JPS5844667B2 - Process for producing L-ascorbic acid-2-sulfate or its salts - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing L-ascorbic acid-2-sulfate or its salts simply and with high yield.

Salts of L-ascorbic acid are compounds that are stable in the weakly acidic to weakly alkaline range and have the formula sulfuric acid ester and the like (in the formula, M is a hydrogen atom or an alkali metal).

Recently, this L-ascorbic acid 2-sulfate ester or its salts has been found to be a substance related to the sulfation of steroid bodies in vivo, and has attracted attention as a pharmacological substance that influences the metabolism of steroid bodies.

The method for producing L-ascorbic acid-2-sulfuric acid ester involves reacting 5,6-O-benzylidene-L ascorbic acid with pyridine and sulfur trioxide, and then recovering the product in the form of potassium salt. It has been known.

However, this method has a low yield of 15-20%;
It is unsuitable as an industrial method.

The present inventors have proposed a method for obtaining L-ascorbic acid 2-sulfate in good yield by first adding 5,60-impropylidene-L-ascorbic acid to a solvent containing a tertiary amine such as pyridine. A method was proposed in which the product was obtained as a potassium salt by reacting with chlorosulfonic acid.

However, since this method uses 2 moles of tertiary amine per mole of chlorosulfonic acid, it has the disadvantage that an excess amount of the tertiary amine remains in the medium, making post-treatment complicated.

The present invention has been made to overcome these drawbacks, and is capable of producing L-ascorbic acid-2-in a high yield with simple operations.
This is a method for producing sulfuric esters or their salts.

That is, according to the present invention, L-ascorbic acid protected at the 5,6-position with a ketone or aldehyde is reacted with an alkali salt of chlorosulfonic acid, or alternatively, L-ascorbic acid protected at the 5,6-position with a ketone or aldehyde is reacted with an alkali salt of chlorosulfonic acid. After reacting the alkali salt of L-ascorbic acid with chlorosulfonic acid, the product is treated with acid to remove the protective group, and L-
L-ascorbic acid-2-sulfate or its salts can be produced in a high yield of 80% or more by converting the ascorbic acid-2-sulfate ester into a salt using a conventional method as desired. .

In the method of the present invention, the ketone or aldehyde used to protect the 5°6-position of L-ascorbic acid is
For example, it is represented by the general formula (in the formula, R1 and R2 are the same or different and each is a hydrogen atom, a lower alkyl group, an aryl group, or they combine with each other to form a cycloalkane). Examples of such substances include formaldehyde, acetaldehyde, acetone, propionaldehyde, diisopropyl ketone, benzophenone, and cyclohexanone.

Furthermore, the sulfation reaction in the method of the invention is advantageously carried out in a polar solvent such as dimethylformamide, dimethylacetamide, diethylacetamide, dimethylsulfoxide.

In addition, the reaction to remove the protecting group from this sulfated product is
This is advantageously carried out by dissolving the sulfated product in water and treating it with an acid.

In order to carry out the method of the present invention preferably, L-
Ascorbic acid, such as 5,6-〇-impropylidene-L-ascorbic acid, 5゜6-0-cyclohexylidene-L-ascorbic acid, is dissolved in a polar solvent, such as dimethylformamide, and Add an alkaline salt of sulfonic acid, such as potassium salt or sodium salt, and stir to react, or add an alkaline salt of L-ascorbic acid protected at the 5,6-position, such as potassium salt or sodium salt, to a polar solvent. Dissolve, add chlorosulfonic acid, and stir to react.

This reaction is completed in several tens of minutes to several hours at room temperature.

Next, the reaction solution is adjusted to pH around 7 with alkali hydroxide, and then the solvent is distilled off.

The protecting group is then removed by dissolving the residue in water and acidifying with a mineral acid such as hydrochloric acid.

At this time, the alkali metals bonded to the sulfate groups and hydroxyl groups are also hydrolyzed and become free forms, so if it is desired to recover them as salts, an aqueous alkaline solution, such as an aqueous sodium hydroxide solution, is further added to neutralize.

In this way, L-ascorbic acid-2-sulfate or its salts can be obtained with a high yield of 80% or more.

The invention will now be explained in more detail by means of examples.
1 and 5.6-0-inpropylidene-L-
150 ml of dimethylformamide containing 21.6 g of ascorbic acid are added dropwise, keeping the temperature within the range 0-10°C.

After the dropwise addition is completed, the temperature is raised to room temperature, and the mixture is stirred for 3 hours to react.

After the reaction is complete, adjust the pH to 7.0 with a 2N aqueous potassium hydroxide solution.
The salt from which insects were removed is separated in a furnace, and the p liquid is concentrated under reduced pressure to form a paste.

This residue is dissolved in water, adjusted to pH 2.3 with 2N hydrochloric acid, and crystallized to obtain 26.5 g of white crystals.

The crystals were dissolved in 30 TrL of water, stirred at 60° C. for 45 minutes, and then allowed to cool to room temperature.

After cooling, the mixture is concentrated under reduced pressure, and the resulting paste-like residue is dissolved in water and crystallized to obtain 20.5 g (80%) of L-ascorbic acid-2-sulfate.

White needle-like crystals, decomposition point 55-56°C. 5 in the above,
When the same treatment was performed with a solution of 25.6 g of 5.6-0-cyclohexylidene dissolved in 150 ml of dimethylformamide instead of the dimethylformamide solution of 6-0-impropylidene-L-ascorbic acid, L −
Ascorbic acid-2-sulfate ester 20.1 (81,2
% achieved.

In addition, chlorosulfonic acid is used as a raw material instead of the above potassium chlorsulfonate, and 56-O-isopropylidene-L-ascorbic acid (or 5.6-0
-cyclohexylidene L-ascorbic acid) potassium salt solution in dimethylformamide and treated in the same manner, L-ascorbic acid-2-sulfate 19
．． 3 g (75.4%) were obtained.

Example 2 In the same manner as in Example 1 above, pH 2,
When adjusted to 3, 30.79 white needle-like crystals were obtained.

The obtained crystals were dissolved in 30 ml of water, stirred at 60°C for 45 minutes, and then allowed to cool to room temperature.

After cooling, the mixture is neutralized with 2N KOH solution (pH 7.0) and crystallized by adding methanol to obtain the potassium salt of L-ascorbic acid-2-sulfate 32.1.9.

(Yield 87.2%) White foliate crystals Decomposition point 136-14
0'C elemental analysis value (as C6H609SK2/2H20) C (equity) H (%) Theoretical value 19.56 2.74 Actual value 19.36 2.54 Example 3 Synthesized in the same manner as Example 2, 28. 4! ! White needle-like crystals were obtained.

The crystals were dissolved in 30 ml of water, stirred at 60° C. for 45 minutes, and then allowed to cool to room temperature.

After cooling, neutralize with 2N-NaOH solution (pH 7.0),
When methanol is added and crystallized, 27.3. ! A sodium salt of L-ascorbic acid-2-sulfuric acid ester of i' is obtained.

White powder Decomposition point 80-84℃ Elemental analysis value (as C6H609SNa2・2H20)
C (To) H (1) Theoretical value 21.44 3.00 Actual value 21.24 3.03

Claims (1)

[Claims] 1. After reacting L-ascorbic acid protected at the 5,6-position with a ketone or aldehyde and chlorosulfonic acid in the form of an alkali salt, the product is treated with an acid to remove the protecting group. 1. A method for producing L-ascorbic acid-2-sulfate or its salts, which comprises eliminating the L-ascorbic acid-2-sulfate ester and converting it into a salt by a conventional method as desired.