperature is preferably adjusted to a value between 40 and 65 ° C during the reaction.

The dipotassium ascorbate-2-sulfate dihydrate formed during the reaction is preferably precipitated by adding methanol or ethanol.

Exemplary embodiments of the invention are explained below.

Ways of Executing the Invention

example 1

10 N potassium hydroxide solution is gradually added to a suspension of 2-keto-L-gulonic acid methyl ester (54 g: 0.26 mol) in water (45 ml) at room temperature until a pH of 8.7 is reached. Trimethylamine-sulfur-trioxide complex (38 g: 0.273 mol) is then added, the temperature is raised to 50 ° and the pH is adjusted to 9.99 by further addition of 10 N potassium hydroxide solution. During the following three hours, this pH is maintained by the successive addition of a further 10 N potassium hydroxide solution (a total of 55 ml). Towards the end of the reaction, the temperature is raised to 60 ° C. and the pressure in the reaction vessel is reduced in order to drive off trimethylamine formed. The reaction mixture is then cooled to 15 ° C. Potassium sulfate crystals are separated off by filtration. 96% ethanol (250 ml to 122 ml filtrate) is gradually added to the filtrate over 60 minutes. The suspension obtained is stirred at 15 ° C. for a further hour and finally filtered. The filter residue containing the desired end product in crystalline form is washed with 70% ethanol (80 ml). The result is 77.47 g of crystalline, yellowish dipotassium ascorbate-2-sulfate dihydrate with a purity of 78.8% (according to HPLC analysis). Example 2

10 N potassium hydroxide solution is gradually added to a suspension of 2-keto-L-gulonic acid methyl ester (Ilb) (44 g: 0.21 mol) in a methanol / water mixture (30 ml + 20 ml) a pH of 8.4 is reached. At the same time, the temperature is increased to 58 ° C. Then trimethylamine-sulfur-trioxide complex (32.33 g: 0.23 mol) is added, the pH is adjusted to 10.0 by further addition of 10 N potassium hydroxide solution and the temperature is increased further to 60 ° C. During the following 65 minutes, the pH value of 10.0 is maintained by successively adding a further 10 N potassium hydroxide solution (in total 52 ml) and with stirring. The trimethylamine formed is evaporated under reduced pressure and the temperature is then reduced to 20 ° C. Potassium sulfate crystals (3.72 g) are separated by filtration. Methanol (180 ml) is gradually added to the filtrate over 30 minutes while stirring at room temperature. The suspension obtained is stirred at an unchanged temperature for a further 30 minutes and finally filtered. The filter residue containing the desired end product in crystalline form is washed with 80% methanol (60 ml). This results in 58.36 g of dry product with a melting point of 149-151 ° C. The product contains 94% dipotassium ascorbate-2-sulfate (according to HPLC analysis) and is therefore pure enough to be used as an additive for fish feed . The yield is 70.5%. Example 3

Concentrated sulfuric acid (0.5 ml) is added to a solution of 2-keto-L-gulonic acid monohydrate (50 g: 0.236 mol) in methanol (130 ml) and this reaction mixture is heated under reflux for one hour. The reaction solution is then cooled to 58 ° C., sodium bicarbonate (3 g) is added and the suspension is stirred for 1.5 hours at unchanged temperature. The resulting precipitate (3.42 g), which contains unesterified 2-keto-gulonic acid in the form of the sodium salt and sodium sulfate, is separated off by filtration. The filtrate - a solution of pure 2-keto-L-gulonic acid methyl ester (Ilb) - is concentrated (until only 40 ml of methanol remain). Water (25 ml) and trimethylamine-sulfur-trioxide complex (32 g: 0.23 mol) are added to the resulting suspension. In the course of the following hour, a pH of 10.0 is adjusted and kept constant by successive addition of potassium hydroxide solution (47 ml) with stirring. The temperature is increased from 50 to 60 ° C. during the sulfation reaction. The product is isolated in the same way as in Example 2. This results in 65 g of final product with a purity of 93.5%.

Example 4

Concentrated sulfuric acid is added to a solution of diacetone-2-keto-L-gulonic acid (III) (100 g: 0.365 mol) in methanol (190 ml). acid (1.6 ml) added and this reaction mixture heated to 67 ° C over four hours. During the esterification reaction, fresh methanol (150 ml) is gradually added and the resulting mixture of acetone and methanol is distilled off. The reaction solution is cooled to 50 ° C and sodium bicarbonate ^* (6.4 g) carefully added. The resulting suspension is stirred for one hour at the same, unchanged temperature. The crystals contained in the suspension are removed by filtration. The filtrate is concentrated (until only 60 ml of methanol remain). Water (40 ml) and trimethylamine-sulfur-trioxide complex (50 g: 0.36 mol) are added to the concentrated filtrate and the sulfation reaction is carried out with the addition of 10 N potassium hydroxide solution (60 ml) at 60 ° C in 90 minutes and at pH 10.0. The product is isolated in the same way as in Example 2. This results in 97.35 g of final product with a purity of 94.1% (according to HPLC analysis).

Claims

Claims 1. Procedure for the preparation of dipotassium ascorbate 2-sulfate dihydrate of the formula

in which trimethylamine-sulfur-trioxide complex is added in molar excess to a concentrated solution of a 2-keto-L-gulonic acid ester in water or a water / methanol mixture, the pH of this reaction mixture by successive addition of potassium hydroxide solution is set to a value in the range between 9.3 and 10.2 and is kept at this value for the duration of the reaction. 2. The method according to claim 1, characterized in that the 2-keto-L-gulonic acid ester is 2-keto-L-gulonic acid methyl ester. 3. The method according to claim 2, characterized in that the 2-keto-L-gulonic acid methyl ester is dissolved in a water / methanol mixture and that this solution is obtained by adding sulfuric acid in a catalytic amount to a solution of 2-keto-L-gulonic acid monohydrate or of diacetone-2-keto-L-gulonic acid in methanol, after a predetermined reaction time, non-esterified acid together with sulfates by addition precipitated from bicarbonate and the precipitate is separated. 4. The method according to any one of claims 1 to 3, characterized in that the molar excess in which the trimethylamine-sulfur-trioxide complex is added to the solution of the 2-keto-L-gulonic acid ester in water or the water / methanol mixture is between 4 and 10%. 5. The method according to any one of claims 1 to 4, characterized in that the dipotassium ascorbate 2-sulfate dihydrate formed during the duration of the reaction is precipitated by adding methanol or ethanol. 6. The method according to any one of claims 1 to 5, characterized in that the temperature is set to a value between 40 and 65 ° C during the reaction. 7. The method according to claim 6, characterized in that after the duration of the reaction to drive off trimethylamine, the temperature is set to a higher value and the pressure is reduced and that the temperature is subsequently lowered to a lower value for the precipitation of potassium sulfate.