JPS6259601A - Production of etherified cyclodextrin - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as, e.g., a solubilizing agent in high yields, by partially etherifying cyclodextrin in a mixed solvent system of an aqueous alkali solution and an organic solvent and etherifying the product in the presence of an alkaline agent in an organic solvent. CONSTITUTION:Cyclodextrin is reacted with an alkylating agent (e.g., dimethyl sulfate) in a mixed solvent system of an aqueous alkali solution and an organic solvent (e.g., aqueous NaOH solution/dichloroethane) to partially etherify the cyclodextrin. When unreacted cyclodextrin can be scarcely recognized, the reaction mixture is separated into an organic solvent layer and a water layer. A solid alkaline agent (e.g., NaOH) is added to the organic solvent layer containing the formed partially etherified cyclodextrin, and the product is completely etherified by adding dropwise an alkylating agent thereto to obtain the aimed etherified cyclodextrin.

Description

[Detailed Description of the Invention] [Field of Industrial Application] The present invention is useful as a quality improver, stabilizer, and solubilizer for pharmaceuticals, agricultural chemicals, cosmetics, etc., and is also important as a catalyst for the chemical industry. This invention relates to a new method for producing etherified cyclodextrin.

[Conventional technology]

Regarding the preparation method of etherified cyclodextrin,
Many reports have been made to date.

For example, Irvine et al. reported that a product with an etherification rate of about 40% was obtained by reacting cyclodextrin with dimethyl sulfate in an aqueous sodium hydroxide solution [J, [: hem, Soc, , 125.
2190, (1924>). However, this method is extremely inefficient, as is clear from the fact that the etherification rate of 40% was obtained by repeating the reaction 20 times. Ta.

In addition, Szejtli et al. recently reported that heptakis 2,6-dimethyl cyclopropylene was synthesized in a 60% yield using dimethyl sulfuric acid in the presence of a mixture of barium hydroxide and barium oxide in a mixed solvent of dimethyl sulfoxide and dimethyl formamide. Synthesizing dextrin [Starch/StMrke 32
．． 165 (1980)). Furthermore, as an improvement on this method, a synthesis method in the presence of heterogeneous sodium hydroxide dispersed in dimethyl sulfoxide has been published [Hungarian patent application (Hung, Pat, Appl, ) 8
38/83), and a review of such conventional synthetic methods has been summarized and reported by Craft et al.
ahedron), 39-11417.1983).

However, since these conventional methods need to be carried out in a non-aqueous system, the reaction has to be in a solid-liquid heterogeneous system, and the reaction takes a long time (for example, 5tarch/StM
In the RKE method, the reaction was allowed to take place for about 4 days), and it was also necessary to strictly control the temperature conditions. In addition, the chemicals used in these reactions must be dehydrated in advance, making the operation very complicated, and many of these chemicals are expensive, which poses an economical problem.

Furthermore, the method of separating and purifying the etherified cyclodextrin produced by these methods from the reaction solution is a very complicated process, which has been a major obstacle in producing the substance on an industrial scale.

(Object of the Invention) Therefore, the object of the present invention is to eliminate the need for solvents that require purification such as dimethyl sulfoxide and dimethyl formamide used in conventional methods, and to eliminate the need for barium hydroxide and barium oxide, which are dangerous and difficult to handle. It is an object of the present invention to provide a method for producing etherified cyclodextrin at a high yield in a short period of time at a low cost at room temperature and under normal pressure without using a cyclodextrin.

(Structure of the Invention) The present inventors focused on the fact that the starting material cyclodextrin is water-soluble, whereas the etherified cyclodextrin is easily soluble in organic solvents, and developed a method for combining cyclodextrin and an alkylating agent. By conducting the reaction in a water-organic solvent two-phase system to obtain a partially etherified cyclodextrin, and then further reacting this with an alkylating agent in an organic solvent, it can be efficiently and economically advantageous. The present inventors discovered that etherified cyclodextrin can be produced by the following methods, and completed the present invention.

The present invention provides a method for producing an etherified cyclodextrin by reacting a cyclodextrin and an alkylating agent, which includes: a) reacting the cyclodextrin and the alkylating agent in a mixed solvent of an aqueous alkali solution and an organic solvent; b) a second reaction step in which the partially etherified product of the cyclodextrin is further reacted with an alkylating agent in the presence of an alkaline agent in an organic solvent; This is a method for producing an etherified cyclodextrin, characterized in that it combines the following.

The cyclodextrin used in the present invention is
Cyclodextrin-forming enzyme (Cycloma) in starch
itodextrin glucanotransfer
6 to 12 obtained by acting on
It is a crown-shaped non-reducing dextrin in which glucose molecules are cyclically bonded through α-1,4-glucoside bonds.Industrially, α-cyclodextrin consists of 6 glucose molecules, dextrin,
T-cyclodextrin, which consists of eight molecules, is well known. In the present invention, any of these cyclodextrins can be used.

Next, as the alkylating agent used in the present invention, commonly used alkyl sulfates such as dimethyl sulfate, diethyl sulfate, dipropyl sulfate, etc. are preferably used.

In the present invention, first, the above cyclodextrin and an alkylating agent are reacted in a mixed solvent of an aqueous alkali solution and an organic solvent. As the alkali agent used in this first reaction step, hydroxides of alkali metals or alkaline earth metals, or mixtures thereof, which are generally available at low cost, are suitable, and the concentration in the aqueous alkali solution is 10 to 50% by weight. % is appropriate. Next, as the organic solvent, any organic solvent can be used as long as it satisfies the conditions that cyclodextrin is insoluble, etherified cyclodextrin is soluble, and is incompatible with water. Examples include chloroform, methylene chloride, carbon tetrachloride, dichloroethane, or mixtures thereof. The amount of this organic solvent used is (cyclodextrin)
5-100ml per 1g of IJ, preferably 10-3
Preferably, it is in the range of 0 m1. The cyclodextrin concentration in the total reaction solution is suitably in the range of 8 to 30 W/V%, and the alkylating agent is suitably used in an equivalent amount of 1 to 10 times the cyclodextrin. If it is less than 1 equivalent, unetherified cyclodextrin remains, which is insufficient;
Even if the amount is more than 0 times equivalent, the amount of decomposition of the alkylating agent increases, which is economically disadvantageous.

The etherification reaction in the first reaction step is suitably carried out at a temperature of 40°C or lower, preferably 20 to 30°C for 1 to 12 hours.

In short, the first reaction step is suitably carried out under conditions (amount of alkylating agent, reaction temperature, time, etc.) such that cyclodextrin etherified to an extent that it dissolves in the organic layer can be obtained.

When almost no unreacted cyclodextrin is observed, the organic layer and the aqueous layer are separated, and an organic solvent containing partially etherified cyclodextrin (cyclodextrin in which a portion of the hydroxyl groups at the 2 and 6 positions is etherified) is added. Get layers.

Incidentally, the above liquid separation can be carried out by a conventional method such as decantation.

Furthermore, from the above organic solvent layer, by decomposing the unreacted alkylating agent with a basic reagent such as concentrated aqueous ammonia before separation, it is possible to separate the partially etherified cyclodextrin using a conventional method. .

In the present invention, in the second reaction step, 2.
In order to completely etherify the 6-position hydroxyl group, the partially etherified cyclodextrin obtained in the first reaction step above is reacted with an alkylating agent in the presence of an alkaline agent in an organic solvent. The desired single component etherified cyclodextrin, i.e. 2,6-
This method is characterized by obtaining a cyclodextrin in which the hydroxyl group at the position is completely etherified.

In the present invention, the organic solvent layer containing the partially etherified cyclodextrin returned by liquid separation in the first reaction step can be used as is or as needed without decomposing and deactivating the unreacted alkylating agent contained therein. It is preferable that the organic solvent is partially distilled off or added, or subjected to other treatments before being subjected to the second reaction.

Unlike the first reaction step, the alkaline agent in the second reaction step is added to the reaction system not as an aqueous solution but as a solid. That is, a solid alkali agent is added to an organic solvent containing cyclodextrin (IJ) to be partially etherified, and then an alkylating agent is added dropwise to cause a heterogeneous alkylation (etherification) reaction.

The alkaline agent, organic solvent, and alkylating agent that can be used in the second reaction step are the same as those described above as those that can be used in the first reaction step.

The amount of organic solvent used is 5 to 100 mJ, preferably 10 to 3 Qn per 1 g of partially etherified cyclodextrin.
+1, and the amount of alkaline agent used is in the range of 1 to 50 g, preferably 5 to 25 g, per 1 g of partially etherified cyclodextrin. Further, the alkylating agent is 1 to 10 times more active than the partially etherified cyclodextrin.

The etherification reaction in the second reaction step is suitably carried out at a temperature of 20° C. or lower for about 1 to 4 hours.

According to the present invention, by combining the above first reaction step and second reaction step, an etherified cyclodextrin consisting of a single component in which the hydroxyl groups at the 2,6-positions are completely etherified is obtained. be able to. For example, in the methylation of β-cyclodextrin (β-CD) with dimethyl sulfate, approximately 3
Methyl etherification proceeds in a range of 3% or more and less than about 67%, and a mixture in which 7 to 13 hydroxyl groups are methyl etherified is obtained, and in the subsequent second reaction step, 67% of the total hydroxyl groups, that is, 14 hydroxyl groups, are methyl etherified. Etherified cyclodextrin (heptakis-2) in which the hydroxyl group of
, 6-di○-methyl-β-cyclodextrin) is obtained.

Furthermore, in the present invention, triether You can also obtain an incarnation.

The present invention will be explained in more detail with reference to Examples below.

Example 1 1 g of β-cyclodextrin was dissolved in 6 ml of 30% sodium hydroxide solution, and 10 ml of dichloroethane was added thereto, followed by vigorous stirring at room temperature. While keeping the temperature of the system below 30° C., 10 ml of dimethyl sulfuric acid was slowly added dropwise and stirring was continued. After 90 minutes, 2.6 g of sodium hydroxide was added as a solid to the reaction system.

In about 3 hours, β-cyclodextrin was partially methylated and migrated from the aqueous layer to the organic layer.

Here, in order to easily separate the aqueous and organic layers - phlegm 5Qn+j! was added, and the aqueous layer was removed by decantation.

When the product was examined by thin layer chromatography using a developing solvent of chloroform/methanol=9=1, three Rf values were observed: 0644.0.60.0.73, indicating the degree of methylation in the organic solvent. different products were mixed.

Then, the following processing was performed. 2.6 g of sodium hydroxide was newly added as a solid to the organic solvent layer obtained by liquid separation, and dimethyl sulfuric acid was slowly added dropwise while stirring vigorously. After 90 minutes, another 2.6 g of sodium hydroxide was added, and after 3 hours, 5Qmj2 of water was added and the reaction system was heated to 10% in a water bath.
Excess dimethyl sulfate was decomposed by adding 9Qmj2 of concentrated ammonia water while keeping the temperature below .degree. After removing the aqueous layer by decantation, the organic layer was washed repeatedly with dilute hydrochloric acid and water, and after drying with sodium sulfate, dichloroethane was distilled off using a rotary evaporator. In the yield 0.81goTLC results, a single spot was observed at an Rf value of 0.74. '
From the results of the H-NMR spectrum and the C-NMR spectrum, the introduction of methyl groups into the C-2 and C-6 positions was confirmed, and elemental analysis showed that the theoretical value when 14 methyl groups were introduced ( C: 49.76%, H: 7.27
%) showed very good agreement. Measured value (C: 49.63
%, H: 6.94%).

Example 2 1 g of β-cyclodextrin was treated according to the reaction procedure of Example 1 to obtain a mixture of partially etherified cyclodextrins. The TLC results show that the Rf value is 0.
Three points were recognized: 45.0.61.0.73. After removing the aqueous layer, 2.6 g of sodium hydroxide was added and IQ ml of dimethyl sulfate was added all at once. 1 hour later, 2
．． 6 g of sodium hydroxide was added again and stirred for several hours.

After further refluxing for 2 hours, excess dimethyl sulfate was decomposed with concentrated ammonia solution, the dichloroethane layer was washed with dilute hydrochloric acid and water, and after drying with sodium sulfate, dichloroethane was distilled off using a rotary evaporator. According to the TLC results, a spot appeared at a slightly high position with an Rf value of 0.79. 'H-N
According to the MR spectrum, the δ value was 3.47 ppm (C
-Chemical shift of methyl form at position 6), 3.70 ppm
(Chemical shift of C-2 position methyl form) plus 3.56p
A clear chemical shift was observed at pm, with C-3
Progression of position methylation was observed.

Example 3 3 g (Dr-cyclodextrin was dissolved in a solution of 13 g of sodium hydroxide dissolved in 3 Q ml of water, and 3 Q+ni of dichloroethane was added. To this, 3 Q of dimethyl sulfate was added.
ml was added and stirred at 30°C or lower under water cooling. On the way, 2.
Add 5 g of sodium hydroxide in 5 portions, 2.
The reaction was terminated after 5 hours. After removing the aqueous layer by decantation, add NaOH6 to the dichloroethane layer.
5 g was added thereto, and 33 mj2 of dimethyl sulfate was slowly added dropwise over 1 hour.

1 hour later, 1.5 hours later, 2 hours later, 2.5 hours later, 3
After an hour, 2.5 g of sodium hydroxide was added and after 4 hours the excess dimethyl sulfate was destroyed with concentrated ammonia. This organic layer was washed with water, dried with mirabilite, and then dried in a rotary evaporator to obtain a product (2.9 g, 97%).

TLC of this product was chloroform:methanol=9:
Using the developing solvent of No. 1, it was confirmed that the Rf value was 0.68 and that it consisted of a - component.

Example 4 3 g of α-cyclodextrin was dissolved in a solution of 13 g of granular sodium hydroxide in 30 ml of water, and 30 ml of dichloroethane was added. Add 33% of dimethyl sulfate to this
ml was added and stirred at 30°C or lower under water cooling. On the way, 2.
Add 5 g of sodium hydroxide in 5 portions, and after 3 hours,
The reaction was terminated. After the aqueous layer was removed by decantation, 6.5 g of sodium hydroxide was added as granules to the dichloroethane layer, and 33 ml of dimethyl sulfuric acid was slowly added dropwise over 1 hour. Sodium hydroxide every 30 minutes
．． 5 g each was added, and the reaction was completed in 4 hours. After excess dimethyl sulfate was decomposed by treatment with concentrated ammonia, the organic layer was washed with water, dried over sodium sulfate, and then dried using a rotary evaporator to obtain a product (2.7 g, 90%). TLC of this product using a developing solvent of chloroform:methanol-9=1 confirmed that it was a single component with a spot at an Rf value of 0.54.

Example 5 1 g of β-cyclodextrin was treated according to the first reaction step of Example 1, resulting in a mixture of partially etherified cyclodextrins (according to TLC results, Rf value 0.4).
After removing the aqueous layer, 2.6 g of sodium hydroxide was added in the form of granules, and 1Qmj2 of dimethyl sulfate was added at once. 20°~3
After stirring at 0°C for 1 hour, 2.6g of hydroxide) I
After 5 hours, the mixture was heated to 70° C. and refluxed for 3 hours to obtain cyclodextrin (cyclodextrin) in which the 2-, 3-, and 6-positions were completely methylated. (Yield 1
．． 1 g) Furthermore, the reaction continued for about 20 hours without raising the temperature (although the introduction of a methyl group into the C-3 position was confirmed).

〔Effect of the invention〕

According to the present invention, by using cyclodextrin as a starting material and combining the first reaction step of a water-organic solvent two-phase mixed solvent system and the second reaction step of a solid (alkali agent)-organic solvent system, the second reaction By performing the process without using water, cyclodextrin in which the hydroxyl groups at the 2- and 6-positions are completely etherified can be easily and quickly produced with a high yield, and the cyclodextrin can be separated and purified.

Furthermore, by appropriately controlling the reaction time and temperature of the second reaction step, it is possible to produce and separate cyclodextrin in which not only the 2- and 6-position hydroxyl groups but also the 3-position hydroxyl group is etherified.

The present inventors previously filed an application for a method for producing etherified cyclodextrin in which the second reaction step is a water-organic solvent two-phase mixed solvent system and a phase transfer catalyst is used. No. 233854].

However, compared to that method, the method of the present invention requires a shorter time from partial etherification to complete etherification of the hydroxyl groups at the 2- and 6-positions, and the alkylating agent is used in both the first and second reaction steps. This method has been improved so that less amount of

Claims (1)

[Claims] A method for producing an etherified cyclodextrin by reacting a cyclodextrin and an alkylating agent, comprising: a) reacting a cyclodextrin and an alkylating agent in a mixed solvent of an aqueous alkali solution and an organic solvent; b) a second reaction step in which the partially etherified product of the cyclodextrin is further reacted with an alkylating agent in the presence of an alkaline agent in an organic solvent; A method for producing an etherified cyclodextrin, characterized by combining the steps.