CH618693A5 - Process for the preparation of a mono- or di-alkali metal salt or an alkaline earth metal salt of L-ascorbic acid-2-sulphate and use thereof - Google Patents

Description

The invention relates to a process for the preparation of a mono- or di-alkali salt or an alkaline earth salt of L-ascorbic acid 2-sulfate by protecting the 5- and 6-position of L-ascorbic acid with a ketone or an aldehyde and sulfating the product obtained a sulfating agent in DMF and by subsequent neutralization with an alkali hydroxide or an alkaline earth hydroxide and removal of the protective group, and the use of these salts as poultry feed additive.

It is known to prepare salts of L-ascorbic acid sulfate by reacting pyridine-sulfur trioxide with 5,6-O-benzylidene-L-ascorbic acid and then converting the product into the potassium salt (TM Chu et al, Steroids 1968, 12, (3) 309-321). In this known process, however, the yields are low. They are only 15-20% and the product is not very pure.

It is therefore an object of the present invention to provide an economical process for producing a mono- or di-alkali salt or an alkaline earth metal salt of L-ascorbic acid 2-sulfate, which leads to a product of high purity in high yields.

According to the invention, this object is achieved by

that chlorosulfonic acid is used as the sulfating agent in the presence of pyridine or urea, or sulfur trioxide, alkali chlorosulfonate or sulfuryl chloride.

The L-ascorbic acid is protected in the 5-position and in the 6-position by a ketone such as acetone, methyl ethyl ketone, diisopropyl ketone, cyclohexanone or benzophenone or by an aldehyde such as acetaldehyde, propionaldehyde, benzaldehyde, chlorobenzaldehyde or methylbenzaldehyde or the like. The alkali metal salt of the L-ascorbic acid provided with a protective group in the 5-position and 6-position can be treated with the sulfating agent and an excess of dimethylformamide. The sulfated product is neutralized with an alkali metal hydroxide or an alkaline earth metal hydroxide, the di-alkali salt of L-ascorbic acid sulfate, which has a protective group in the 5- and 6-position, being formed. The product is then acidified with an inorganic acid such as sulfuric acid, hydrochloric acid or an organic acid such as acetic acid to remove the protecting group in the 5- and 6-positions and to form the mono-salt of L-ascorbic acid 2-sulfate . If desired, the 2,3-di-alkali metal salt of L-ascorbic acid 2-sulfate can be prepared by reaction with alkali metal hydroxide. In the reaction, 1-2 moles of sulfating agent (or 1-2 moles of the complex of sulfating agent) are reacted with 1 mole of L-ascorbic acid with a protective group in the 5- and 6-position. The reaction temperature of the sulfation is preferably in the range from -40 to 20 ° C. and in particular 0-10 ° C.

The reaction time is 1-20 h. Dimethyiformamide, dioxane, tetrahydrofuran or the like can be used as the solvation medium. After sulfation, the product is neutralized with an alkali metal hydroxide or an alkaline earth metal hydroxide at a low temperature, thereby forming the monoalkali metal salt or the monoerodalkali metal salt of the L-ascorbic acid sulfate which is protected in the 5- and 6-positions. The product is separated and acidified with an inorganic or organic acid and heated in the acidified state to remove the protective group in the 5- and 6-positions. The monoalkali metal salt or the alkaline earth metal salt of L-ascorbic acid 2-sulfate is formed. The product can be converted to the dialkali metal salt or the alkaline earth metal salt of L-ascorbic acid 2-sulfate.

example 1

21.6 g of 5,6-O-isopropylidene-L-ascorbic acid are dissolved in 150 ml of dimethylformamide. 137 ml of a solution of 48 g of sulfuric anhydride in 700 ml of dimethylformamide is added dropwise to the acid solution at 0-10 ° C. The mixture is stirred at room temperature for 3 hours after this addition and then 2N-KOH is added to the reaction mixture to adjust the pH to 7.0. The product is then filtered off and the filtrate is concentrated, and dissolved in water and mixed with 2N-HCl in order to adjust the pH to 2.3. 24.8 g of the monopotassium salt of 5,6-0-isopropylidene-L-ascorbic acid 2-sulfate are obtained. The product is dissolved in 30 ml of water and the solution is stirred at 60 ° C. for 45 minutes and then it is concentrated under reduced pressure and the product is recrystallized from water, giving 29.8 g of white needle-like crystals of the monopotassium salt of L- Ascorbic acid 2-sulfate with a decomposition point of 55-56 ° C in a yield of 85.6%. Elemental analysis: CGH709SK. 3H20 calculated: C 20.69 H 3.76 found: C 20.81 H 3.72

Example 2

According to Example 1, 26.4 g of the monopotassium salt of 5,6-0-isopropylidene-L-ascorbic acid 2-sulfate are dissolved in 30 ml of water and the solution is stirred at 60 ° C. for 45 h and then cooled and treated with 2N- KOH added to adjust the pH to 7.0. Then methanol is added to the solution and the product is crystallized out and 29.9 g of white flaky crystals of the dipotassium salt of L-ascorbic acid 2-sulfate are obtained with a decomposition point of 136-140 ° C. in a yield of 81.2 %. Elemental analysis: CcHG09SK2. 2HaO calculated: C 19.56 H 2.74 found: C 19.36 H 2.54

Example 3

43.2 g of 5,6-O-isopropylidene-L-ascorbic acid are dissolved in 300 ml of dimethylformamide. 274 ml of a solution obtained by dissolving 48 g of sulfuric anhydride in 700 ml of dimethylformamide are added dropwise to the previously obtained solution at 0-10 ° C. The mixture is stirred at room temperature for 3 hours after this addition and then 2N-NaOH is added to adjust the pH to 7.0. The product is filtered off and the filtrate is concentrated and then dissolved in water and mixed with 2N-HCl, the pH being adjusted to 2.3. 24.6 g of white acicular crystals of the monopotassium salt of 5,6-0-isopropylidene-L-ascorbic acid 2-sulfate are obtained. The product is dissolved in 60 ml of water and the solution is stirred at 60 ° C. for 45 min and cooled and washed with 2N-

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NaOH added to adjust the pH to 7.0. Then methanol is added to the solution and the product is crystallized. 83.3 g of white needle-like crystals of the disodium salt of L-ascorbic acid 2-sulfate are obtained with a melting point of 70-73 ° C. in a yield of 88.7%. Elemental analysis: C0H0O9SNa2. 4H20 calculated: C 19.36 H 3.79 found: C 19.52 H 3.69

Example 4

Instead of the 5,6-O-isopropylidene-L-ascorbic acid according to Example 1, 25.6 g of 5,6-O-cyclohexylidene-L-ascorbic acid according to Example 1 are sulfated and the whole is mixed with 2N-KOH in order to Adjust pH to 7.0. The product is dissolved in water and 2N-HCl is added to the solution to adjust the pH to 2.3, whereby 30.4 g of white crystals are obtained. The crystals are dissolved in 30 ml of water and the solution is stirred at 60 ° C. for 2 h and concentrated under reduced pressure. The product is recrystallized from water, giving 29.0 g of white needle-like crystals of the monopotassium salt of L-ascorbic acid 2-sulfate with a decomposition point of 55 to 56 ° C. in a yield of 83.3%.

Example 5

According to Example 1, 15.8 g of 5,6-O-isoproylidene-L-ascorbic acid are reacted and a saturated solution of calcium hydroxide is added to the solution of the product in order to adjust the pH to 7.0. Then methanol is added to the solution and the product crystallizes out. 34.2 g of white powdery crystals of the calcium salt of L-ascorbic acid 2-sulfate with a decomposition point of 70-72 ° C. are obtained in a yield of 87.4%.

Elemental analysis: CcHG09SCa. 3H20 calculated: C 20.69 H 3.47 found: C 20.50 H 3.30

Example 6

9.6 g of pyridine are dissolved in 300 ml of dimethyiformamide and 7.0 g of chlorosulfonic acid are added dropwise to the solution at 0-10 ° C. 13.0 g of 5,6-O-isopropylidene-L-ascorbic acid are added to the reaction mixture and the mixture is stirred at room temperature for 8 h and 2N-KOH is added to adjust the pH to 7.0. The product is filtered off and the filtrate is concentrated and dissolved in water and then the whole is mixed with 2N-HCl in order to adjust the pH to 2.3. The solution is stirred at 60 ° C for 45 min and then concentrated under reduced pressure. The residue is recrystallized from water and methanol, giving 11.0 g of white needle-like crystals of L-ascorbic acid 2-sulfate with a decomposition point of 55 ° C.

Example 7

The monopotassium salt of 5,6-O-isopropylidene-L-ascorbic acid 2-sulfate according to Example 6 is dissolved in 7 ml of water and the solution is stirred at 60 ° C. for 45 minutes and mixed with 2N-KOH to give the Adjust pH to 7.0. Methanol is then added in order to crystallize out the product. 8.0 g of white flaky crystals of the dipotassium salt of L-ascorbic acid 2-sulfate are obtained with a decomposition point of 136-140 ° C.

Example 8

According to Example 6, the sulfation is carried out using 9.6 g of pyridine, 300 ml of dimethyiformamide, 7.0 g of chlorosulfonic acid and 10.8 g of 5,6-O-isopropylidene-L-ascor-

binsäure performed. Then 2N-NaOH is added to the obtained solution to adjust the pH to 7.0. The product is filtered off and the filtrate is concentrated and dissolved in water and 2N-HCl is added to the solution 5 to adjust the pH to 2.3. The solution is stirred at 60 ° C for 45 min and then cooled. This solution is then mixed with 2N NaOH up to a pH of 7.0. Then methanol is added, whereupon 14.6 g of the disodium salt of L-ascorbic acid 2-sulfate are obtained in the form of white needle-like crystals with a melting point of 70-73 ° C.

Example 9

The monopotassium salt of 5,6-O-isopropylidene-L-ascorbic acid-2-sulfate, which was prepared according to Example 6 using 5.4 g of 5,6-O-isopropylidene-L-ascorbic acid, is shown in FIG. 7 ml of water are dissolved and the solution is stirred at 60 ° C. for 45 minutes and then cooled and then mixed with a saturated solution of calcium hydroxide to adjust the pH to 7.0. Then methanol is added and the whole is recrystallized, giving 6.91 g of white powdery crystals of the monocalcium salt of L-ascorbic acid 2-sulfate with a decomposition point of 70-72 ° C.

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Example 10

The process according to Example 6 is repeated, but 6.5 g of 5,6-O-cyclohexylidene-L-ascorbic acid are used. 5.4 g of the monopotassium salt of L-ascorbic acid 2-sulfate with a decomposition point of 55 ° C. are obtained.

Example 11

35 18.5 g of potassium chlorosulfonate are added to 130 ml of dimethylformamide. A solution of 21.6 g of 5,6-O-isopropylidene-L-ascorbic acid in 150 ml of dimethyiformamide is then added dropwise to the solution at 0-10 ° C. The mixture is stirred at room temperature for 3 hours after this addition and then 2N KOH is added to this solution until a pH of 7.0 is reached. The product is filtered off and the filtrate is concentrated. The product is dissolved in water and 2N-HC1 is added to a pH of 2.3. This gives 26.5 g of white needle-like crystals. 45 The crystals are dissolved in 30 ml of water and the solution is stirred at 60 ° C. for 1 h and then concentrated. The residue is recrystallized from water, 20.5 g of white needle-like crystals of the monopotassium salt of L-ascorbic acid 2-sulfate having a decomposition point of 55-56 ° C. being obtained.

Example 12

The procedure according to Example 11 is repeated, except that chlorosulfonic acid and the sodium salt of 5,6-0 - cyclohexylidene-L-ascorbic acid are used instead of the potassium chlorosulfonate and 5,6-O-isopropylidene-L-ascorbic acid with chlorosulfonic acid and the sodium salt . 25.6 g of the monopotassium salt of L-ascorbic acid 2-sulfate are obtained with a decomposition point of 60 55-56 ° C.

Example 13

2N-KOH are added to the solution of the monopotassium salt of L-ascorbic acid 2-sulfate according to Example 11 in order to adjust the pH to 7.0. Then methanol is added and 31.3 g of white flaky crystals of the dipotassium salt of L-ascorbic acid 2-sulfate are obtained with a decomposition point of 136-140 ° C.

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Example 14

The procedure according to Examples 11 and 13 is repeated, except that 2N-NaOH is set instead of 2N-KOH. This gives 27.8 g of white needle-like crystals of the disodium salt of L-ascorbic acid 2-sulfate with a melting point of 70-72 ° C.

Example 15

18.5 g of chlorosulfonic acid are added dropwise to a solution of 10.8 g of urea in 150 ml of dimethyiformamide and the solution is stirred at room temperature for 2 hours. A solution of 25.6 g (0.1 mol) of 5,6-O-cyclohexylidene-L-ascorbic acid in 150 ml of dimethyiformamide is added to the solution at 10 ° C. and the mixture is then stirred at room temperature for 8 hours and 2N-KOH was added to adjust the pH to 7.0. The product is filtered off and the filtrate is concentrated. The product is dissolved in water and 2N-HC1 is added to adjust the pH to 2.0. The solution is stirred at 60 ° C for 30 min and concentrated under reduced pressure. The product is recrystallized from water, giving 20.4 g of white needle-like crystals of the monopotassium salt of L-ascorbic acid 2-sulfate.

Example 16

The procedure according to Example 15 is repeated. The monopotassium salt of L-ascorbic acid 2-sulfate is dissolved in water and 2N-KOH is added to a pH of 7.0. Methanol is then added to the mixture obtained, 30.3 g of the dipotassium salt of L-ascorbic acid 2-sulfate having a decomposition point of 136-140 ° C. in the form of white flaky crystals.

Example 17

The process according to Examples 15 and 16 is repeated, but using sulfuric anhydride and 2N-NaOH instead of the chlorosulfonic acid and 2N-KOH. 29.6 g of white needle-like crystals of the disodium salt of L-ascorbic acid 2-sulfate with a decomposition point of 70-73 ° C. are obtained.

Example 18

17.5 g of sulfuryl chloride are added dropwise to 130 ml of dimethylformamide. A solution of 26.4 g of 5.6-0 - benzylidene-L-ascorbic acid in 150 ml of dimethyl sulfoxide is added dropwise to the solution at 0-10 ° C. and the mixture is stirred at room temperature for 3 hours. Then 2N-KOH is added to the solution, the pH being adjusted to 7.0. The product is filtered off and the filtrate is concentrated. The product is dissolved in water and 2N-HC1 is added to the solution until a pH of 2.3 is reached. The solution is stirred at 60 ° C for 45 min and then concentrated under reduced pressure. The residue is recrystallized from water, 3.0 g of white needle-like crystals of the monopotassium salt of L-ascorbic acid 2-sulfate having a decomposition point of 55 to 56 ° C. being obtained.

Example 19

The procedure according to Example 18 is repeated, using 5,6-0-cyclohexylidene-L-ascorbic acid, dimethyiformamide and 2N-NaOH instead of the 5,6-O-benzylidene-L-ascorbic acid, dimethyl sulfoxide and 2N-KOH will. The monosodium salt of L-ascorbic acid 2-sulfate is obtained. This product is dissolved in water and 2N NaOH is added to the solution to adjust the pH to 7.0. Then methanol is added and the product crystallizes out. 24.2 g of the disodium salt of L-ascorbic acid 2-sulfate are obtained in the form of white needle-like crystals with a decomposition point of 70-73 ° C.

The compounds obtained introduce into steroid material, such as in heparin-effect anticoagulants, antihemostat, cholesterol or the like. Sulfate groups, which improves metaboslism in the human and animal body. These compounds are also useful as medicines. You prevent e.g. the breaking of the eggshells. These compounds are also suitable as additives for animal feed and food and as cosmetic materials.

The mono- and disodium salt and the calcium salt of L-ascorbic acid 2-sulfate have not yet been described. In contrast, the potassium salt of L-ascorbic acid 2-sulfate is known. However, this potassium salt leads to potassium disorders. The other salts obtainable according to the invention do not lead to such potassium disorders and they have antihygroscopic and antioxidative properties. Therefore, these compounds are stable in cosmetic preparations, in food or feed and in pharmaceutical preparations.

It has been proposed to prevent the eggshells from becoming brittle by feeding vitamin C. However, there is no satisfactory effect because the vitamin C is broken down. This decomposition is particularly significant in summer.

When transporting eggs, more than 5% of the eggshells are damaged. It is therefore extremely important to prevent the eggshells from breaking. The compounds according to the invention are outstandingly suitable for preventing the eggshells from becoming brittle or breaking. This effect can be achieved by mixing 1-100 ppm and preferably 10-50 ppm of the compound into the feed or drinking water of the domestic poultry and in particular the hens, or by injecting 0.5-5 mg of the compound into each hen. If the compound is added to the feed or drinking water, it is preferred to first prepare a basic mixture consisting of the compound and an additive. Lactose, wheat flour, talc, starch, powdery feed, emulsifier or the like can be used as an additive.

Some tests to prevent the eggshell from breaking are described below.

500 hens (white leghorn) 36 weeks old are divided into 5 groups of 100 hens each. A basic feed is produced according to Table 1. This is mixed with 30 ppm of vitamin C or 30 ppm of the monopotassium salt, the disodium salt or the dicalcium salt of L-ascorbic acid 2-sulfate. The mixture is then kept at room temperature for 30 days and the feed obtained is fed to the hens. After 30 days or 60 days after the start of feeding, the strength and thickness of the individual egg shells of the eggs from each group are measured. The average strength and thickness of the eggshells of each group are given in Table 2.

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TABLE 1 Composition of the basic feed

Components

(%)

5

Corn

25.00

oats

15.00

Soybean flour

15.00

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wheat

10.00

Fish meal

7.00

Tapicoca flour

6.00

15

Corn gluten

5.50

CaCOs

4.50

Wheat bran

3.25

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molasses

3.00

Wheat flour

2.75

dehydrated alfalfa flour

2.75

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Mineral mix

1.00

100.00

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** Composition: the mineral mixture:

Mineral%

CaHPOé 65.0 35

CaCOs 19.5

iodized salt 13.5

Trace element mixture 2.0 40

100.00

TABLE 2 Strength and thickness of the eggshells

additive

Test after 30 days after 60 days no additive

Strength thickness

3.51 kg 0.331 mm

(100%) (100%)

3.49 kg 0.330 mm

(100%) (100%)

30 ppm vitamin C.

Strength thickness

3.54 kg 0.339 mm

(100.8%) (102.4%)

3.50 kg 0.339 mm

(100.2%) (102.7%)

30 ppm of the monopotassium salt of L-ascorbic acid 2-sulfate

Strength thickness

3.86 kg 0.356 mm

(109.9%) (107.5%)

3.85 kg 0.357 mm

(110.3%) (108.0%)

30 ppm of the disodium salt of L-ascorbic acid 2-sulfate

Strength thickness

3.86 kg 0.357 mm

(109.9%) (107.8%)

3.88 kg 0.358 mm

(111.2%) (108.5%)

30 ppm of the calcium salt of ascorbic acid 2-sulfate

Strength thickness

3.88 kg 0.359 mm

(110.5%) (108.4%)

3.90 kg 0.362 mm

(111.7%) (109.7%)

With an increase in the strength of the egg shells by 10% compared to the comparison eggs (without additives), the egg shells may break during transport.

65 are constantly avoided. In Table 2, the percentages of strength and thickness refer to the standard eggs (without addition).

Claims (2)

618 693 2 PATENT CLAIMS 1. A process for producing a mono- or di-alkali salt or an alkaline earth salt of L-ascorbic acid 2-sulphate by protecting the 5- or 6-position of L-ascorbic acid with a ketone or an aldehyde and sulfating the obtained Product with a sulfating agent in DMF and by subsequent neutralization with an alkali metal hydroxide or alkaline earth metal hydroxide and removal of the protective group, characterized in that the sulfating agent used is chlorosulfonic acid in the presence of pyridine or urea or sulfur trioxide, alkali metal chlorosulfonate or sulfuryl chloride. 2. Use of a mono- or di-alkali salt or an alkaline earth metal salt of L-ascorbic acid 2-sulfate according to claim 1 as a poultry feed additive.