JP2667201B2 - Method for producing L-ascorbic acid - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a method for producing L-ascorbic acid using 2-keto-L-gulonic acid as a starting material.

Prior Art As one of the methods for producing L-ascorbic acid,
There is known a method in which 2-keto-L-gulonic acid is used as a starting material, and an acid is acted on the starting material to produce L-ascorbic acid in one step at a time. As such a method, specifically, for example, a method of reacting 2-keto-L-gulonic acid with concentrated hydrochloric acid using acetic acid as a solvent [US Pat.
940)], ethanol and acetone were added to the sodium salt of 2-keto-L-gulonic acid, the mixture was neutralized with hydrochloric acid, and the precipitated sodium chloride was collected by filtration.
To obtain L-ascorbic acid while maintaining the temperature (Japanese Patent Laid-Open No. 58-17 / 1983)
7986), a method in which a mineral acid is allowed to act on 2-keto-L-gulonic acid in an inert solvent in the presence of a surfactant (Japanese Unexamined Patent Publication No.
15931), a slurry of substantially anhydrous 2-keto-L-gulonic acid is formed in an inert organic solvent in the presence of a surfactant, and the slurry is reacted with a substantially anhydrous acid catalyst to produce L-L-keto-L-gulonic acid. Method for ascorbic acid [PCT, W087 / 00839
(1987)].

On the other hand, a large amount of 2-
A method for obtaining keto-L-gulonic acid has been proposed (for example,
58-162296, JP-A-60-70073, etc.), and it is desired to quickly establish an industrial production technique for producing L-ascorbic acid by using this raw material as it is.

However, although the above-mentioned known method has been improved to some extent in terms of yield and the like, it is still difficult to say that it is still sufficient in terms of yield from the viewpoint of an industrial production method, and in addition, a colored substance is contained in the reaction solution. Is contained in a large amount as an impurity, and a large purification load for removing these impurities is a bottleneck when adopted as an industrial production method.

Means for Solving the Problems The present inventors have studied a method for producing L-ascorbic acid from 2-keto-L-gulonic acid as a starting material, and as a result, have found that the target substance has a high yield of almost 90% or more. An industrially advantageous production method was established, which was obtained in a yield and produced a small amount of impurities. That is, the present inventors perform a lactonization reaction of 2-keto-L-gulonic acid in a mixed solvent of an inert organic solvent such as toluene and benzene and an aliphatic ketone such as acetone and methyl ethyl ketone. It has been found that the reaction proceeds favorably. In addition, it has been found that the reaction proceeds more advantageously by regulating the amounts of water and acid in this reaction.

That is, the present invention provides an L-characterizing method comprising reacting an acid with 2-keto-L-gulonic acid in a mixed solvent of an inert organic solvent and an aliphatic ketone in the presence of water and a surfactant.
This is a method for producing ascorbic acid.

The reaction of the present invention is carried out in a mixed solvent obtained by adding a fixed amount of an aliphatic ketone to an inert organic solvent.

Examples of the inert organic solvent that can be used in the present invention include halogens such as benzene, toluene, xylene, and chlorobenzene, and aromatic hydrocarbons that may be substituted with lower alkyl, such as chloroform and ethylene dichloride. Halogenated hydrocarbons, for example, aliphatic hydrocarbons such as hexane, heptane and octane;
For example, ethers such as tetrahydrofuran, dioxane, and isopropyl ether or a mixture thereof can be exemplified. Preferred are aromatic hydrocarbons such as benzene and toluene.

Examples of the aliphatic ketone that can be used by being mixed with the inert organic solvent include a ketone having an alkyl having 1 to 6 carbon atoms and a cyclic ketone having a cycloalkyl having 5 to 6 carbon atoms. The alkyl may be a linear alkyl or a branched alkyl, and preferably an alkyl having 1 to 4 carbon atoms can be used. These two alkyls attached to the carbonyl may be the same or different. Specific examples of such aliphatic ketones include acetone, methyl ethyl ketone, diethyl ketone, methyl isobutyl ketone, and cyclohexanone, and acetone and methyl ethyl ketone are preferably used.

Such ketones need to be present in a specific amount in the inert organic solvent. The mixing amount of the ketone is in the range of approximately 0.02 to 0.3 volume, preferably 0.05 to 0.2 volume per 1 volume of the inert organic solvent. By maintaining the ketone concentration within this range from the start of the reaction to the end of the reaction, the reaction can proceed more smoothly. The ketone solvent may be further added during the reaction as long as it does not deviate from the above range.

When the mixing amount of the ketone is less than the above range, the generation of decomposition products during the reaction increases, and the coloration of the reaction solution becomes remarkable, which complicates the purification process and is an industrially advantageous method. Absent. If the ratio exceeds the above range, unreacted raw materials tend to increase and the yield of the target product tends to decrease.

In the present invention, the lactonization reaction of 2-keto-L-gulonic acid is performed in the above-mentioned mixed solvent. The concentration of 2-keto-L-gulonic acid in the mixed solvent is not limited at all, but is usually 5 to 40% by weight, preferably 10 to 10% by weight from the viewpoint of economy.
30% by weight.

In the present invention, the reaction is allowed to proceed by adding an acid in the presence of water and a surfactant. In this case, the amounts of water and acid should be regulated as follows. The amount of water is 1.5 to 3.5 times mol, preferably 1.8 to 3 times mol, of 2-keto-L-gulonic acid. This amount of water is present in the solvent for the reaction. For example, when the raw material 2-keto-L-gulonic acid is a hydrate or contains water, such water is also considered as the amount of water in the reaction. Further, the water content contained in the acid catalyst used for proceeding the reaction and the water content contained in the mixed solvent are similarly calculated as the amount of water. If the amount of water deviates from the above range, the generation of decomposition products increases, which causes a decrease in yield.

Examples of the surfactant that can be used in the present invention include nonionic surfactants such as polyoxyethylene alkyl allyl ether and polyoxyethylene alkyl ether, and cations such as quaternary ammonium salts and pyridinium salts. Examples of the surfactant include anionic surfactants such as higher aliphatic and alkyl allyl sulfonates, and these may be used alone or in combination of two or more. In the present invention, cationic surfactants, especially quaternary ammonium salts, such as trimethyltetradecyl ammonium chloride, trimethyl dodecyl ammonium chloride, trimethyl cetyl ammonium chloride, trimethyl octyl ammonium chloride, dimethyl ethyl cetyl ammonium chloride, trimethyl stearyl ammonium chloride, It is preferable to use dimethylbutylcetylammonium bromide and trimethyldodecylammonium bromide.
The addition amount of such a surfactant is 0.01 to 10 W / W%, preferably 0.05 to 3.0 W / W based on 2-keto-L-gulonic acid.
%.

Next, mineral acids can be mentioned as acids that can be used as catalysts. Such mineral acids include, for example, hydrochloric acid and phosphoric acid, and hydrochloric acid is particularly preferred.
In the mixed solvent, the amount of the acid used to favorably advance the reaction is 0.5 to 2 moles, preferably 0.5 to 1.5 moles relative to 2-keto-L-gulonic acid in the presence of water in the above range. It is. Since water is required for the reaction, it is preferable to use 20 to 45% hydrochloric acid, usually 35% concentrated hydrochloric acid. When water is added during the reaction, the amount of acid can be adjusted using a solvent, particularly a solution of hydrogen chloride in the ketones. The same applies when the amount of acid is insufficient using 35% concentrated hydrochloric acid. The acid may be added in two portions within the above range.

Under the above conditions, the raw material 2-keto-L-gulonic acid is lactonized by the action of an acid to produce ascorbic acid. The reaction proceeds in a heterogeneous system. As the reaction proceeds, the 2-keto-L-gulonic acid in the mixed solvent becomes itchy or oily (usually after about 30 minutes to 1 hour from the start of the reaction). At this point, the water and acid may be adjusted to predetermined amounts. The amount of water remaining in the reaction solution can also be adjusted by removing water from the reaction solution using a conventional dehydration means such as an azeotropic method. This dehydration operation is preferably completed in as short a time as possible. When the aliphatic ketone or the acid catalyst is distilled off together with water by azeotropic dehydration or the like, it may be appropriately replenished. The reaction temperature is approximately 40-80 ° C, preferably 50-70 ° C. The reaction is usually completed in 3 to 8 hours.

In order to separate the target substance from the reaction mixture, a method known per se, for example, a method such as filtration, concentration, or extraction can be used. If necessary, a high-purity product can be obtained by a method such as recrystallization.

Effects of the Invention According to the production method of the present invention, L-ascorbic acid can be produced in a high yield of 90% or more. Further, since the generation of impurities such as a reaction decomposition product which causes coloring is extremely small, a complicated purification step is not required, so that it is extremely useful as an industrial production method.

Hereinafter, the present invention will be described more specifically with reference to Examples and Comparative Examples.

Example 1 2-keto-L-gulonic acid (content 91.2%, water 8.4%) 1
00 g was added to a mixed solvent of 570 ml of toluene and 67 g of acetone containing 65% by weight of hydrogen chloride (65 ml as acetone). To this solution, 7.7 ml of water and 110 mg of trimethylcetylammonium chloride were further added (the amount of water was 1.90 times the molar amount of 2-keto-L-gulonic acid). Stirring was continued for 6 hours while heating the reaction solution to 60 ° C. Reaction solution 20
After cooling to ℃, the reaction solution was poured into water 1, stirred, allowed to stand, and the aqueous layer was separated. Further, 400 ml of water was added to the organic layer, followed by re-extraction, and the aqueous layers were combined. When L-ascorbic acid produced was quantified using high performance liquid chromatography, it was found to be 78.2 g (yield 94.5%). On the other hand, 2.7% of 2-keto-L-gulonic acid remained. Further, the absorbance (E ^1% _{430 nm) of} this aqueous layer was 0.160.

The high performance liquid chromatography was measured under the following conditions (the same applies hereinafter).

-Column: Aminex HPX-87H manufactured by Bio Rad-Eluent: 0.1 M ammonium sulfate-Column temperature: room temperature-Detection: UV ₂₁₀ nm and differential bending (refractive index) Example 2 2-keto-L-gulonic acid (content 89.9%, moisture 8.4%) 1
01.4 g was added to a mixed solvent of 576 ml of toluene and 30 ml of acetone. To this was added 110 mg of trimethyltetradecylammonium chloride, and 10 ml of 35% concentrated hydrochloric acid (d = 1.17, HC
4.1 g as l and 7.7 g as water) were added. The water content in the reaction solution was 16.2 g (1.19 g based on 2-keto-L-gulonic acid).
Times).

When the reaction solution was heated to 60 ° C. and stirred for 1 hour, 2-keto-L-gulonic acid crystals became oily. Here, 51.8 g of an acetone solution containing 15.8% by weight of hydrogen chloride (8.18 g of HCl, 55 ml of acetone) was added, and the mixture was stirred at the same temperature for 5 hours and cooled to 20 ° C (2-keto-L-gulonic acid). The total acid amount was 0.72 fold mole of the total acid).

The reaction solution was poured into water 1, stirred, allowed to stand, and the aqueous layer was separated. Further, 600 ml of water was added to the organic layer for re-extraction, and the aqueous layers were combined.

The amount of L-ascorbic acid produced was quantified by high performance liquid chromatography and found to be 77.7 g (yield 94%). On the other hand, 2.3% of 2-keto-L-gulonic acid remained. The absorbance of the reaction solution (E ^1% _{430 nm)} was 0.17
Met.

Example 3 2-keto-L-gulonic acid (content 89.9%, moisture 8.4%) 1
01.4 g was added to a mixed solution of 576 ml of toluene and 24 ml of methyl ethyl ketone. To this was added 110 mg of trimethylcetyl ammonium chloride, and 13.2 ml of 35% concentrated hydrochloric acid (d =
1.17, 5.4 g as HCl and 10.0 g as water) were added. The amount of water contained in the reaction solution is calculated to be 18.5 g (2.14 times the molar amount of 2-keto-L-gulonic acid).

When the reaction solution was heated to 60 ° C. and stirred for 1 hour, 2-keto-L-gulonic acid crystals became oily. Here, 45 g of methyl ethyl ketone solution containing 18% by weight of hydrogen chloride (H
8.1 g of Cl and 46 ml of methyl ethyl ketone) were added, and the mixture was stirred at the same temperature for 5 hours and then cooled to 20 ° C. (2-
The total amount of the acid was 0.79 times the mole of keto-L-gulonic acid).

The reaction solution was poured into water 1, stirred, allowed to stand, and the aqueous layer was separated. Further, 600 ml of water was added to the organic layer for re-extraction, and the aqueous layers were combined.

The amount of L-ascorbic acid produced was quantified by high performance liquid chromatography and found to be 76.9 g (yield 93%). On the other hand, 2.0% of 2-keto-L-gulonic acid remained. The absorbance of the reaction solution (E ^1% _{430 nm)} is 0.1
55.

Example 4-6 The following results were obtained in the same manner as in Example 2 except that methyl isobutyl ketone, diethyl ketone, and cyclohexanone were used instead of methyl ethyl ketone.

Example 7 2-keto-L-gulonic acid (content 91.2%, water 8.4%) 3
2 g was added to a mixed solvent of 180 ml of benzene and 20 ml of acetone. To this, 140 mg of trimethylcetyl ammonium chloride was added, and 10 ml of 35% hydrochloric acid (d = 1.17, 4.09 as HCl).
g) was added. The water content in the reaction solution was 10.3 ml (2-
(3.8-fold mol based on keto-L-gulonic acid).
When the reaction solution was heated to 60 ° C. and stirred for about 1 hour, 2-keto-L-gulonic acid crystals became oily. At this time, about 8 ml as a distillate was distilled off under reduced pressure using a Soxhlet extractor. When the composition of this distillate was investigated, 3.8 g of water and acetone
3.0 g and 0.8 g of hydrochloric acid.

After stirring at the same temperature for 5 hours, the mixture was cooled to 20 ° C. The reaction solution was stirred in 300 ml of water, allowed to stand, and the aqueous layer was separated. Further, 200 ml of water was added to the organic layer for re-extraction, and the aqueous layers were combined. When L-ascorbic acid produced was quantified using high performance liquid chromatography, 24.9 g (yield 94.
1%) was present. On the other hand, 4.6% of 2-keto-L-gulonic acid remained. Furthermore, the absorbance of this aqueous layer ▲ E
^1% _{430 nm} ▼ was 0.170.

Example 8 2-keto-L-gulonic acid (content 99.4%, moisture 0.5%) 1
5 g was added to a mixed solvent of 90 ml of benzene and 8 ml of acetone.
Add 100 mg of trimethylcetyl ammonium chloride and 3
6 ml of 5% hydrochloric acid (d = 1.17, 2.46 g as HCl) was added. The water content in the reaction solution was 4.6 g (3.2-keto-L-gulonic acid.
3 times). After stirring for 1 hour and 15 minutes at 60-65 ° C, 2-keto-L-gulonic acid became oily. At this point, a Soxhlet extractor is used to distill about 2.5 ml.
(Weight 2.4 g) was distilled off under reduced pressure. The composition of this distillate was 1.4 g of water and 0.1 g of acetone 0.8HCl. The mixture was further stirred at the same temperature for 3 hours. After the reaction solution was cooled to 30 ° C., the precipitated precipitate was collected by filtration. After washing with a small amount of benzene, it was dried under reduced pressure. Gray crude ascorbic acid 1
3.4 g (purity 94.2%, yield 93.4%) was obtained. The crude crystals contained 0.16 g of 2-keto-L-gulonic acid (residual rate: 1).
%) Was included. When this crude crystal was dissolved in water and the absorbance thereof was measured, it was 0.145 at (E ^1% _{430 nm} ). The mother liquor obtained by filtering the crude crystals was extracted twice with 50 ml of water. When L-ascorbic acid was quantified in the aqueous layer using high performance liquid chromatography, 0.23 g (yield 1.7%) was detected. On the other hand, 0.36 g of 2-keto-L-gulonic acid (residual rate 2.4%) was detected.

Example 9 2-keto-L-gulonic acid (purity 91.2%, water 8.4%) 3
0 g was added to a mixed solution of 120 ml of toluene and 10 ml of acetone in which 3 g of hydrogen chloride was dissolved. After adding 300 mg of trimethylcetyl ammonium chloride, the mixture was heated to 65 ° C. 35% H
3 ml of Cl (d = 1.17, 1.23 g as HCl) were added. The water content in the reaction solution is calculated to be 4.8 ml (1.89 times mol based on 2-keto-L-gulonic acid). After stirring for about 1 hour, about 1.5ml
Distilled water (weight 1.3 g) was distilled off under reduced pressure. The composition of this distillate was water 0.3, acetone 0.9, and HCl 0.1 g. After stirring at the same temperature for 3 hours, cool to 30 ° C or less, and add 300 ml of water.
And extracted twice. The aqueous layers were combined, and L-ascorbic acid produced under the conditions of the high performance liquid chromatography was quantified. As a result, 23.5 g (yield 94.9%) was found. Also, 0.4 g of 2-keto-L-gulonic acid (residual rate 1.5%) remained. The absorbance of this extract was measured.
^1% _{430 nm} ▼ was 0.19.

Example 10 In a mixed solvent of 58 ml of toluene and 30 ml of acetone in which 11.1 g of hydrogen chloride was dissolved, 2-keto-L-gulonic acid (content
89.9%, moisture 8.4%) 100g, further 11.8g 35% hydrochloric acid
(D = 1.17, 4.1 g as HCl) and 0.12 g of trimethylcetyl ammonium chloride were added. The water in the reaction solution is 1
It is calculated to be 6.1 ml (1.93 times mol based on 2-keto-L-gulonic acid). The reaction was warmed to 60 ° C. and stirred for 6 hours. After cooling to 20 ° C., the reaction solution was poured into water 1, stirred, allowed to stand, and the aqueous layer was separated. The organic layer was re-extracted with 400 ml of water, and the aqueous layers were combined. When L-ascorbic acid produced was quantified using high performance liquid chromatography, it was found to be 76.6 g (yield 93.9%). Also, 1.4% of 2-keto-L-gulonic acid remained. The absorbance (E ^1% _{430 nm) of the} extracted water was 0.168.

Example 11 To a mixed solution of 11.1 g of hydrogen chloride and 580 ml of toluene and 110 ml of acetone was added 2-keto-L-gulonic acid (content: 8).
9.9%, moisture 8.4%) 100g, then 11.8g of 35% hydrochloric acid
(D = 1.17, 4.1 g as HCl) and 0.12 g of trimethylcetyl ammonium chloride were added. The water in the reaction solution is 1
It is calculated to be 6.1 ml (1.93 times mol based on 2-keto-L-gulonic acid). The reaction was warmed to 60 ° C. and stirred for 6 hours. After cooling to 20 ° C., the reaction solution was poured into water 1, stirred and allowed to stand, and then the aqueous layer was separated. The organic layer was re-extracted with 400 ml of water, and the aqueous layers were combined. When L-ascorbic acid produced was quantified using high performance liquid chromatography, 74.6 g (yield 91.5%) was found. Also, 2.5% of 2-keto-L-gulonic acid remained. The absorbance (E ^1% _{430 nm) of the} extracted water was 0.135.

Comparative Example 1 2-keto-L-gulonic acid (content 91.2%, moisture 8.4%) 3
2g was made into 180ml benzene. 140 mg of trimethylcetyl ammonium chloride was added, and 10 ml of 35% hydrochloric acid was further added.
(D = 1.17, 4.09 g as HCl) was added. The water content in the reaction solution was 10.3 ml (3.2-keto-L-gulonic acid.
8 times mol).

After heating the reaction solution to 60 ° C. and stirring for about 1 hour, 2-
Since the crystals of keto-L-gulonic acid became oily, about 8 ml of water was distilled off under reduced pressure using a Soxhlet extractor. 5 at the same temperature
After stirring for a total of 6 hours, the mixture was cooled to 30 ° C. or less. The reaction solution was poured into 300 ml of water, and after standing still, an aqueous layer was separated. The organic layer was re-extracted with 200 ml of water.

The aqueous layers were combined and the amount of L-ascorbic acid produced by high performance liquid chromatography was quantified to be 22.1 g (yield 83.
5%) was present. Also, 1.3% of 2-keto-L-gulonic acid remained. When the absorbance of this reaction solution was measured, ＥE ^1% _{430 nm} 0.4 was 0.45.

Comparative Example 2 2-keto-L-gulonic acid 20 g (content 92.1%, water 8.3
%) In 80 ml of toluene. 200 ml of hexadecyltrimethylammonium chloride was added, and the mixture was heated to 65 ° C. After adding 1.2 ml of 35% hydrochloric acid, hydrochloric acid gas (hydrogen chloride) was introduced at a rate of 80 ml / min for 2 hours and 30 minutes. The solvent was distilled off under reduced pressure at 30 ° C or lower. After 100 ml of toluene was added to the residue and mixed well, the mixture was distilled off under reduced pressure at 30 ° C. or lower. To the residue was added again 100 ml of toluene, and the mixture was stirred well and cooled to 20 ° C. or lower. The precipitated solid was collected by filtration, washed with a small amount of toluene, and then dried under reduced pressure.

It was dissolved in 300 ml of water and L-ascorbic acid produced by high performance liquid chromatography was quantified. As a result, 14.1 g (yield 84.4%) was found. Also, 2-keto-L-gulonic acid was not detected. When the absorbance was measured, ▲ E
^1% _{430 nm} ▼ was 0.47.

The mother liquor from which the solid was filtered was concentrated under reduced pressure to dryness. The residue was dissolved in 300 ml of water and quantified by high performance liquid chromatography. L-ascorbic acid 0.18 g (yield 1.1 g)
Existed.

Comparative Example 3 2-keto-L-gulonic acid 20 g (content 91.2%, water 8.4
%) 92.4 was added to 552 ml of toluene. Thereby, 100 mg of trimethylcetyl ammonium chloride was added, and 3 more
9.4 ml of 5% concentrated hydrochloric acid (d = 1.17, 3.85 g as HCl, as water
7.1 g) was added. The amount of water contained in the reaction solution is 14.9g
(1.90 times mol based on 2-keto-L-gulonic acid). While heating the reaction solution to 60 ° C., 10.4 g of hydrochloric acid gas was blown in for 6 hours, and then cooled to 20 ° C. (2.
The total amount of acid relative to -keto-L-gulonic acid was 0.9 moles).

Ascorbic acid produced by treating the reaction solution in the same manner as in Example 1 was quantified by high performance liquid chromatography to find that it was 30.6 g (40% yield). 46.3 g of 2-keto-L-gulonic acid remained (residual rate 55%). When the absorbance of this extract was measured, it was found that {E ^1% _{430 nm} } was 0.1 ^%.
Was 2.

Comparative Example 4 2-keto-L-gulonic acid (content: 91.2%, moisture: 8.4%) 9
2.4 g was added to 550 ml of toluene and 40 ml of acetone. Add 100 mg of trimethylcetyl ammonium chloride to this,
Further, 11 ml of 35% concentrated hydrochloric acid (d = 1.17, 4.55 g as HCl, 8.45 g as water) was added. The reaction solution was heated to 60 ° C., stirred for 1 hour, added with 200 g of an acetone solution containing 9.55 g of hydrogen chloride, stirred at the same temperature for 5 hours, and then stirred at 20 ° C.
(Total amount of acid to 2-keto-L-gulonic acid is
0.9 times mol).

Ascorbic acid produced by treating the reaction solution in the same manner as in Example 1 was quantified by high performance liquid chromatography.
The amount was 64.9 g (yield: 84.9%). 8.4 g of 2-keto-L-gulonic acid remained (residual rate 10.0%). Further, when the absorbance of this extract was measured, the value of {E ^1% _{430 nm} } was 1.5.

Claims (5)

(57) [Claims] (1) 0.05 to 0.2 with respect to 1 volume of an inert organic solvent.
In a mixed solvent of an aliphatic organic ketone and an inert organic solvent mixed with a volume of an aliphatic ketone, in the presence of water and a surfactant,
An acid is added to 2-keto-L-gulonic acid, and the amount of water is 2-keto-L.
1.8 to 3 times the molar amount of gulonic acid and the amount of acid is 2
-A method for producing L-ascorbic acid, which comprises reacting keto-L-gulonic acid in an amount of 0.7 to 1.5 times mol. 2. The method according to claim 1, wherein the inert organic solvent is an aromatic hydrocarbon. 3. The method according to claim 1, wherein the aliphatic ketone is a ketone having 1 to 6 carbon atoms or a cyclic ketone having 5 to 6 carbon atoms. 4. The method according to claim 1, wherein the acid is hydrochloric acid. 5. The method according to claim 1, wherein the surfactant is a quaternary ammonium salt.