JP7077165B2 - Method for producing sulfate ester compound - Google Patents

Description

The present invention relates to a method for producing a sulfate ester compound from a substance having a hydroxyl group.

There are a wide variety of substances in the world in which sulfuric acid esters are formed by dehydration and condensation between alcohol or phenolic hydroxyl groups and inorganic sulfuric acid. Sulfuric acid ester compounds are widely applied to a wide range of fields such as industry, cosmetics, foods and medicine depending on the type.

For example, sulfuric acid ester compounds typified by alcohol sulfate, alcohol ether sulfate, fatty acid monoglyceride sulfate and the like can be used as anionic surfactants in toiletry products such as shampoos, kitchen detergents, clothing detergents, household detergents and cosmetics. Very widely used as a center.

Further, it is known that a sulfate ester compound of a polysaccharide has various physiological activities such as anticoagulant activity, antiviral activity, anti-inflammatory activity, and hyaluronidase activity inhibitory ability. For example, it has been shown to be useful as an antiretroviral drug and is drawing attention.

On the other hand, sulfated polysaccharides are called mucopolysaccharides, which means polysaccharides obtained from viscous secretions in the animal world, and there are grooves with sulfate groups such as chondroitin sulfate and hebalan sulfate. The situation of its wide distribution is well known.
The simplest method for converting neutral polysaccharides to sulfated polysaccharides or introducing new sulfate groups into natural sulfated polysaccharides to convert their functions is to use concentrated sulfuric acid cooled to 0 ° C or lower. There is a method of adding a sample and continuing stirring. For example, in D-glucose, a mixture of mono-sulfuric acid and poly-sulfuric acid can be obtained (Non-Patent Document 1).

An alternative and widely used method is a reaction solution method containing chlorosulfonic acid and pyridine (Non-Patent Document 2). However, due to side reactions, etc., it is not widely used except for industrial applications, and currently widely used are tertiary amines such as pyridine, trimethylamine and dimethylformamide (DMF) and sulfur trioxide. The mixed reaction solution is used as a sulfate esterification reagent (Non-Patent Document 3).
However, these methods have the disadvantages that the reagents are too reactive, are inconvenient to handle due to their toxicity, or are difficult to control the reaction conditions. In addition, sugar chains may be cleaved due to side reactions.

Ryo Takano et al. (Non-Patent Document 4) applied a reaction using sulfuric acid as a sulfate reagent and dicyclohexylcarbodiimide (DCC) as a condensing agent in DMF to monosaccharides and polysaccharides, and this is an effective method for sulfation of polysaccharides. I found something. Since this reaction depends on temperature and time, by adjusting these, products having various degrees of sulfation can be obtained, and thus a highly active product can be obtained.
However, the price of dicyclohexylcarbodiimide (DCC), which is a condensing agent or a dehydrating agent used in this method, is high, and there are problems such as safety.

Further, Patent Document 1 also describes a reaction solution method containing a mixed solution of sulfuric acid, pyridine and acetic anhydride, but in this method, it is necessary to premix sulfuric acid and pyridine to produce pyridinium sulfate. In addition, since pyridine is used, environmental and safety problems associated with industrial mass production and pyridine remaining in the sulfate ester are not preferable for living organisms.

On the other hand, the applicant added cellulose pulp to a mixed solution of dimethyl sulfoxide, anhydrous acetic acid and sulfuric acid, and stirred at room temperature for about 2 hours to defibrate the cellulose pulp to produce cellulose nanofibers and to form sulfuric acid ester. , Has invented a method for producing sulfated modified cellulose nanofibers and applied for a patent (PCT / JP2018 / 001070). In this method, the reaction temperature is room temperature and the amount of sulfuric acid added is about 1% by weight, so that the decomposition of cellulose is avoided because the conditions are mild, and the reagent used is biologically friendly and inexpensive, so that the cost is low. Safe sulfate esterified cellulose nanofibers can be produced.

Japanese Unexamined Patent Publication No. 11-49795

K. Nagasawa, Y. et al. Tohira, Y. Inou, N.M. Tanora, Carboydr. Res. , Vol. 18, 95 (1971). E. Percival. J. Chem. Soc. 119 (1945). M. L. Worform, T.I. M. shen Han, J.M. Am. Chem. Soc. , Vol. 81, P.M. 1764 (1959). Ryo Takano, Shuichi Yoshikawa, Chemistry and Biology Vol. 34, 598 (1996).

The present invention does not use sulfuric acid esterifying agents such as chlorosulfonic acid and sulfur trioxide, which are harmful to living organisms and the environment, reaction solvents such as pyridine, trimethylamine and dimethylformamide, and condensing agents such as dicyclohexylcarbodiimide. , Provide a safe method for producing a sulfuric acid ester.

As a result of diligent studies to achieve the above-mentioned problems, the present inventor agitates a substance having a hydroxyl group in a solution containing dimethyl sulfoxide, sulfuric acid and a carboxylic acid anhydride without using special reagents, equipment or reaction conditions. Thereby, a sulfuric acid ester compound can be obtained. Furthermore, since the concentration of sulfuric acid in the reaction solution is low, it is unlikely that the substance to be esterified with sulfuric acid will be altered during the reaction. That is, the present invention is characterized by having the following configuration, and solves the above-mentioned problems.

[1] A method for producing a sulfuric acid ester compound, which comprises adding a substance having a hydroxyl group to a sulfuric acid esterification reaction solution containing dimethyl sulfoxide, carboxylic acid anhydride and sulfuric acid to cause a sulfuric acid esterification reaction. Method for producing a compound.
[2] The method for producing a sulfuric acid ester compound according to the above [1], wherein the substance having a hydroxyl group is a saccharide.
[3] The method for producing a sulfuric acid ester compound according to the above [1], wherein the substance having a hydroxyl group is an estrogen.
[4] The method for producing a sulfuric acid ester compound according to the above [1], wherein the substance having a hydroxyl group is an alcohol. [5] The carboxylic acid anhydride is a fatty acid anhydride having 1 to 4 carbon atoms. The method for producing a sulfuric acid ester compound according to any one of the above [1] to [4].
[6] The method for producing a sulfuric acid ester compound according to any one of claims 1 to 5, wherein the concentration of sulfuric acid with respect to the dimethyl sulfoxide is 0.05% by weight to 15% by weight.
[7] The method for producing a sulfuric acid ester compound according to any one of the above [1] to [6], wherein the concentration of the carboxylic acid anhydride with respect to the dimethyl sulfoxide is 3% by weight to 60% by weight.
[8] The sulfuric acid ester according to any one of the above [1] to [7], wherein the concentration of the substance containing a hydroxyl group with respect to the sulfuric acid esterification reaction solution is 0.1% by weight to 50% by weight. Method for producing a compound.
[9] The method for producing a sulfuric acid ester compound according to any one of the above [1] to [8], wherein the reaction temperature of the sulfuric acid esterification reaction is 10 to 80 ° C.

In the present invention, a sulfate ester compound can be obtained by stirring a substance having a hydroxyl group in a solution containing dimethylsulfoxide, sulfuric acid and a carboxylic acid anhydride without using special reagents, equipment or reaction conditions. .. In addition, the reaction drug is easily available and highly safe. Further, since the concentration of sulfuric acid in the reaction solution is low, it is unlikely that the substance having a hydroxyl group, which is the precursor of the sulfate ester compound, is denatured during the reaction.

IR spectra of the sulfate esterified cellulose obtained in Example 1 and the raw material cellulose IR spectrum of sulfate-esterified glucose obtained in Example 2 and raw material glucose IR spectrum of sulfate esterified D-glucosamine hydrochloride obtained in Example 3 and raw material D-glucosamine hydrochloride IR spectra of the sulfate esterified N-acetyl-D-glucosamine obtained in Example 4 and the raw material N-acetyl-D-glucosamine. IR spectrum of sulfate-esterified sucrose and raw sucrose obtained in Example 5 IR spectrum of sulfate-esterified starch obtained in Example 6 and raw material potato starch IR spectra of the sulfate esterified resorcinol obtained in Example 7 and the raw material resorcinol. IR spectra of sulfate-esterified PVA obtained in Example 8 and raw material PVA IR spectrum of cellulose treated in Comparative Examples 1 and 2 IR spectrum of sucrose treated in Comparative Example 3 and raw sucrose

The method for producing a sulfuric acid ester compound of the present invention produces a sulfuric acid ester compound by adding a substance having a hydroxyl group to a sulfuric acid esterification reaction solution containing dimethyl sulfoxide, a carboxylic acid anhydride and sulfuric acid and stirring the mixture.
By using the sulfuric acid esterification reaction solution, it is possible to produce a sulfate ester compound at a low sulfuric acid concentration and without heating.

もう一つは、アルブライト・ゴールドマン酸化メカニズムが示すように、ジメチルスルホキシドは下記式（２）に示すように、無水酢酸と作用して中間体のカチオンＡと酢酸アニオンを生成する。酢酸アニオンは硫酸からプロトンＨ^＋を奪った結果、硫酸アニオン（ＨＳＯ_４ ^－）が生成し、生成した硫酸アニオンは水酸基にアタックすることにより硫酸エステル化合物が形成されると推測する。

Although the reaction mechanism for producing the sulfate ester compound of the present invention is not yet clearly understood, the following two mechanisms can be considered.
One is that sulfuric acid acts as a sulfate esterifying agent, and carboxylic acid anhydrides such as acetic anhydride act as a dehydrating agent or a condensing agent. Dimethyl sulfoxide increases the nucleophilicity of the ^anion part HSO _4- of sulfuric acid by solvating the cation part (H ⁺ ) of sulfuric acid (formula (1) below), so that sulfuric acid can be used even under mild reaction conditions. It is presumed that an esterification reaction can be carried out.

Second, as shown by the Albrite Goldman oxidation mechanism, dimethyl sulfoxide acts with acetic anhydride to form intermediate cations A and acetate anions, as shown in formula (2) below. It is speculated that the acetate anion deprives sulfuric acid of the proton H ⁺ , resulting in the formation of a sulfate anion (HSO _4- ⁾ , and the generated sulfate anion attacks the hydroxyl group to form a sulfate ester compound.

The substance having a hydroxyl group is not particularly limited, and is an alcohol (unitary alcohol, polyhydric alcohol), an alcohol having an ether bond, an alcohol having a functional group such as an amino group, a saccharide, a compound having a hydroxyl group such as estrogen. All you need is.

Among the saccharides, the sulfate ester compound of the saccharide was found to have antiviral activity, hyaluronidase activity inhibitory function, atopic dermatitis therapeutic effect, anticholesterol effect, antiblood coagulation effect, etc. preferable.

Sugars are not particularly limited. The following monosaccharides, disaccharides, polysaccharides, oligosaccharides and the like can be mentioned. However, monosaccharides, disaccharides or polysaccharides are not limited to these.
Examples of the monosaccharide include glucose, fluthose, glucuronic acid or uronic acid, N-acetylglucosamine, glucosamine, galactosamine, deoxyribose, xylulose and the like.
Examples of the disaccharide include maltose, sucrose and lactose.
Examples of polysaccharides and oligosaccharides include dextran, starches (amylose, amylopectin), glycogen, hemicellulose or xylan, cellulose, hyaluronic acid, chitosan, chitin, glycosaminoglycan (mucopolysaccharide), agar or agarose. ..

Substances having a hydroxyl group are further estrogen such as estrone, estradiol and estriol, and complex carbohydrates such as proteoglycan.

Substances with hydroxyl groups are also applied to alcohols. Among the unit price alcohols, the sulfate ester compound of lauryl alcohol is particularly preferable because it is often used as a surfactant in industry and daily life. Examples of the dihydric alcohol include ethylene glycol, diethylene glycol and polyethylene glycol, or propylene glycol, dipropylene glycol and polypropylene glycol. Further, examples of the polyhydric alcohol include polyols such as glycerin and polyvinyl alcohol. Sulfuric acid ester compounds of these substances are applied to applications such as surfactants, electrolytes, and conductive materials.

The carboxylic acid anhydride contained in the sulfuric acid esterification reaction solution is not particularly limited, but the larger the number of carbon atoms, the higher the price and the lower the safety. Further, it is not preferable because it has a low promoting effect on the production of the sulfate ester compound. From these viewpoints, acetic anhydride, propionic anhydride, and fatty acid anhydride are particularly preferable. Acetic anhydride is most preferable in terms of safety, cost and reaction efficiency.

The concentration of carboxylic acid anhydride in dimethylsulfoxide depends on the molecular weight of the carboxylic acid anhydride. For example, in the case of acetic anhydride having a low molecular weight, the preferable concentration is 0.5% by weight to 50% by weight, more preferably 3% by weight to 30% by weight. If the concentration of carboxylic acid anhydride is too high, a side reaction called carboxylic acid ester reaction may occur, which is not preferable.
The water content of sulfuric acid used as the sulfuric acid agent is preferably 30% by weight or less. It is more preferably 15% or less, and most preferably 5% or less. A high water content causes a competitive reaction, which may increase the required amount of carboxylic acid anhydride, which is not preferable.

The concentration of sulfuric acid in dimethyl sulfoxide may be adjusted appropriately depending on the stability of the substance to be sulfate esterified. It is preferably 0.05% by weight to 30% by weight. More preferably, it is 0.1% by weight to 20% by weight. It is particularly preferably 0.3 to 10% by weight, and most preferably 0.5% to 5% by weight. If the sulfuric acid concentration is lower than this range, the reaction rate is too slow, which is not preferable. Further, if it is higher than this range, a side reaction may occur or a substance sensitive to sulfuric acid such as saccharide may be decomposed, which is not preferable.

The concentration of the substance to be sulfate esterified in the reaction solution may be applied by their molecular weight or a stirrer. For example, it is 0.1% by weight to 50% by weight. When the viscosity or molecular weight is high, a low concentration region is preferable. On the other hand, if the substance has a low viscosity or molecular weight, a high concentration range is preferable from the viewpoint of production cost. However, if the concentration is too high, the uniformity of the reaction may decrease, which is not preferable.

The production temperature of the sulfate esterification may be appropriately set depending on the heat resistance of the substance to be sulfate esterified. For example, 10 to 80 ° C. It is more preferably 15 to 65 ° C, more preferably 20 to 50 ° C. If the temperature is lower than this range, the reaction will be slowed down, which is not preferable. On the other hand, if the temperature is higher than this temperature range, a side reaction may occur, which is not preferable.

The manufacturing process of the sulfate ester compound will be described below.

Preparation of Sulfuric Acid Esterification Reaction Solution Dimethyl sulfoxide, acetic anhydride, and sulfuric acid are mixed at the above-mentioned compounding ratio to prepare a reaction solution. The mixing temperature is not particularly limited, but is preferably 10 ° C to 25 ° C. If the temperature is too high, there is a risk of heat generation during mixing and decomposition of dimethyl sulfoxide and acetic anhydride may occur, which is not preferable. Further, the order in which the reaction solutions are added is not particularly limited. For example, a method of dropping sulfuric acid while stirring a mixed solution of dimethyl sulfoxide and acetic anhydride, and a method of dropping sulfuric acid while stirring dimethyl sulfoxide and then mixing with a carboxylic acid anhydride can be mentioned.

Production of Sulfate Ester Compound A substance to be sulfate-esterified is added to the above reaction solution, and the mixture is stirred at a predetermined temperature, and after a predetermined reaction time, washing and neutralization are performed.

The method for washing, neutralizing, and purifying the produced sulfuric acid ester compound after the washing or neutralizing sulfuric acid esterification reaction is not particularly limited, but the following method can be used depending on the modification rate of the sulfuric acid ester compound and its solubility in water. Can be mentioned.

For example, if the sulfate compound is insoluble or difficult to dissolve in water, the sulfuric acid group of the unreacted sulfuric acid or the sulfate compound is neutralized by adding an alkali after the production reaction and stirring for several minutes to several tens of minutes. Convert unreacted sulfuric acid to sulfate and sulfate ester compounds to sulfate. Next, the sulfate ester salt is recovered by filtration. Further, distilled water is added, the mixture is stirred, and then the mixture is filtered and washed to obtain a sulfate ester salt.

On the other hand, in order to obtain an acid-type sulfate ester compound, water or alcohol (methanol, ethanol) is added after the reaction is completed, the sulfate ester compound is recovered by filtration, and the acid-type sulfate ester compound is recovered by washing. It is also possible to do.

The alkali for neutralization is not particularly limited, but may be applied depending on the use of the sulfate ester compound. For example, potassium hydroxide, sodium hydroxide, lithium hydroxide or carbonates or acetates thereof, aqueous ammonium ammonium solution, organic amines and the like can be mentioned. If a divalent or trivalent counter ion is required depending on the application, an alkaline substance such as calcium hydroxide or calcium acetate, aluminum acetate, magnesium acetate, or copper acetate can be used.

On the other hand, when the sulfate ester compound is soluble in water, the sulfate ester compound may be produced, the obtained reaction mixture may be neutralized with an alkali, and then the sulfate ester salt may be recovered by ultrafiltration. Alternatively, if the sulfuric acid ester compound is soluble in water but insoluble or slightly soluble in alcohol, the acid type can be obtained by washing with an alcohol such as ethanol without neutralization after the sulfuric acid esterification reaction. Recover the sulfate ester compound. Then, a method of obtaining a sulfate ester salt by adding the same amount of alkali as the sulfate ester group to neutralize it can also be mentioned.

When the sulfate ester compound is dissolved in alcohol, the sulfate ester is recovered by washing with a mixed solution of alcohol such as ethanol and a ketone solvent such as acetone or diethyl ether without neutralization after the sulfate esterification reaction. do. Then, a method of obtaining a sulfate ester salt by adding the same amount of alkali as the sulfate ester group to neutralize it can also be mentioned.

Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples. Examples are examples of the method for producing a sulfuric acid ester compound of the present invention.
The details of the raw materials used are as follows, and the evaluation of the obtained sulfuric acid ester was measured as follows.

(Substances and reaction reagents to be used for sulfate ester)
Cellulose pulp was used as the raw material cellulose. The cellulose pulp is a commercially available wood pulp (manufactured by Georgia Pacific, trade name: fluff pulp ARC48000GP, water content: 9% by weight). The raw material cellulose was cut into pieces (about 1 cm to 3 cm square) to fit in a sample bottle before defibration.
Acetic anhydride, sulfuric acid, DMSO, glucose, D-glucosamine hydrochloride, N-acetyl-D-glucosamine, sucrose, resorcinol, PEG, PVA and the like were purchased from Nacalai Tesque. Commercially available potato starch was used as the starch.

(Stirrer)
The stirrer used was a Mighty stirrer (model HE-20G) manufactured by Koike Precision Instruments Mfg. Co., Ltd. An oval type strong stirrer was used.

(IR spectrum)
The obtained sulfate ester compound was analyzed by a Fourier transform infrared spectrophotometer (FT-IR) to confirm the presence or absence of sulfate ester modification. The presence or absence of sulfate esterification modification was confirmed by the presence or absence of an absorption band derived from the sulfate ester groups at frequencies around 1250 cm ^-1 and 820 cm ^-1 . The measurement was performed using "NICOLET MAGNA-IR760 Spectrometer" manufactured by NICOLET, and the analysis was performed in the reflection mode.

(Quantification of sulfur content of sulfate ester compound)
Combustion absorption-Sulfur content was quantified using the IC method. That is, a dried sulfuric acid ester compound (0.01 g) was put in a magnetic board and burned in an oxygen atmosphere (flow rate: 1.5 L / min) in an annular furnace (1350 ° C.), and the generated gas component was converted to 3% hydrogen peroxide. It was absorbed in water (20 ml). The obtained absorption liquid was made up to 100 ml with pure water, and the sulfate ion concentration (% by weight) was calculated from the ion chromatography measurement results of the diluted liquid. The sulfur content was converted from the sulfate ion concentration by the following formula. An ion chromatograph ICS-1500 manufactured by Thermo Fisher Scientific Co., Ltd. was used for the analysis.
Sulfur content (% by weight) = sulfate ion concentration x 32/96

[Example 1]
18 g of DMSO, 2 g of anhydrous acetic acid (concentration in defibration solution: 9.9% by weight) and 0.26 g of sulfuric acid (concentration in defibration solution: 1.28% by weight) were placed in a 50 ml sample bottle at room temperature of 23 ° C. A sulfuric acid esterification reaction solution was prepared by stirring with a magnetic stirrer for about 30 seconds.
Then, 0.6 g of cellulose pulp was added, and the mixture was further stirred at the same room temperature for 110 minutes. After stirring, the reaction solution was added and mixed in 150 ml of a 0.2 wt% sodium hydroxide aqueous solution to neutralize sulfuric acid. Then, it was washed with distilled water by a filtration method to obtain sulfate esterified cellulose. Next, after drying in a blower dryer at 105 ° C. for 3 hours, analysis was performed by FT-IR, and the obtained IR spectrum is shown in FIG.
Absorption bands characteristic of sulfate esters were detected near frequencies 1250 cm ^-1 and 820 cm ^-1 . The sulfur content measured by the combustion absorption IC method was 2.8% by weight.

[Example 2]
The sulfuric acid esterification reaction was carried out in the same manner as in Example 1 except that 2 g of glucose was used instead of cellulose. Ethyl acetate solution 200 containing 50% by weight ethanol was added to the obtained reaction solution, and the mixture was stirred for about 10 minutes and then centrifuged (12000 rpm, 15 minutes). After centrifugation, the supernatant was removed, the same mixed solution of ethyl acetate and ethanol was added to the solid content remaining at the bottom of the centrifuge bottle, and the mixture was stirred and then centrifuged again. After washing three times in the same procedure, it was dried and FT-IR analysis was performed. From the obtained IR spectrum (FIG. 2), an absorption band characteristic of the sulfate ester was detected. The sulfur content measured by the combustion absorption IC method was 2.5% by weight.

[Example 3]
The sulfuric acid esterification reaction was carried out in the same manner as in Example 2 except that 0.6 g of D-glucosamine hydrochloride was used instead of glucose. The reaction time was 150 minutes. The obtained reaction solution was washed and analyzed in the same manner as in Example 2. From the obtained IR spectrum (FIG. 3), an absorption band derived from a sulfate ester was detected. The sulfur content measured by the combustion absorption IC method was 12.3% by weight.

[Example 4]
A sulfuric acid esterification reaction was carried out in the same manner as in Example 3 except that N-acetyl-D-glucosamine was used instead of D-glucosamine hydrochloride. The obtained reaction solution was washed and analyzed in the same manner as in Example 3. From the IR spectrum (FIG. 4), an absorption band characteristic of the sulfate ester was detected. The sulfur content measured by the combustion absorption IC method was 9.1% by weight.

[Example 5]
A sulfuric acid esterification reaction was carried out in the same manner as in Example 2 except that a mixed solution of 2 g of sucrose, 17 g of DMSO, 3 g of acetic anhydride and 0.5 g of sulfuric acid was used instead of glucose. The reaction time was 180 minutes. The obtained reaction solution was washed and analyzed in the same manner as in Example 2. From the IR spectrum (FIG. 5), an absorption band characteristic of the sulfate ester was detected. The sulfur content measured by the combustion absorption IC method was 7.5% by weight.

[Example 6]
The sulfuric acid esterification reaction was carried out in the same manner as in Example 2 except that 2 g of potato starch was used instead of glucose. The obtained reaction solution was washed and analyzed in the same manner as in Example 2. From the IR spectrum (FIG. 6), an absorption band characteristic of the sulfate ester was detected. The sulfur content measured by the combustion absorption IC method was 3.1% by weight.

[Example 7]
The sulfuric acid esterification reaction was carried out in the same manner as in Example 2 except that 0.6 g of resorcinol and 0.5 g of sulfuric acid were used instead of glucose. The obtained reaction solution was washed with the same washing solvent as in Example 2. The sulfate esterified compound was recovered using a separating funnel instead of centrifugation. From the result of FT-IR analysis (FIG. 7), the absorption band characteristic of the sulfate ester was detected. Absorption bands by DMSO were also detected due to insufficient cleaning.

[Example 8]
The sulfuric acid esterification reaction was carried out in the same manner as in Example 2 except that PVA was used instead of glucose. The obtained reaction solution was washed and analyzed in the same manner as in Example 2. From the result of FT-IR analysis (FIG. 8), the absorption band characteristic of the sulfate ester was detected.

[Comparative Example 1]
Cellulose was treated, washed and dried in the same manner as in Example 1 except that pyridine was used instead of DMSO. As a result of FT-IR analysis of the dried pulp-like sample (Fig. 9), no absorption band derived from the sulfate ester was detected, and an absorption band derived from the carbonyl group of the acetyl group was detected at 1730 cm ^-1 . ..
From this result, it was found that the acetylation modification reaction of cellulose occurred in the mixed solution of pyridine, acetic anhydride and sulfuric acid at the same temperature and time as in the example, but the sulfuric acid esterification reaction hardly occurred.

[Comparative Example 2]
As a result of FT-IR analysis of a pulp-like sample treated, washed and dried in the same manner as in Comparative Example 1 except that dimethylacetamide was used instead of pyridine (Fig. 9), absorption and acetyl derived from sulfuric acid ester were obtained. No absorption band was detected due to the conversion. From this result, it was found that cellulose did not react with acetic anhydride or sulfuric acid in a mixed solution of dimethylacetamide, acetic anhydride and sulfuric acid at the same temperature and time as in the examples.

[Comparative Example 3]
The sulfuric acid esterification reaction was carried out in the same manner as in Comparative Example 2 except that sucrose was used instead of the cellulose pulp. After completion of the reaction, sucrose remained in its original granularity. It was washed and analyzed in the same manner as in Comparative Example 2. From the results of FT-IR analysis (FIG. 10), the absorption band characteristic of the sulfate ester could not be detected near frequencies 1250 cm-1 and 820 cm-1. From this result, it was found that the sulfuric acid esterification reaction hardly occurred in the mixed solution of dimethylacetamide, acetic anhydride and sulfuric acid.

From the evaluation results of the above examples, the sulfate esterification method of the present invention did not require any special reagent or process, and the sulfate ester could be synthesized by using a biologically friendly reagent and mild reaction conditions.

As a synthetic method with high safety and low side reactions, it is highly expected as a method for producing sulfate esters used in fields where safety and hygiene are strictly required, such as pharmaceuticals, medical care, healthcare, cosmetics and foods.

Claims (3)

A method for producing a sulfuric acid ester compound, in which a substance having a hydroxyl group is added to a sulfuric acid esterification reaction solution containing dimethyl sulfoxide, a carboxylic acid anhydride and sulfuric acid to cause a sulfuric acid esterification reaction, and the carboxylic acid anhydride is obtained by anhydrous acetic acid. A method for producing a sulfuric acid ester compound, which is propionic acid anhydride or butyric acid anhydride . The method for producing a sulfuric acid ester compound according to claim 1, wherein the concentration of sulfuric acid with respect to dimethyl sulfoxide is 0.05% by weight to 15% by weight. The method for producing a sulfuric acid ester compound according to claim 1 or 2 , wherein the concentration of the carboxylic acid anhydride with respect to the dimethyl sulfoxide is 3% by weight to 60% by weight.

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