CA1056838A - Process for producing l-ascorbic acid-2-sulfate - Google Patents
Process for producing l-ascorbic acid-2-sulfateInfo
- Publication number
- CA1056838A CA1056838A CA212,951A CA212951A CA1056838A CA 1056838 A CA1056838 A CA 1056838A CA 212951 A CA212951 A CA 212951A CA 1056838 A CA1056838 A CA 1056838A
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- Prior art keywords
- ascorbic acid
- sulfate
- positions
- alkali metal
- earth metal
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/62—Three oxygen atoms, e.g. ascorbic acid
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Furan Compounds (AREA)
- Cosmetics (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
The present invention provides a process for producing mono- or di-alkali metal salt or alkaline earth metal salt of L-ascorbic acid-2-sulfate which comprises reacting L-ascorbic acid having a protective substituent in the 5- and 6-positions derived from a ketone or aldehyde with the sulfating agent and dimethyl formamide and neutralizing the product obtained with an alkali metal hydroxide or an alkaline earth metal hydroxide and removing the protective substituent at 5- and 6-positions. The invention also includes a method of producing eggs having shells of improved strength which comprises administering to laying fowl a mono or di-alkali metal salt or alkaline earth metal salt of L-ascorbic acid-2-sulfate. The invention still further includes as novel compounds sodium and calcium salts of L-ascorbic acid-2-sulfate.
The present invention provides a process for producing mono- or di-alkali metal salt or alkaline earth metal salt of L-ascorbic acid-2-sulfate which comprises reacting L-ascorbic acid having a protective substituent in the 5- and 6-positions derived from a ketone or aldehyde with the sulfating agent and dimethyl formamide and neutralizing the product obtained with an alkali metal hydroxide or an alkaline earth metal hydroxide and removing the protective substituent at 5- and 6-positions. The invention also includes a method of producing eggs having shells of improved strength which comprises administering to laying fowl a mono or di-alkali metal salt or alkaline earth metal salt of L-ascorbic acid-2-sulfate. The invention still further includes as novel compounds sodium and calcium salts of L-ascorbic acid-2-sulfate.
Description
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The present invention relates to a process for economi-cally producing high purity L-ascorbic acid-2-sulfate and salts thereof which are useful as medicines, domestic medicines, animal medicines and additives for food and feed and cosmetic materials, in high yield.
The production of salts of L-ascorbic acid-sulfate by reacting pyridine-sulfur trioxide with 5,6-0-benzylidene-L-ascorbic acid and then converting the product to the potassium salt thereof has been reported. [T.M. Chu et al. Steroids 1968, 12 (3) 309 -3~1]. However, in the process, the yield is low, e.g. 15-20%
and a product having high purity could not be obtained.
The present invention provides a process for producing the aforesaid product having high purity in an industrial and economical manner.
According to the present invention there is provided a process for producing L-ascorbic ac:id-2-sulfate or a salt thereof having high purity in an industrial and economical manner which comprises reacting L-ascorbic ac~id having a protective substituent in the 5- and 6-positions derived from a ketone or aldehyde with a sul~ating agent and neutralizing the product obtained with an alkali metal hydroxide or an alkaline earth me-tal hydroxide and acidifying the product obtained to remove the protective substituent at 5- and 6-positions.
The L-ascorbic acid has a protective substituent at the 5- and 6-positionS derived from a ketone e,g. acetone~ methylethyl ketone, diisopropyl ketone, cyclohexanone, and benzophenone or an aldehyde e.g. acetaldehyde, propionaldehyde, benzaldehyde, chlorobenzaldehyde or methyl benzaldehyde.
The L-ascorbic acid having the protective substituent at the 5- and 6-pOSitions is treated with a sulfating agent e.g.
sulfuric anhydride, chlorosulfonic acid, sulfuryl chloride or an , - - ~ . . : ..................................... . -, :.. :.
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alkali metal chlorosul~onate and dimethyl formamide if desirable together wi-th tertiary amine e.g. pyridine, triethylamnine, or urea, so as to produce a sulfateO
An alkali metal salt of L-ascorbic acid having a pro-tective substituent at 5- and 6-positions can be treated with the sulfating agent and excess of dimethyl formamide.
The sulfated product is neutralized with an alkali metal hydro-xide or an alkaline earth metal hydroxide to form a di-alkali salt of L-ascorbic acid sulfate having the protective substi-tutent at 5- and 6-positions, and then the prodùct was acidified with an inorganic acid e.g. sulfuric acid, hydrochloric acid or an organic acid e.g. acetic acid to remove the protective substituent at 5- and 6-positions and to produce a mono-alkali metal salt of L-ascorbic acid-2-sulfate. If desirable, a 2,3-di-alkali metal salt of L-ascorbic acid-2-sulfate can be pro-duced by reacting it with an alkali metal hydroxide.
In the process, 1 to 2 mole of a sulfating agent (or 1 to 2 mole of a complex of the sulfating agent) per mole of the L-ascorbic acid having the protective substituent at 5-and 6-positions is used. The react.~on temperature during the sulfation is in a range of -40C to 20C preferably 0 to 10C
and the reaction time is in a range of 1 to 20 hours. The solvent medium may be for example, dimethyl formamide, dioxane or tetrahydrofuran. After the sulfation, the product is neu- -tralized by an alkali metal hydroxide or an alkaline earth metal hydroxide at low temperature to produce the mono-alkali metal or alkaline earth metal salt of L-ascorbic acid having ~;
the protective substituent at 5- and 6-positions. The product is separated and warmed under acidic conditions with the inor-ganic acid or organic acid to remove the prot~ctive substituent at 5- and 6-positions and produce a mono-alkali metal salt or
The present invention relates to a process for economi-cally producing high purity L-ascorbic acid-2-sulfate and salts thereof which are useful as medicines, domestic medicines, animal medicines and additives for food and feed and cosmetic materials, in high yield.
The production of salts of L-ascorbic acid-sulfate by reacting pyridine-sulfur trioxide with 5,6-0-benzylidene-L-ascorbic acid and then converting the product to the potassium salt thereof has been reported. [T.M. Chu et al. Steroids 1968, 12 (3) 309 -3~1]. However, in the process, the yield is low, e.g. 15-20%
and a product having high purity could not be obtained.
The present invention provides a process for producing the aforesaid product having high purity in an industrial and economical manner.
According to the present invention there is provided a process for producing L-ascorbic ac:id-2-sulfate or a salt thereof having high purity in an industrial and economical manner which comprises reacting L-ascorbic ac~id having a protective substituent in the 5- and 6-positions derived from a ketone or aldehyde with a sul~ating agent and neutralizing the product obtained with an alkali metal hydroxide or an alkaline earth me-tal hydroxide and acidifying the product obtained to remove the protective substituent at 5- and 6-positions.
The L-ascorbic acid has a protective substituent at the 5- and 6-positionS derived from a ketone e,g. acetone~ methylethyl ketone, diisopropyl ketone, cyclohexanone, and benzophenone or an aldehyde e.g. acetaldehyde, propionaldehyde, benzaldehyde, chlorobenzaldehyde or methyl benzaldehyde.
The L-ascorbic acid having the protective substituent at the 5- and 6-pOSitions is treated with a sulfating agent e.g.
sulfuric anhydride, chlorosulfonic acid, sulfuryl chloride or an , - - ~ . . : ..................................... . -, :.. :.
; .
3~
alkali metal chlorosul~onate and dimethyl formamide if desirable together wi-th tertiary amine e.g. pyridine, triethylamnine, or urea, so as to produce a sulfateO
An alkali metal salt of L-ascorbic acid having a pro-tective substituent at 5- and 6-positions can be treated with the sulfating agent and excess of dimethyl formamide.
The sulfated product is neutralized with an alkali metal hydro-xide or an alkaline earth metal hydroxide to form a di-alkali salt of L-ascorbic acid sulfate having the protective substi-tutent at 5- and 6-positions, and then the prodùct was acidified with an inorganic acid e.g. sulfuric acid, hydrochloric acid or an organic acid e.g. acetic acid to remove the protective substituent at 5- and 6-positions and to produce a mono-alkali metal salt of L-ascorbic acid-2-sulfate. If desirable, a 2,3-di-alkali metal salt of L-ascorbic acid-2-sulfate can be pro-duced by reacting it with an alkali metal hydroxide.
In the process, 1 to 2 mole of a sulfating agent (or 1 to 2 mole of a complex of the sulfating agent) per mole of the L-ascorbic acid having the protective substituent at 5-and 6-positions is used. The react.~on temperature during the sulfation is in a range of -40C to 20C preferably 0 to 10C
and the reaction time is in a range of 1 to 20 hours. The solvent medium may be for example, dimethyl formamide, dioxane or tetrahydrofuran. After the sulfation, the product is neu- -tralized by an alkali metal hydroxide or an alkaline earth metal hydroxide at low temperature to produce the mono-alkali metal or alkaline earth metal salt of L-ascorbic acid having ~;
the protective substituent at 5- and 6-positions. The product is separated and warmed under acidic conditions with the inor-ganic acid or organic acid to remove the prot~ctive substituent at 5- and 6-positions and produce a mono-alkali metal salt or
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alkaline earth metal salt of L-ascorbic acid-2-sulfate. The product can be converted to di-alkali metal salt or alkaline-earth metal salt of L-ascorbic acid-2 sulfate.
The following are important embodiments of the process of the present invention.
1) A mono- or di-alkali metal salt or alkaline earth metal salt of L-ascorbic acid-2-sulfate is preferably produced by reacting L-ascorbic acid having a protective substituent in 5-and 6-positions derived from a ketone or aldehyde with a sulfat-ing agent selected from sulfuric anhydride, chlorosulfonic acid,sulfuryl chloride and an alkali chlorosulfonate in the presence of dimethyl formamide, so as to produce a sulfate and then neutralizing the product with an alkali metal hydroxide or an alkaline earth metal hydroxide and then removing the protective substituent at 5- and 6-positions, 2) The compound may also be preferably produced by reacting L-ascorbic acid having a protective substituent in the 5-and 6-positions derived from a ketone or aldehyde, with the sulfating agent and dimethyl-formam:ide in the presence of a tertiary amine or urea so as to produce a sulfate, neutralizing the product obtained with an alkali metal hydroxide or an al-kaline earth metal hydroxide and then removing the protective substituent at 5- and 6-positionsO
. . .
' ~ ', ' " " , ,' ~ '"' . '',~ , '... .
alkaline earth metal salt of L-ascorbic acid-2-sulfate. The product can be converted to di-alkali metal salt or alkaline-earth metal salt of L-ascorbic acid-2 sulfate.
The following are important embodiments of the process of the present invention.
1) A mono- or di-alkali metal salt or alkaline earth metal salt of L-ascorbic acid-2-sulfate is preferably produced by reacting L-ascorbic acid having a protective substituent in 5-and 6-positions derived from a ketone or aldehyde with a sulfat-ing agent selected from sulfuric anhydride, chlorosulfonic acid,sulfuryl chloride and an alkali chlorosulfonate in the presence of dimethyl formamide, so as to produce a sulfate and then neutralizing the product with an alkali metal hydroxide or an alkaline earth metal hydroxide and then removing the protective substituent at 5- and 6-positions, 2) The compound may also be preferably produced by reacting L-ascorbic acid having a protective substituent in the 5-and 6-positions derived from a ketone or aldehyde, with the sulfating agent and dimethyl-formam:ide in the presence of a tertiary amine or urea so as to produce a sulfate, neutralizing the product obtained with an alkali metal hydroxide or an al-kaline earth metal hydroxide and then removing the protective substituent at 5- and 6-positionsO
3) The compound may also be preferably produced by reacting L-ascorbic acid having a protective substituent in the 5- and 6- positions derived from a ketone or aldehyde with chlorosul-: . .
fonic acid or an alkali ch~orosulfonate and excess of dimethylformamide, so as to produce a sulfate, neutralizing the product obtained with an alkali metal hydroxide or an alkaline earth metal hydroxide and then removing the protective substituent at 5- and 6-positions.
The resulting products may be shown by the formula XO3SO ~ OX' O~ \ CH-CH20H
of~
wherein X is an alkali metal or an alkaline earth metal atom, and X' is a hydrogen atom, an alkali metal or an alkaline earth metal atom.
The present invention will be further illustrated by way of the following Examples.
E~ample 1 -A 21.6 g of 5,6-O-isopropylidene-L-ascorbic acid was dissolved in 150 ml of dimethyl formamide. A 137 ml of solution prepared by dissolving 48 g sulfuric anhydride in 700 ml of dimethyl formamide was added dropwise to said solution at a temp- -~erature of O to 10C. The mixture was stirred at room temperature for 3 hours after the addition and 2N-KOH was added to the reaction mixture to adjust the pH to 7Ø The product was -filtered and the filtrate was concentrated and dissolved in water and 2N-HCl was added to the solution to adjust the pH to 2.3. 24.8 g of mono-potassium salt of 5,6-O-isopropylidine-L-ascorbic acid-2-sulfate was thus obtained. The product was dissolved in 30 ml of water and the solution was stirred at 60C for 45 minutes, and was concentrated under reduced pressure and the product was recrystallized from water to yield 29.8 g of white needle-like crystals of mono~potassium salt of L-ascorbic acid 2-sulfate having a decomposition point of 55 to ~;
56C (Yield 85.6%).
.. . .
Elementary Analysis C6H79SK 3H20 Calculated (~) Found (%) C: 20.69 20.81 ~o 3.76 3.72 Example 2 In accordance with the process of Example 1, 26.4 g of mono-potassium salt of 5,6 0-isopropylidene-L-ascorbic acid-2-sulfate was dissolved in 30 ml of water and the solution was stirred at 60C for 45 hours and then was cooled and 2N-KOH
was added to the solution to adjust the pH to 7Ø Methanol was then added to the solution to crystallize it, whereby 29.9 g of white flake cystals of di-potassium salt of L-ascorbic acid-2-sulfate having decomposing point of 13~ to -140C was given (Yield 81.2~).
Elementary Analysis C6H609SK2 2H20 Calculated (~) Found(~) C: 19.56 19.36 H: 2.74 2.54 `
~xample 3 ;~
A 43.2 g of 5,6-0-isopropylidene-L-ascorbic acid was dissolved in 300 ml of dimethyl formamide. A 274 ~1 of solu-tion prepared by dissolving 48 g oE sulfuric anhydride in 700 s~
ml of dimethyl formamide was added dropwise to the solution at a temperature from 0 to 10C. The mixture was stirred at room `;~
temperature for 3 hours after the addition, and 2N-NaOH was ~ -added to the reaction mixture to adjust the pH to 7Ø
The product was filtered and the filtrate was concen-trated and dissolved in water and 2N-HCl was added to the sol-3~ ution to adjust the pH to 2.3. 24.6 g of white needle-like crystals of mono-sodium salt of 5,6-0-isopropylidine-L-asorbic ,:-:
acid 2-sulfate were obtained.
The product was dissolved in 60 ml of water and the solution was stirrea at 60C for 45 minutes and cooled, and 2N-NaO~ was added to the solution to adjust the pH to 7Ø
Methanol was then added to the solution to crystallize it. 83.3 g of white needle-like crystals of di-sodium salt of L-ascorbic acid-2-sulfate having melting point of 70 to 73C was obtained (Yield 88.7%).
Elementary Analysis C6H60gS~a2 ~ 2 Calculated (%) Found (%) C: 19.36 19.52 H: 3.79 3.69 Example 4 Instead of 5,6-0-isopropylidene-L-ascorbic acid of Example 1, 25.6 g of 5,6-0-cyclohexylidine-L-ascorbic acid was sulfated a~d 2N-KOH was added to the solution to~adjust the pH to 7Ø The product was dissolved in water and then 2N~HCl was added to the solution to adjust the pH to 2.3, whereby 30.4 g of white crystals were obtained.
The crystals were dissolved in 30 ml of water and the solution was stirred at 60C for 2 hours and concentratcd under reduced pressure. The product was recrystallized from water to give 29.0 g of white needle-like crystals of mono-potassium salt of L-ascor~ic acid-2-sulfate having a decomposition point ;
of 55 to 56C. (Yield 83.3%). -Example_5 ~-In accordance with the process of Example 1, 15.8 g of 5,6-0-isopropylidene-L-ascorbic acid was converted and a satur-ated solution of calcium hydroxide was added to the solution of the product to ad]ust the pH to 7Ø Methanol was then added to the solution to crystallize it. 34.2 g of white - 6 - -~
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powdery crystals of calcium salt of L-ascorbic acid-2-sulfate having a decomposing temperature of 70 to 72C were obtained (Yield 87.~%).
Elementary Analysis C6H609SCa 3H20 Calculated (%) Found (~) C:20.69 20.50 H:3.47 3.30 ::
Example 6 9,6 g of pyridine was dissolved in 300 ml of dimethyl formamide and 7.0 g of chlorosulfonic acid was added dropwise to the solution at a temperature of from 0 to 10C. 13.0 g of 5,6-0-isopropylidene-L-ascorbic acid was added to the reaction mixture and the mixture was stirred at room temperature for 8 hours, and 2N-KOH was added to the solution to adjust the pH
to 7Ø The product was filtered and the filtrate was concen- ~
trated and dissolved in water, and then 2N-MCl was added to the , -solution to adjust the pH to 2.3. The solution was stirred at 60C ~or 45 minutes and was concentrated under reduced pressure. ;
The residue was recrystallized from water and methanol to give 11.0 g of white needle-like crystals of L-ascorbic acid-2-sulfate having a decomposition point of 55C.
Example 7 The mono-potassium salt of 5,6~0-isopropylidene-L-ascorbic acid-2-sulfate prepared in accordance with the process of Example 6, was dissolved in 7 nl of water and the solution was stirred at 60C for 45 minutes and 2N-KOH was added to the solution to adjust the p~ to 7Ø Methanol was added to crys-tallize the solution. 8.0 g of white flake crystals of di-potassium salt of L~ascorbic acid-2-sulfate having a decomposi-` tion temperature of 136 to 140~C were obtained.
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Example 8 In accordance with the process of Example 6, sulfation was carried out by using 9.6 g of pyridine, 300 ml of dimethyl formamide, 7.0 ~ of chlorosulfonic acid and 10.8 g of 5,6-0-isopropylidene-L-ascorbic acid, and then 2N-NaOH was added to the resulting solution to adjust the pH to 7Ø The product was filtered and the filtrate was concentrated and dissolved in water and 2N-HCl was added to the solution to adjust the pH
to 2.3 and the solution was stirred at 60C for 45 minutes and cooled. Then 2N-NaOH was added to the solution to adjust the pH to 7.0 and methanol was added to crystallize it. 14.6 g of white needle-like crystals of di-sodium salt of L-ascorbic acid-2-sulfate having a melting point of 70 to 73C were obtained.
Example 9 The mono-potassium salt of 5,6-O-isopropylidene-L-ascorbic acid-2-~sulfate prepared in accordance with the process of Example 6 using 5.4 y of 5,6-0-isopropylidene-L-ascorbic acid, was dissolved in 7 ml of water and the solution was stirred at 60C for ~5 minutes and cooled. A saturated solution of calcium hydroxide was then added to the solution to adjust the pH to 7Ø
Methanol was then added to recrystallize the solution. 6.91 g of white powder crystals of mono-calcium salt of L-ascorbic acid-2-sulfate having a decomposition point of 70 to 72C were obtained.
Example 10 In accordance with the process of Example 6 except using c~c/o~7~)<Y~ en e.
6.5 g of 5,6-0- ~ -L-ascorbic acid instead of 5,6-0-isopropylidene-L-aseorbic aeid, 5.4 g of mono-potassium salt of L-aseorbie aeid-2-sulfate having a deeomposing point of 55C
were obtained.
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Example 11 18.5 g of potassium chlorosulfonate was added to 130 ml of dimethyl formamide. A solution of 21.6 g of 5,6-0-isopropy- -lidene-L-ascorbic acid in 150 ml of dimethyl formamide was added dropwise to the solution at a temperature from 0 to 10C.
The mixture was stirred at room temperature for 3 hours after the addition, and then 2N-KOH was added to the solution to adjust the pH to 7Ø The product was filtered and the filtrate was concentrated and dissolved in water, and then 2N-HCl was added to the sol~tion to adjust the pH to 2.3. 26.5 g of white needle-like crystals were obtained.
The crystals were dissolved in 30 ml of water and the solution was stirred at 60C for 1 hour and was concentrated.
The residue was recrystallized from water to give 20.5 g of white needle-like crystals of mono-potassium salt of L-ascorbic acid-2-sulfate having a decomposition temperature of 55 to 56C. -~
Example 12 ~n accordance with the process of Example 11 except using chlorosulfonic acid and sodium salt of 5,6-0-cyclohexylidene-L-ascorbic acid instead of potassium chlorosulfonate and 5,6-0-isopropylidene-L-ascorbic acid, 25.6 g of mono-potassium salt of L-ascorbic acid-2-sulfate having a decomposition temperature of 55 to 56C were obtained.
Example 13 2W-KOH was added to the solution of mono-potassium salt of L-ascorbic acid-2-suIfate prepared in accordance with the process of Example 11 to adjust the pH to 7Ø Methanol was then added to crystallize the solution 31.3 g of white flake crystals of di-potassium salt of L-ascorbic acid-2-sulfate having a decomposing point of 136 to 140C were obtained.
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Example 14 In accordance with the process of Examples (11) and (13) except using 2M-NaOEI instead of 2N-KOH, 27.8 g of white needle-like crystals of di-sodium salt of L-ascorbic acid-2-sulfate having a melting point of 70 to 72C were obtained. ;~
Example 15 An 18.5 g of chlorosulfonic acid were added dropwise to a solution o~ 10.8 g of urea in 150 ml of dimethyl formamide and then the solution was stirred at room temperature for 2 hours. A solution of 25.6 g (0.1 mole) of 5,6-0-cyclohexylidene-L-ascorbic acid in 150 ml of dimethyl formamide was added to the solution at 10C, and then the mixture was stirred at room temperature for 8 hours and 2N-KOH was added to the solution to adjust the pH to 7.Q. The product was filtered and the filtrate was concentrated and dissolved in water and 2N-HCl was added to the solution to adjust the pH to 2Ø The solution was stirred at 60C for 30 minutes and was concentrated under reduced pres-sure and the product was recrystallized from water to give 20.4 g of white needle-like crystals of mono-potassium salt of L-ascorbic acid-2-sulfate.
gxample 16 In accordance with the process of Example 15, the mono-potassium salt of L-ascorbic aeid-2-sulfate was dissolved in water and 2N-KOH was added to the solution to adjust the pH to 7Ø Methanol was then added to crystallize the solution, 30.3 g of white flake crystals of di-potassium of L-ascorbic acid-2-sulfate having a deeomposition point of 136 to 140C.
Example 17 In aeeordance with the proeess of Examples 15 and 16 except using suLfuric anhydride and 2N-NaOH instead of chloro-sulfonic acid and 2N-KOH, 29.6 g of white needle-like crystals of di-sodium salt of L-ascorbic acid-2-sulfate having a decomp-osition point of 70 to 73C were obtained.
Example 18 A 17.5 g of sulfuryl chloride was added dropwise to 130 ml of dimethyl formamide. A solution of 26.~ g of 5,6-0-benzylidene-L-ascorbic acid in 150 ml of dimethyl sulfoxide was added dropwise to the solution at a temperature from O to lO~C
and the mixture was stirred at room temperature for 3 hours.
Then the 2N-KOH was added to the solution to adjust the pH to 7Ø The product was filtered and the filtrate was concentrated and dissolved in water and 2N-HCl was added to the solution to adjust the pH to 2.3. The solution was stirred at 60C for 45 minutes and concentrated under reduced pressure. The residue was recrystallized from water to give 3.0 g of white needle-like crystals of mono-potassium salt of L-ascorbic acid-2-sulfate having a decomposition point of 55 to 56C.
Example 19 In accordance with the process of Example 18 except using 5,6-0-cyclohexylidene-L-ascorbic acid, dimethyl formamide and 2N-NaO~ instead of 5,6-0-benzylidene-L-ascorbic acid, di-methyl sulfoxide and 2N-KOH, mono-sodium salt of L-ascorbic acid-2-sulfate was obtained. The product was dissolved in water and 2N-NaOH was added to the solution to adjust the pH to 7Ø
Methanol was then added to crystallize the solution 2~.2 g of white needle-like crystals of di-sodium salt of L-ascorbic acid-2-sulfate having a decomposing point of 70 to 73C were obtained.
The compounds of the present invention supply a sulfate group to steroid materials such as anticoagulants having hepar-in like effect, antihemostat and cholesterol, so as to improve ;
metabolism for human body and animal and also are useful as do-mestic medicine and animal medicine as the compounds impart the ' ' ~',.
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.. .,: . " . , , :, , ,, . . . . ~ ., eE-Eect for preventing the breakage of eggshells. The compounds are also useful as an additive for food and feed and cosmetic material.
The mono-and di-sodium salts and calcium salt of L-ascor-bic acid-2-sulfate produced by the process of the invention, are novel, impart no potassium trouble compared to the known potassium salt of ~-ascorbic acid-2-sulfate, have high antihygros-copic property and antioxidative property and are quite stable in a medicine or animal medicine composition, feed, food and a cosmetic composition. It has been proposed to prevent the breakage of eggshells by feeding the fowl vitamin-C. However this effect could not be satisfactorily imparted because of the decomposition of vitamin-C, which is remarkable in summer. The damage of eggshells during the transportation is higher than 5%
and it is economically quite important to prevent the breakage of eggshells. The compounds of the invention are useful for preventing the breakage of eggshells. The effect can be attained by adding l to 100 ppm preferably lO to 50 ppm of the compound of the invention in a feed or drinking water for domestic fowl especially hens or injecting 0.5 to 5 mg of the compound into each hen. When the compound is added to feed or drinking water, it is preferable to prepare a master batch containing the com-pound and an additive such as lactose, wheat flour, talc, starch, powdery feed and an emulsifier.
The test experiment of the breakage of eggshells will be illustrated in detail.
500 of hens (White leghorn) of 36 week age were divided ;-to five groups of each 100 hens. Each composition of basal ration of Table 1 was admixed with 30 ppm of vitamin-C, or 30 ppm of mono-potassium salt, di-sodium salt or di-calcium salt of L ascorbic acid-2-sulfate and the composition was kept at ., , . ., .... . , . .
.
-room temperature for 30 days and the composition was fed to eachgroup of hens.
After 30 days and 60 days from the initiation of feeding the improved composition, strength and thickness of individual eggshells of eggs in each group were measured. The average strength and average thickness of the eggshells in each group are shown in Table 20 Table Composition of basal ration Ingredient% of Diet (Complete laying mash) , Corn 25.00 Oats 15.00 .. -Soybean meal 15.00 . .
Wheat 10.00 Fish meal 7.00 ;... ..
Tapioca flour 6.00 Corn gl.utten feed5.50 CaCO ~.50 -.
Whea~ bran 3.25 Molasses 3.00 Wheat middlings2.75 Dehydrated alfalfa meal 2.75 Mineral mixture1.00 100. 00 ** Composition Mineral _ oO
CaHP04 65.0 CaC03 19.5 Iodized salt 13.5 Trace element mixture 2.0 .
100. 00 Table 2 trength and thickness of eggshells _ - . -Additive Item of After 30 days After 60 days ; test .
~, _ . , None strength 3.51 kg 3.49 kg :
(100%) (100%) .
thickness 0.331 mm 0.330 mm : (100%) (100%) : .
Table 2 (continued) .
~ .
AdditiveItem of After 30 days After 60 days test _ 30 ppm strength 3.5~ kg 3.50 kg vitamin C (100.8%) (100.2%) thickness 0.339 mm 0.339 mm (102.4%) (103.7%) . .
30 ppm strength 3.86 kg 3.85 kg mono~potassium (109.9%) (110.3%) salt of L-ascor~
bic acid-2-sul-fate thickness 0.356 mm 0.357 mm -(107.5%) (108.0%) 30 ppm disodium strength 3.86 kg 3.88 kqsalt of L-ascor- (109.9%) (111.2%) bic ac'd-2-sul-fate thickness 0.357 mm 0.358 mm . (107.8%) (108.5%) . . .. . _ _ 30 ppm calcium ;strength 3.88 kg 3.90 kg salt of L-ascor- .(110.5%) (111.7%) bic acid 2-sul-fate thickness 0.359 mm 0.362 mm (108.~%) (109.7%) ~= _ When the strength of eggshells increases 10% to that of the standard (non~additive), the break of eggshells in transporta-tion has been essentially completely prevented. In Table 2, the .
percentages o~ the strength and thickness are based on those of the standard (non-additive). ~ ~.
, . .
,, ' "
. . -. :
.- .
: ' : :
~,. .
~ 14 -- .
.. . ,. ~ . ~, : , :. . .:
.. :. .. -, . . . ~ ..... . .
fonic acid or an alkali ch~orosulfonate and excess of dimethylformamide, so as to produce a sulfate, neutralizing the product obtained with an alkali metal hydroxide or an alkaline earth metal hydroxide and then removing the protective substituent at 5- and 6-positions.
The resulting products may be shown by the formula XO3SO ~ OX' O~ \ CH-CH20H
of~
wherein X is an alkali metal or an alkaline earth metal atom, and X' is a hydrogen atom, an alkali metal or an alkaline earth metal atom.
The present invention will be further illustrated by way of the following Examples.
E~ample 1 -A 21.6 g of 5,6-O-isopropylidene-L-ascorbic acid was dissolved in 150 ml of dimethyl formamide. A 137 ml of solution prepared by dissolving 48 g sulfuric anhydride in 700 ml of dimethyl formamide was added dropwise to said solution at a temp- -~erature of O to 10C. The mixture was stirred at room temperature for 3 hours after the addition and 2N-KOH was added to the reaction mixture to adjust the pH to 7Ø The product was -filtered and the filtrate was concentrated and dissolved in water and 2N-HCl was added to the solution to adjust the pH to 2.3. 24.8 g of mono-potassium salt of 5,6-O-isopropylidine-L-ascorbic acid-2-sulfate was thus obtained. The product was dissolved in 30 ml of water and the solution was stirred at 60C for 45 minutes, and was concentrated under reduced pressure and the product was recrystallized from water to yield 29.8 g of white needle-like crystals of mono~potassium salt of L-ascorbic acid 2-sulfate having a decomposition point of 55 to ~;
56C (Yield 85.6%).
.. . .
Elementary Analysis C6H79SK 3H20 Calculated (~) Found (%) C: 20.69 20.81 ~o 3.76 3.72 Example 2 In accordance with the process of Example 1, 26.4 g of mono-potassium salt of 5,6 0-isopropylidene-L-ascorbic acid-2-sulfate was dissolved in 30 ml of water and the solution was stirred at 60C for 45 hours and then was cooled and 2N-KOH
was added to the solution to adjust the pH to 7Ø Methanol was then added to the solution to crystallize it, whereby 29.9 g of white flake cystals of di-potassium salt of L-ascorbic acid-2-sulfate having decomposing point of 13~ to -140C was given (Yield 81.2~).
Elementary Analysis C6H609SK2 2H20 Calculated (~) Found(~) C: 19.56 19.36 H: 2.74 2.54 `
~xample 3 ;~
A 43.2 g of 5,6-0-isopropylidene-L-ascorbic acid was dissolved in 300 ml of dimethyl formamide. A 274 ~1 of solu-tion prepared by dissolving 48 g oE sulfuric anhydride in 700 s~
ml of dimethyl formamide was added dropwise to the solution at a temperature from 0 to 10C. The mixture was stirred at room `;~
temperature for 3 hours after the addition, and 2N-NaOH was ~ -added to the reaction mixture to adjust the pH to 7Ø
The product was filtered and the filtrate was concen-trated and dissolved in water and 2N-HCl was added to the sol-3~ ution to adjust the pH to 2.3. 24.6 g of white needle-like crystals of mono-sodium salt of 5,6-0-isopropylidine-L-asorbic ,:-:
acid 2-sulfate were obtained.
The product was dissolved in 60 ml of water and the solution was stirrea at 60C for 45 minutes and cooled, and 2N-NaO~ was added to the solution to adjust the pH to 7Ø
Methanol was then added to the solution to crystallize it. 83.3 g of white needle-like crystals of di-sodium salt of L-ascorbic acid-2-sulfate having melting point of 70 to 73C was obtained (Yield 88.7%).
Elementary Analysis C6H60gS~a2 ~ 2 Calculated (%) Found (%) C: 19.36 19.52 H: 3.79 3.69 Example 4 Instead of 5,6-0-isopropylidene-L-ascorbic acid of Example 1, 25.6 g of 5,6-0-cyclohexylidine-L-ascorbic acid was sulfated a~d 2N-KOH was added to the solution to~adjust the pH to 7Ø The product was dissolved in water and then 2N~HCl was added to the solution to adjust the pH to 2.3, whereby 30.4 g of white crystals were obtained.
The crystals were dissolved in 30 ml of water and the solution was stirred at 60C for 2 hours and concentratcd under reduced pressure. The product was recrystallized from water to give 29.0 g of white needle-like crystals of mono-potassium salt of L-ascor~ic acid-2-sulfate having a decomposition point ;
of 55 to 56C. (Yield 83.3%). -Example_5 ~-In accordance with the process of Example 1, 15.8 g of 5,6-0-isopropylidene-L-ascorbic acid was converted and a satur-ated solution of calcium hydroxide was added to the solution of the product to ad]ust the pH to 7Ø Methanol was then added to the solution to crystallize it. 34.2 g of white - 6 - -~
.. . . . . .
.- . . -:, . .
.. . . , . , . ~ . .
~ ; ,. .
33~
powdery crystals of calcium salt of L-ascorbic acid-2-sulfate having a decomposing temperature of 70 to 72C were obtained (Yield 87.~%).
Elementary Analysis C6H609SCa 3H20 Calculated (%) Found (~) C:20.69 20.50 H:3.47 3.30 ::
Example 6 9,6 g of pyridine was dissolved in 300 ml of dimethyl formamide and 7.0 g of chlorosulfonic acid was added dropwise to the solution at a temperature of from 0 to 10C. 13.0 g of 5,6-0-isopropylidene-L-ascorbic acid was added to the reaction mixture and the mixture was stirred at room temperature for 8 hours, and 2N-KOH was added to the solution to adjust the pH
to 7Ø The product was filtered and the filtrate was concen- ~
trated and dissolved in water, and then 2N-MCl was added to the , -solution to adjust the pH to 2.3. The solution was stirred at 60C ~or 45 minutes and was concentrated under reduced pressure. ;
The residue was recrystallized from water and methanol to give 11.0 g of white needle-like crystals of L-ascorbic acid-2-sulfate having a decomposition point of 55C.
Example 7 The mono-potassium salt of 5,6~0-isopropylidene-L-ascorbic acid-2-sulfate prepared in accordance with the process of Example 6, was dissolved in 7 nl of water and the solution was stirred at 60C for 45 minutes and 2N-KOH was added to the solution to adjust the p~ to 7Ø Methanol was added to crys-tallize the solution. 8.0 g of white flake crystals of di-potassium salt of L~ascorbic acid-2-sulfate having a decomposi-` tion temperature of 136 to 140~C were obtained.
.. .... ...
:
i.: ......... , ~ . : . . .. . . .
,!. , ~5~33~
Example 8 In accordance with the process of Example 6, sulfation was carried out by using 9.6 g of pyridine, 300 ml of dimethyl formamide, 7.0 ~ of chlorosulfonic acid and 10.8 g of 5,6-0-isopropylidene-L-ascorbic acid, and then 2N-NaOH was added to the resulting solution to adjust the pH to 7Ø The product was filtered and the filtrate was concentrated and dissolved in water and 2N-HCl was added to the solution to adjust the pH
to 2.3 and the solution was stirred at 60C for 45 minutes and cooled. Then 2N-NaOH was added to the solution to adjust the pH to 7.0 and methanol was added to crystallize it. 14.6 g of white needle-like crystals of di-sodium salt of L-ascorbic acid-2-sulfate having a melting point of 70 to 73C were obtained.
Example 9 The mono-potassium salt of 5,6-O-isopropylidene-L-ascorbic acid-2-~sulfate prepared in accordance with the process of Example 6 using 5.4 y of 5,6-0-isopropylidene-L-ascorbic acid, was dissolved in 7 ml of water and the solution was stirred at 60C for ~5 minutes and cooled. A saturated solution of calcium hydroxide was then added to the solution to adjust the pH to 7Ø
Methanol was then added to recrystallize the solution. 6.91 g of white powder crystals of mono-calcium salt of L-ascorbic acid-2-sulfate having a decomposition point of 70 to 72C were obtained.
Example 10 In accordance with the process of Example 6 except using c~c/o~7~)<Y~ en e.
6.5 g of 5,6-0- ~ -L-ascorbic acid instead of 5,6-0-isopropylidene-L-aseorbic aeid, 5.4 g of mono-potassium salt of L-aseorbie aeid-2-sulfate having a deeomposing point of 55C
were obtained.
. ' ,~ .
_ ~ _ ,, , .' ' '': ' ' : . ' ~i6~
Example 11 18.5 g of potassium chlorosulfonate was added to 130 ml of dimethyl formamide. A solution of 21.6 g of 5,6-0-isopropy- -lidene-L-ascorbic acid in 150 ml of dimethyl formamide was added dropwise to the solution at a temperature from 0 to 10C.
The mixture was stirred at room temperature for 3 hours after the addition, and then 2N-KOH was added to the solution to adjust the pH to 7Ø The product was filtered and the filtrate was concentrated and dissolved in water, and then 2N-HCl was added to the sol~tion to adjust the pH to 2.3. 26.5 g of white needle-like crystals were obtained.
The crystals were dissolved in 30 ml of water and the solution was stirred at 60C for 1 hour and was concentrated.
The residue was recrystallized from water to give 20.5 g of white needle-like crystals of mono-potassium salt of L-ascorbic acid-2-sulfate having a decomposition temperature of 55 to 56C. -~
Example 12 ~n accordance with the process of Example 11 except using chlorosulfonic acid and sodium salt of 5,6-0-cyclohexylidene-L-ascorbic acid instead of potassium chlorosulfonate and 5,6-0-isopropylidene-L-ascorbic acid, 25.6 g of mono-potassium salt of L-ascorbic acid-2-sulfate having a decomposition temperature of 55 to 56C were obtained.
Example 13 2W-KOH was added to the solution of mono-potassium salt of L-ascorbic acid-2-suIfate prepared in accordance with the process of Example 11 to adjust the pH to 7Ø Methanol was then added to crystallize the solution 31.3 g of white flake crystals of di-potassium salt of L-ascorbic acid-2-sulfate having a decomposing point of 136 to 140C were obtained.
- ': .
' .
$~
Example 14 In accordance with the process of Examples (11) and (13) except using 2M-NaOEI instead of 2N-KOH, 27.8 g of white needle-like crystals of di-sodium salt of L-ascorbic acid-2-sulfate having a melting point of 70 to 72C were obtained. ;~
Example 15 An 18.5 g of chlorosulfonic acid were added dropwise to a solution o~ 10.8 g of urea in 150 ml of dimethyl formamide and then the solution was stirred at room temperature for 2 hours. A solution of 25.6 g (0.1 mole) of 5,6-0-cyclohexylidene-L-ascorbic acid in 150 ml of dimethyl formamide was added to the solution at 10C, and then the mixture was stirred at room temperature for 8 hours and 2N-KOH was added to the solution to adjust the pH to 7.Q. The product was filtered and the filtrate was concentrated and dissolved in water and 2N-HCl was added to the solution to adjust the pH to 2Ø The solution was stirred at 60C for 30 minutes and was concentrated under reduced pres-sure and the product was recrystallized from water to give 20.4 g of white needle-like crystals of mono-potassium salt of L-ascorbic acid-2-sulfate.
gxample 16 In accordance with the process of Example 15, the mono-potassium salt of L-ascorbic aeid-2-sulfate was dissolved in water and 2N-KOH was added to the solution to adjust the pH to 7Ø Methanol was then added to crystallize the solution, 30.3 g of white flake crystals of di-potassium of L-ascorbic acid-2-sulfate having a deeomposition point of 136 to 140C.
Example 17 In aeeordance with the proeess of Examples 15 and 16 except using suLfuric anhydride and 2N-NaOH instead of chloro-sulfonic acid and 2N-KOH, 29.6 g of white needle-like crystals of di-sodium salt of L-ascorbic acid-2-sulfate having a decomp-osition point of 70 to 73C were obtained.
Example 18 A 17.5 g of sulfuryl chloride was added dropwise to 130 ml of dimethyl formamide. A solution of 26.~ g of 5,6-0-benzylidene-L-ascorbic acid in 150 ml of dimethyl sulfoxide was added dropwise to the solution at a temperature from O to lO~C
and the mixture was stirred at room temperature for 3 hours.
Then the 2N-KOH was added to the solution to adjust the pH to 7Ø The product was filtered and the filtrate was concentrated and dissolved in water and 2N-HCl was added to the solution to adjust the pH to 2.3. The solution was stirred at 60C for 45 minutes and concentrated under reduced pressure. The residue was recrystallized from water to give 3.0 g of white needle-like crystals of mono-potassium salt of L-ascorbic acid-2-sulfate having a decomposition point of 55 to 56C.
Example 19 In accordance with the process of Example 18 except using 5,6-0-cyclohexylidene-L-ascorbic acid, dimethyl formamide and 2N-NaO~ instead of 5,6-0-benzylidene-L-ascorbic acid, di-methyl sulfoxide and 2N-KOH, mono-sodium salt of L-ascorbic acid-2-sulfate was obtained. The product was dissolved in water and 2N-NaOH was added to the solution to adjust the pH to 7Ø
Methanol was then added to crystallize the solution 2~.2 g of white needle-like crystals of di-sodium salt of L-ascorbic acid-2-sulfate having a decomposing point of 70 to 73C were obtained.
The compounds of the present invention supply a sulfate group to steroid materials such as anticoagulants having hepar-in like effect, antihemostat and cholesterol, so as to improve ;
metabolism for human body and animal and also are useful as do-mestic medicine and animal medicine as the compounds impart the ' ' ~',.
.
'' '~ :"
.. .,: . " . , , :, , ,, . . . . ~ ., eE-Eect for preventing the breakage of eggshells. The compounds are also useful as an additive for food and feed and cosmetic material.
The mono-and di-sodium salts and calcium salt of L-ascor-bic acid-2-sulfate produced by the process of the invention, are novel, impart no potassium trouble compared to the known potassium salt of ~-ascorbic acid-2-sulfate, have high antihygros-copic property and antioxidative property and are quite stable in a medicine or animal medicine composition, feed, food and a cosmetic composition. It has been proposed to prevent the breakage of eggshells by feeding the fowl vitamin-C. However this effect could not be satisfactorily imparted because of the decomposition of vitamin-C, which is remarkable in summer. The damage of eggshells during the transportation is higher than 5%
and it is economically quite important to prevent the breakage of eggshells. The compounds of the invention are useful for preventing the breakage of eggshells. The effect can be attained by adding l to 100 ppm preferably lO to 50 ppm of the compound of the invention in a feed or drinking water for domestic fowl especially hens or injecting 0.5 to 5 mg of the compound into each hen. When the compound is added to feed or drinking water, it is preferable to prepare a master batch containing the com-pound and an additive such as lactose, wheat flour, talc, starch, powdery feed and an emulsifier.
The test experiment of the breakage of eggshells will be illustrated in detail.
500 of hens (White leghorn) of 36 week age were divided ;-to five groups of each 100 hens. Each composition of basal ration of Table 1 was admixed with 30 ppm of vitamin-C, or 30 ppm of mono-potassium salt, di-sodium salt or di-calcium salt of L ascorbic acid-2-sulfate and the composition was kept at ., , . ., .... . , . .
.
-room temperature for 30 days and the composition was fed to eachgroup of hens.
After 30 days and 60 days from the initiation of feeding the improved composition, strength and thickness of individual eggshells of eggs in each group were measured. The average strength and average thickness of the eggshells in each group are shown in Table 20 Table Composition of basal ration Ingredient% of Diet (Complete laying mash) , Corn 25.00 Oats 15.00 .. -Soybean meal 15.00 . .
Wheat 10.00 Fish meal 7.00 ;... ..
Tapioca flour 6.00 Corn gl.utten feed5.50 CaCO ~.50 -.
Whea~ bran 3.25 Molasses 3.00 Wheat middlings2.75 Dehydrated alfalfa meal 2.75 Mineral mixture1.00 100. 00 ** Composition Mineral _ oO
CaHP04 65.0 CaC03 19.5 Iodized salt 13.5 Trace element mixture 2.0 .
100. 00 Table 2 trength and thickness of eggshells _ - . -Additive Item of After 30 days After 60 days ; test .
~, _ . , None strength 3.51 kg 3.49 kg :
(100%) (100%) .
thickness 0.331 mm 0.330 mm : (100%) (100%) : .
Table 2 (continued) .
~ .
AdditiveItem of After 30 days After 60 days test _ 30 ppm strength 3.5~ kg 3.50 kg vitamin C (100.8%) (100.2%) thickness 0.339 mm 0.339 mm (102.4%) (103.7%) . .
30 ppm strength 3.86 kg 3.85 kg mono~potassium (109.9%) (110.3%) salt of L-ascor~
bic acid-2-sul-fate thickness 0.356 mm 0.357 mm -(107.5%) (108.0%) 30 ppm disodium strength 3.86 kg 3.88 kqsalt of L-ascor- (109.9%) (111.2%) bic ac'd-2-sul-fate thickness 0.357 mm 0.358 mm . (107.8%) (108.5%) . . .. . _ _ 30 ppm calcium ;strength 3.88 kg 3.90 kg salt of L-ascor- .(110.5%) (111.7%) bic acid 2-sul-fate thickness 0.359 mm 0.362 mm (108.~%) (109.7%) ~= _ When the strength of eggshells increases 10% to that of the standard (non~additive), the break of eggshells in transporta-tion has been essentially completely prevented. In Table 2, the .
percentages o~ the strength and thickness are based on those of the standard (non-additive). ~ ~.
, . .
,, ' "
. . -. :
.- .
: ' : :
~,. .
~ 14 -- .
.. . ,. ~ . ~, : , :. . .:
.. :. .. -, . . . ~ ..... . .
Claims (17)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for producing mono- or di-alkali metal salt or alkaline earth metal salt of L-ascorbic acid-2-sulfate which comprises reacting L-ascorbic acid having a protective substitu-ent in the 5- and 6- positions derived from a ketone or aldehyde with the sulfating agent and dimethyl formamide and neutralizing the product obtained with an alkali metal hydroxide or an alka-line earth metal hydroxide and removing the protective substituent at 5- and 6-positions.
2. A process as claimed in claim 1, in which the L-ascorbic acid is reacted with the sulfating agent in the presence of a tertiary amine or urea.
3. A process as claimed in claim 1, for producing mono-or di-alkali metal salt or alkaline earth metal salt of L-ascor-bic acid-2-sulfate which comprises reacting L-ascorbic acid having a protective substiuent in the 5- and 6-positions derived from a ketone or an aldehyde with a sulfating agent selected from sul-furic anhydride, chlorosulfonic acid, sulfuryl chloride or an alkali chlorosulfonate and dimethyl formamide so as to produce a sulfate, neutralizing the product obtained with an alkali metal hydroxide or an alkaline earth metal hydroxide and removing the protective substituent at 5- and 6-positions.
4. A process as claimed in claim 1, for producing mono-or di-alkali metal or alkaline earth metal salt of L-ascorbic acid-2-sulfate which comprises reacting L-ascorbic acid having a protective substituent in the 5- and 6- positions derived from a ketone or aldehyde with chlorosulfonic acid or an alkali chlorosulfonate and excess of dimethyl formamide so as to pro-duce a sulfate, neutralizing the sulfate with an alkali metal hydroxide or an alkaline earth metal hydroxide and removing the protective substituent at 5- and 6- positions.
5. A process as claimed in claim 2, 3 or 4, in which the, protective substituent is removed by acidification.
6. A process as claimed in claim 2, 3, or 4, in which the aldehyde is selected from acetaldehyde, propionaldehyde, benz-aldehyde, chlorobenzaldehyde and methylbenzaldehyde and the ketone is selected from acetone, methylethylketone, diisopropyl-ketone, cyclohexanone and benzophenone.
7. A process as claimed in claim 2, 3, or 4, in which the sulfation is effected at a temperature in the range 0 to 10°C
8. A process as claimed in claim 3, wherein said L-ascorbic acid having a protective substituent in the 5- and 6-positions, is treated with sulfuric anhydride and dimethyl forma-mide.
9. A process as claimed in claim 8, wherein 5,6-0-isopropylidene-L-ascorbic acid is treated with sulfuric anhydride and dimethyl formamide.
10. A process as claimed in claim 8, wherein 5,6-0 cyclohexylidene-L-ascorbic acid is treated with sulfuric anhydride and dimethyl formamide.
11. A process as claimed in claim 3, wherein said L-ascorbic acid having a protective substituent in 5- and 6 positions, is treated with sulfuryl chloride and dimethyl forma-mide.
12. A process as claimed in claim 2 in which the pro-duct obtained is neutralized with sodium or calcium hydroxide to produce a mono or di-sodium or calcium salt of L-ascorbic acid-2-sulfate.
13. A compound selected from sodium and calcium salts of L-ascorbic acid-2-sulfate whenever prepared or produced by the process as claimed in claim 12 or an obvious chemical equivalent thereof.
14. A process as claimed in claim 12 in which the product obtained is neutralized with sodium hydroxide.
15. A compound which is a sodium salt of L-ascorbic acid-2-sulfate whenever prepared or produced by the process as claimed in claim 14 or an obvious chemical equivalent thereof.
16. A process as claimed in claim 12 in which the product obtained is neutralized with calcium hydroxide.
17. A compound which is calcium salt of L-ascorbic acid-2-sulfate whenever prepared or produced by the process as claimed in claim 16 or an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/711,410 US4071534A (en) | 1973-11-07 | 1976-08-03 | Process for producing l-ascorbic acid-2-sulfate |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP48124395A JPS5076065A (en) | 1973-11-07 | 1973-11-07 | |
| JP48124951A JPS5752344B2 (en) | 1973-11-08 | 1973-11-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1056838A true CA1056838A (en) | 1979-06-19 |
Family
ID=26461078
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA212,951A Expired CA1056838A (en) | 1973-11-07 | 1974-11-04 | Process for producing l-ascorbic acid-2-sulfate |
Country Status (6)
| Country | Link |
|---|---|
| CA (1) | CA1056838A (en) |
| CH (1) | CH618693A5 (en) |
| DE (1) | DE2452719C3 (en) |
| FR (1) | FR2249667B1 (en) |
| GB (2) | GB1452845A (en) |
| SU (1) | SU582763A3 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1489734A (en) * | 1975-04-08 | 1977-10-26 | Nippon Chemiphar Co | Ascorbic acid derivative and pharmaceutical compositions containing the same |
| CH679151A5 (en) * | 1989-07-17 | 1991-12-31 | Enco Eng Ag | METHOD FOR PRODUCING dipotassium ascorbate-2-SULPHATE. |
| WO1991013068A1 (en) * | 1990-03-01 | 1991-09-05 | Enco Engineering Chur Ag | Process for the production of dipostassium ascorbate-2-sulphate |
-
1974
- 1974-10-29 GB GB3484575A patent/GB1452845A/en not_active Expired
- 1974-10-29 GB GB4676074A patent/GB1452844A/en not_active Expired
- 1974-11-04 CA CA212,951A patent/CA1056838A/en not_active Expired
- 1974-11-06 FR FR7436797A patent/FR2249667B1/fr not_active Expired
- 1974-11-06 DE DE2452719A patent/DE2452719C3/en not_active Expired
- 1974-11-06 SU SU7402075017A patent/SU582763A3/en active
- 1974-11-06 CH CH1491974A patent/CH618693A5/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| SU582763A3 (en) | 1977-11-30 |
| FR2249667B1 (en) | 1982-07-09 |
| CH618693A5 (en) | 1980-08-15 |
| DE2452719B2 (en) | 1981-04-16 |
| GB1452844A (en) | 1976-10-20 |
| GB1452845A (en) | 1976-10-20 |
| DE2452719C3 (en) | 1982-04-22 |
| DE2452719A1 (en) | 1975-05-15 |
| FR2249667A1 (en) | 1975-05-30 |
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