JP3053510B2 - Method for producing D-kilo-inositol - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to D-chiro-inositol obtained by acid hydrolysis of kasugamycin.
To an improved production method. More specifically, the present invention relates to a method of mixing a kasugamycin acid addition salt as a raw material in the form of an aqueous solution with a strongly acidic ion exchange resin, adsorbing the resin and binding a kasugamycin molecule to the strongly acidic functional group of the resin in the form of an addition salt. By hydrolyzing kasugamycin under mildly acidic conditions due to the acid generated in the solution, as compared with the conventional method using a strong acid, the kasugamycin is more efficiently and with less side reactions under much milder acidic conditions and D- The present invention relates to an improved method for producing D-chiro-inositol, which comprises producing C-chiro-inositol by liberating it, and recovering D-chiro-inositol from the reaction solution in a simple manner and in a high-purity crystalline form in a high yield.

[0002] D-chiro-inositol is a neutral sugar that is very rare in nature and has not been particularly noted before, but recently has a biochemically specific activity. It has been clarified that it is useful as a physiologically active substance, particularly as a medicine.
However, it is an expensive substance because its industrial production method has not been developed and cannot be obtained in large quantities.

[0003]

2. Description of the Related Art Kasugamycin is an antibiotic pesticide that is very safe and has a high disease control activity, and is widely used as an agricultural fungicide in Japan and around the world. At present, kasugamycin is industrially mass-produced by a fermentation method, and is supplied relatively inexpensively and stably as a pesticide drug substance.

[0004] Kasugamycin is a compound whose mother nucleus is a disaccharide of an amino sugar having a very specific structure and D-kilo-inositol, which is very rare in nature.

[0005] Conventionally known methods for producing D-chiro-inositol involve extracting certain plants with alcohol and water and extracting D-chiro-inositol.
A method of collecting kilo-inositol, and liberating D-kilo-inositol from kasugamycin by hydrolyzing kasugamycin in an aqueous solution of a strong acid such as 2N trifluoroacetic acid or 5N hydrochloric acid under heating under strong acidic conditions. A method of separating the neutral sugar from the hydrolysis reaction solution by a complicated method is known (US Pat. No. 5,091,5).
No. 96).

[0006]

The D-kilo-acid obtained by the strong acid hydrolysis of kasugamycin described in the above-mentioned U.S. Pat.
The production method of inositol is a method in which the separation and purification steps of D-kilo-inositol can be somewhat simplified and the yield is better than the production method of D-kilo-inositol by extraction from a plant.

[0007] However, the method of this US patent involves a laboratory-level hydrolysis consisting of hydrolysis under strongly acidic conditions to identify the constituent sugars of kasugamycin when the inventors of kasugamycin determined the structure of kasugamycin. Method ["Journal of Antibiotics" 18
Vol., P. 182 (1965)], and there are a number of disadvantages in using it for industrial-scale production of D-kilo-inositol. That is, in the acid hydrolysis reaction of kasugamycin according to the conventional method, since a very strong acid (5N hydrochloric acid or 2N aqueous trifluoroacetic acid solution or the like) is used, a large amount of impurities are generated due to a side reaction upon cleavage of the kasugamycin molecule. Is inevitable. In addition, it is necessary to dilute the strongly acidic reaction solution with a large amount of water, and then perform a D-kilo-inositol recovery step and distill a large amount of water to concentrate the neutral sugar aqueous solution. It is. Also,
To use a large amount of strong basic ion exchange resin to neutralize a large amount of strong acid used in the hydrolysis reaction, and to use a large amount of strong acidic ion exchange resin to remove by-product basic compounds In addition, large amounts of water are required to wash these resins.

In addition, a large amount of reagents and a large amount of water are required for the regeneration of the ion exchange resin after use, and a large amount of post-treatment of waste water is also required. Furthermore, since the hydrolysis reaction occurs radically, a reaction in which the amino sugar itself, which is another constituent sugar of kasugamycin, is decomposed occurs as a side reaction, and various side reactions including basic side reaction products are generated. There is a drawback that the substance is formed as an impurity and is mixed as an impurity during the separation and purification steps of D-kilo-inositol. Therefore, in the step of recovering D-kilo-inositol, complicated purification treatment such as gel filtration chromatography or activated carbon treatment is required.

An object of the present invention is to utilize a method for producing D-chiro-inositol by acid hydrolysis of kasugamycin, and to efficiently use a simple method without side reactions under mild reaction conditions. Another object of the present invention is to provide a method for industrially and advantageously producing a high-purity target neutral sugar.

[0010]

Means for Solving the Problems The present inventors have studied various methods capable of obtaining D-kilo-inositol, a constituent sugar, from kasugamycin by an acid hydrolysis in a simple manner with high yield and high purity. . As a result, if the amino group of the amino sugar moiety of kasugamycin is kept in a state of being bound in the form of an addition salt with some strong acid, the amino sugar of kasugamycin and the neutral sugar (D-kilo-inositol) can be interspersed. It has been found that the glycosidic bond can be efficiently cleaved under weak acidic conditions with hydrochloric acid in a concentration range of 0.05N to 0.5N to easily hydrolyze kasugamycin into two types of constituent sugars.

As an industrially applicable method, kasugamycin is adsorbed on a strongly acidic ion exchange resin (H ⁺ type), and kasugamycin is bound to the strongly acidic functional group of the strongly acidic ion exchange resin in the form of an addition salt. It has been found that by hydrolyzing kasugamycin in an acid state with an acid, D-kilo-inositol can be efficiently produced from kasugamycin even under weakly acidic conditions.

As a result of further study, it was found that the aqueous solution of kasugamycin hydrochloride or sulfate was combined with about 5 times (by weight) or more of the strongly acidic ion exchange resin of the kasugamycin salt,
Preferably, when the kasugamycin is adsorbed and bound to the strongly acidic ion-exchange resin particles having a sulfonic acid group as a functional group, the kasugamycin hydrochloride or sulfate is contained in the solution phase of the mixture. From hydrogen chloride or sulfuric acid is released from about 0.05N-
Hydrogen chloride or sulfuric acid at a concentration of 0.5N is present, and under the mildly acidic conditions generated at this time, the kasugamycin bound to the resin is hydrolyzed under heating without adding an additional acid. It has also been found that D-chiro-inositol can be efficiently cleaved from kasugamycin molecules and produced.

In the case where kasugamycin is bound to the strongly acidic ion exchange resin in this way, the acidic conditions (0.05 N to 0. 0. N) are much lower than those of the conventional method in which kasugamycin is dissolved in 5N hydrochloric acid and hydrolyzed. In the presence of 5N hydrochloric acid), D-kilo-inositol can be obtained in high purity with very few impurities generated by side reactions.

As described above, an aqueous solution of kasugamycin hydrochloride or sulfate is mixed well with a strongly acidic ion exchange resin,
When the kasugamycin bound to the strongly acidic ion exchange resin is hydrolyzed in the presence of an aqueous solution containing 0.05N to 0.5N HCl or sulfuric acid generated at this time, it is produced as one of the decomposition products of kasugamycin. The basic substance remains adsorbed on the strongly acidic ion-exchange resin, and the target product, neutral D-kilo-inositol, can be separated from the strongly acidic ion-exchange resin as a non-adsorbed fraction without binding to the resin. This can be easily obtained with high yield and high purity.

After the hydrolysis reaction, it can be separated from the strongly acidic ion exchange resin as an acidic reaction solution containing almost pure D-kilo-inositol together with hydrogen chloride or sulfuric acid. D-chiro-inositol can be efficiently separated from as-is amino sugars, unreacted kasugamycin and other impurities.

According to the first invention, an aqueous solution of kasugamycin hydrochloride or sulfate is converted to a strongly acidic ion exchange resin (H
⁺ Form) to bind the kasugamycin molecule to the strongly acidic functional groups of the strongly acidic ion exchange resin in the form of an addition salt, whereby the hydrogen chloride or sulfuric acid released from the kasugamycin is reduced to 0.05 N to 0.5N, preferably 0.1N.
A mixture of an aqueous solution of hydrogen chloride or sulfuric acid containing a concentration of 15 N to 0.2 N and granules of the strongly acidic ion-exchange resin bound to kasugamycin is formed, and the mixture is heated under normal pressure or pressure to form kasugamycin. , And D-kilo-inositol is released from kasugamycin to form an acidic reaction solution containing D-kilo-inositol and hydrogen chloride or sulfuric acid. Upon cooling, the acidic reaction solution was separated from the resin, and the resin was washed with water to elute D-kilo-inositol remaining in the resin, and the eluted D-
The obtained washing water containing kilo-inositol is combined with the reaction solution to obtain an acidic mixed solution, and the acidic mixed solution is passed through a packed column of a basic ion exchange resin (OH ^- type) to obtain the acidic mixed solution. Collecting a neutral eluate containing D-kilo-inositol from the column, and then concentrating the eluate to precipitate crystals of D-kilo-inositol;
A method for producing kilo-inositol is provided.

Next, the first method of the present invention will be specifically described. In the first method of the present invention, the hydrolysis reaction of kasugamycin is carried out in a batch system.

The strongly acidic ion exchange resin used in the present method is prepared by treating a commercially available product with an inorganic acid to prepare an H ⁺ type resin, and then providing it for use. The inorganic acid used for the treatment is 1N to 5N.
There is an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid and the like. The strongly acidic ion exchange resin used is preferably an ion exchange resin having a sulfonic acid group as a functional group, and a commercially available strong acidic ion exchange resin such as Diaion SK1
16 (Mitsubishi Kasei), DIAION P K-228, Amberlite IR 120 B, (manufactured by Organo Corporation) Amberlite 200C, Amberlite 201B, Duolite C-20 (manufactured by Sumitomo Chemical Co., Ltd.), Duolite C-26
4. Duolite XE-636, Dowex 50W
(Muromachi Chemical Industry).

Kasugamycin hydrochloride or sulfate is added to the strongly acidic ion-exchange resin prepared in the H ⁺ form as described above.
An aqueous solution containing 1 to 30% (weight), preferably 5 to 20%, is mixed well.

The weight ratio of the mixture of kasugamycin hydrochloride or sulfate and the strongly acidic ion exchange resin is 0.05N to 0.5N, preferably 0.15N to 0.2N in the solution phase of the obtained mixture. The amount is sufficient to release hydrochloric acid or sulfuric acid.

In the first aspect of the present invention, the hydrolysis reaction of kasugamycin is carried out under normal pressure at 50 to 98 ° C., preferably 90 to 98 ° C.
6 to 40 hours at a temperature of ~ 95 ° C, preferably 10-15
Time can be done.

Further, the hydrolysis reaction of kasugamycin is
A pressure of, for example, 0.1 to 3 kg / cm ^{2 at} a gauge pressure under a pressure sufficient to suppress boiling of water in the reaction mixture;
Preferably 100 to 100 kg under a pressure of 1 to 1.2 kg / cm ²
1.0 to 10 hours at a temperature of 150 ° C., preferably 3 to 5 hours
Time can be done.

When the kasugamycin hydrolysis reaction is carried out under pressure, the reaction vessel is preferably placed in an autoclave. It is not necessary to stir the reaction mixture.

In the first method of the present invention, when the hydrolysis reaction is carried out under pressure, the reaction temperature can be raised to 100 ° C. or higher and the reaction time can be shortened. Pressurization is possible because the hydrolysis reaction of the present method can proceed as desired even under low acidic conditions, and in the case of the conventional hydrolysis method using a strong acid, even under normal pressure. Since there are many side reactions, this is a great advantage as compared with a case where a hydrolysis reaction cannot be performed at 100 ° C. or more under pressure.

In the present method, it is possible to carry out the hydrolysis reaction of kasugamycin under a considerably high pressure at a high reaction temperature of 120 ° C. to 150 ° C., which makes it possible to carry out the hydrolysis at a normal pressure. Can also reduce the reaction time to about 1/4. This is very economically advantageous when viewed as an industrial production process.

After the completion of the hydrolysis reaction of kasugamycin, the whole reaction mixture is cooled to or near room temperature, and the acidic reaction solution is separated from the strongly acidic ion exchange resin by filtration or centrifugation. Next, the remaining resin is washed with water, preferably 0.8 to 1 times the amount of water.

By this water washing, the residual D-
Since kilo-inositol can be eluted, the obtained washing water contains the eluted neutral sugars (this water washing can be omitted if desired, but if omitted, D-kilo-
The final yield of inositol may be reduced somewhat).

This washing water is an acidic reaction solution (containing D-kilo-inositol) separated from the resin obtained earlier.
To obtain an acidic mixture.

Next, in order to neutralize the mixture, the mixture is passed through a column packed with a basic ion exchange resin (OH ^- type) (either strong or weak basic). In this case, the flow rate of the mixed solution through the basic ion exchange resin column is preferably equivalent to a liquid volume of 1 to 3 times the resin volume per hour.

The basic ion exchange resin used here is prepared by packing a predetermined amount of resin into a column and treating it with an aqueous alkali solution such as 1 to 3 N sodium hydroxide several times the amount of the resin. OH ^- type.

The basic ion-exchange resin used (OH ^-
Type) is an ion exchange resin containing a quaternary ammonium group as a functional group, for example, Duolite A-113PL
US (Sumitomo Chemical Industries) and Amberlite-IRA
410 (manufactured by Organo Corporation).

By passing the solution through this basic ion exchange resin column, the contained hydrogen chloride or sulfuric acid is neutralized, but a small amount of acidic substance produced as a by-product in the hydrolysis reaction of kasugamycin coexists. Together with the inorganic acid.

The neutralized eluate flowing out of the basic ion-exchange resin column is concentrated under reduced pressure to a concentrated aqueous solution. Inositol can be precipitated as crystals.

In the first method of the present invention, a step of obtaining a neutral eluate containing D-kilo-inositol from a column packed with a basic ion exchange resin (OH ^- type) is carried out. The packed column of the ion-exchange resin is washed with water, whereby the D-kilo-inositol remaining in the resin is eluted to obtain washing water containing the same, and the washing water is mixed with the aforementioned D-kilo-inositol. Into an aqueous eluate,
It can be modified to additionally perform the step of concentrating the combined liquid to precipitate crystals of D-chiro-inositol. Such modified implementations are illustrated in Examples 1-2 below.

Although the first method of the present invention is carried out using purified or prepurified hydrochloride or sulfate of kasugamycin, prior to the step of hydrolysis of kasugamycin, the method is carried out first. Impurity kasugamycin (in the form of free base) is adsorbed on a strongly acidic ion exchange resin using a raw material containing impurities as a raw material, and then washed with water,
By doing so, a step of removing impurities is performed, and then a new (0.1-0.5N) hydrochloric acid or sulfuric acid is added and heated to thereby hydrolyze the kasugamycin bound to the resin. Can be modified. By using this modified method, it is possible to produce D-chiro-inositol even when crude kasugamycin containing a large amount of impurities, such as an unpurified culture solution obtained by fermentation production, is directly used as a raw material.

As a result of further studies, the present inventor has found that, unlike the method of the first invention, when granular particles of a strongly acidic ion exchange resin are packed in a column and used, kasugamycin hydrochloride or When an aqueous solution of sulfate is continuously introduced and passed, and the kasugamycin salt is bound to the resin under warming conditions to release 0.05N to 0.5N HCl or sulfuric acid in the column-passing solution, the acid hydrolysis of kasugamycin occurs. It has been found that the decomposition reaction can be allowed to proceed, whereby D-kilo-inositol can be efficiently and continuously produced (column method).

Therefore, according to the second aspect of the present invention, an aqueous solution of kasugamycin hydrochloride or sulfate is continuously introduced into a column packed with particles of a strongly acidic ion exchange resin (H ⁺ type) under heating conditions. Through which the kasugamycin molecule is bound in the form of an addition salt to the strongly acidic functional groups of the strongly acidic ion exchange resin in the packed column, with the concomitant release of the kasugamycin from hydrogen chloride or sulfuric acid in the form of an addition salt. reaction and produced in the resin column effluent at a concentration of 05N～0.5N, hydrogen chloride the permeate flows down through the column while in contact with <br/> strong acid ion-exchange resin that combines kasugamycin Alternatively, the reaction of hydrolyzing kasugamycin under the action of sulfuric acid to produce D-chiro-inositol occurs in parallel in the flow-through of the column, and continuously flows out of the column to give D-kilo-inositol. Obtaining an effluent containing kilo-inositol and hydrogen chloride or sulfuric acid as an acidic reaction solution;
Next, the acidic reaction solution is mixed with a basic ion exchange resin (OH
⁽ -Type) through a packed column to obtain a neutral eluate containing D-kilo-inositol coming out of the column, and further concentrating the eluate to precipitate crystals of D-kilo-inositol. The method for producing D-kilo-inositol is provided.

The residence time of the aqueous solution of the kasugamycin salt through a column packed with a strongly acidic ion exchange resin ( H ⁺ type) and the liquid passing through the column during the reaction is 6 to 15 hours, preferably 8 to 15 hours.
Except that the flow rate of the passing solution in the column is adjusted to 12 hours to carry out the kasugamycin hydrolysis reaction,
The method of the second invention can be carried out in the same manner as the operating conditions of the method of the first invention. The second embodiment of the present invention will be described later with reference to a third embodiment.
Is exemplified.

The strongly acidic or basic ion exchange resin used in the method of the present invention can be recycled by regenerating with an aqueous alkali or acid solution. The amount of acid and alkali used for hydrolysis reaction and resin regeneration can be reduced to about one third of the amount used in the conventional method of decomposing kasugamycin with a strong acid, and the equipment can be small,
Also, labor such as disposal of waste water is greatly reduced.

Next, the present invention will be described specifically with reference to examples.

Example 1 (Normal Pressure Batch Method) 20 g of kasugamycin hydrochloride was weighed into a 500 ml eggplant-shaped flask, and 100 ml of water was added to dissolve the solution to obtain an aqueous solution. Use this as a strongly acidic ion exchange resin [Diaion S
K116 (H ⁺ type) (manufactured by Mitsubishi Kasei)] (Two times the amount of 2N hydrochloric acid is added to a commercially available resin and mixed well to adjust the resin to the H ⁺ type until the pH of the washing solution becomes 5 or more. (Washed resin) 150 ml was added and mixed well. The entire mixture (solution phase HCl concentration 0.15 N, pH 1.1)
5) was heated on an oil bath at 95 ° C. for 12 hours to perform a hydrolysis reaction of kasugamycin.

After cooling the entire reaction mixture, the ion-exchange resin was separated by filtration to obtain a solid residue and a filtrate. The resin was washed with 150 ml of water.

About 250 ml of an acidic mixed solution obtained by combining the washing solution and the filtrate (reaction solution) is mixed with a strongly basic ion exchange resin [ Duolite A-113PLUS (Sumitomo Chemical Industries)].
(OH ^- type) (2N-Na twice as much as commercial resin)
OH solution was added and mixed well to make the resin OH ^- type, and the resin was washed with water until the pH of the washing solution became 8.5 or less) 100
The mixture is placed on a packed column (25 mm in inner diameter, 310 mm in length) and passed through the column at a flow rate of 100 ml / hr for neutralization. Further, the resin is washed with the same volume of water as the resin in the column. 350 ml of a mixed solution of the obtained eluate and washing water was heated at 60 ° C. under reduced pressure.
To about 40 ml. Ethanol 36 was added to this concentrate.
0 ml was added.

After the precipitation of the crystals, they were separated by filtration to obtain 7.4 g of crude crystals (yield 89%). Further, this was recrystallized from 250 ml of a mixture of ethanol and water (9: 1),
6.8 g of colorless crystals of kilo-inositol were obtained (yield: 8).
2%).

The analytical values and physical properties of the crystals were as follows. Appearance: colorless crystals Melting point: 238 ° C. Liquid chromatographic analysis: showed a single peak.

Analysis conditions: Column: ZORBAX-NH ₂
(4.6 × 250) Detector: Shodex RI SE-51 Solvent: 80% MeCN-H ₂ O Flow rate: 2.5 ml / min [α] _D (23 ° C.): + 65 ° (c 1.0, H ₂ O)

From the above, it was confirmed that the colorless crystals were pure D-kilo-inositol.

Example 2 (Pressurized batch method) 20 g of kasugamycin hydrochloride was weighed into a 300 ml glass flask for autoclave, and 100 ml of water was added to dissolve the solution to obtain an aqueous solution. To this, a strongly acidic ion exchange resin [Diaion SK116 (manufactured by Mitsubishi Kasei)] (H ⁺
(Type) (preparation of resin is the same as in Example 1) 150 ml was added and mixed well. The solution phase of the resulting mixture contained 0.15N HCl and exhibited a pH of 1.15.

The flask containing the above mixture was placed in an autoclave, and heated at 120 ° C. for 3 hours under a gauge pressure of 1.2 kg / cm ² to hydrolyze kasugamycin. The subsequent operation was performed in the same manner as in Example 1 to obtain 7.7 g of crude crystals (yield 92.5%). Example 1
The crystals were recrystallized according to the above to give 7.42 g (yield: 89.1%) of colorless crystals of D-chiro-inositol.

Example 3 (Column method) 150 ml of a strongly acidic ion-exchange resin DIAION SK116 (H ⁺ type) packed in a glass column installed in an oven set at 95 ° C. (manufactured by Mitsubishi Kasei) 20 g of kasugamycin hydrochloride was added to 10 parts of a resin prepared in the same manner as in Example 1 (column inner diameter: 30 mm, length: 310 mm).
An aqueous solution dissolved in 0 ml of water was placed thereon and passed through the column at a flow rate such that the solution passed in about 12 hours to hydrolyze kasugamycin. The effluent from the column was collected, and then the column was washed with water. Both the effluent and the washing water are combined and cooled, and 250 ml of the mixture is put into a packed column of 100 ml of a strongly basic ion exchange resin [ Duolite A-113PLUS , OH ^- type] (prepared in the same manner as in Example 1). Neutralized for about 2 hours. After obtaining the eluate from the Duolite A-113PLUS column, the column was washed with water, and the washed solution was combined with the eluate. The obtained mixture was concentrated under reduced pressure at a temperature of 60 ° C. or lower to about 40 ml. 360 ml of ethanol was added to the concentrated solution to precipitate crystals, and the crystals were separated by filtration to obtain 7.9 g of crude crystals (yield: 95%). The crude crystals were recrystallized from 300 ml of a mixture of ethanol and water (9: 1) to obtain 7.74 g of colorless crystals (93% yield).

The analytical values and physical properties of the D-kilo-inositol crystals obtained in this example were identical to those in Example 1.

Comparative Example 1 Kasugamycin was hydrolyzed according to the method described in US Pat. No. 5,091,596.

That is, 22 g of kasugamycin hydrochloride was dissolved in 110 ml of 5N hydrochloric acid. The solution (pH value <
0.2) was reacted at 90 ° C. for 8 hours, and the reaction solution was diluted with water 0.17.
1 diluted. In order to neutralize the acidity of the diluent and remove unreacted kasugamycin and the like, 300 g of a strongly acidic ion exchange resin and a strongly basic ion exchange resin [Amberlite-IR]
120, H ⁺ type and Amberlite-IRA 410,
OH ^- type (individually 2N- hydrochloric acid respectively, 2N- treated with caustic soda, each H ⁺ form and OH ^-. Type and was passed through a column packed column Resin hybrid bed prepared in neutral The flow-through was collected, the column was washed with water, 850 ml of a mixture of the wash water and the flow-through was treated with 1.7 g of activated carbon at 5 ° C. for 2 hours, decolorized, and concentrated to dryness to obtain a D-kilo-m. 7.6 g of crude powder of inositol (81.5% yield) was obtained.

The subsequent operation was carried out in the same manner as in Example 1 to obtain 7.2 g of a crystal (yield: 78.5%).

Comparative Example 2 The method of Comparative Example 1 was repeated using 0.1N hydrochloric acid instead of 5N hydrochloric acid, and the pH value of the reaction solution was 1.78.

No D-kilo-inositol was produced in the reaction solution (analyzed by liquid chromatography).

Comparative Example 3 The method of Comparative Example 1 was repeated using 1N hydrochloric acid instead of 5N hydrochloric acid, and the pH value of the reaction solution was 0.87.

The yield of D-chiro-inositol in the reaction mixture was 34.4% (analyzed by liquid chromatography).

[0059]

According to the present invention, D-kilo-inositol can be produced from kasugamycin under very mild acidic conditions with high yield, high purity and almost no side reaction. In the case of large-scale production, the use of strong acids does not require the use of a small amount of ion-exchange resin for neutralization, and thus the power consumption for treating wastewater and distilling water is greatly reduced. In addition, there is a great advantage in that the capacity of the production equipment per unit yield can be reduced to about 1/3.

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Kiyoshi Hirasawa 3-8 Morinosato, Atsugi-shi, Kanagawa Prefecture (72) Inventor Tomio Takeuchi 5-1-1-11 Higashi-Gotanda, Shinagawa-ku, Tokyo 701 (56) References JP-A-3-11026 (JP, A) JP-A-61-56142 (JP, A) JP-A-56-138125 (JP, A) JP-B-37-18476 (JP, B1) (58) (Int.Cl. ⁷ , DB name) C07C 29/09 C07C 29/76 C07C 35/14 C07C 35/16

Claims (5)

(57) [Claims] An aqueous solution of kasugamycin hydrochloride or sulfate is mixed with granules of a strongly acidic ion exchange resin (H ⁺ type) to form kasugamycin molecules in the form of an addition salt to a strongly acidic functional group of the strongly acidic ion exchange resin. To reduce the amount of hydrogen chloride or sulfuric acid released from kasugamycin by 0.0
A mixture of an aqueous solution of hydrogen chloride or sulfuric acid containing a concentration of 5N to 0.5N, preferably 0.15N to 0.2N, and granules of the strongly acidic ion exchange resin bound to kasugamycin is formed, and this mixture is formed. Heating is carried out under normal pressure or under pressure to carry out a hydrolysis reaction of kasugamycin, in which D-kilo-inositol is released from kasugamycin to form an acidic reaction solution containing D-kilo-inositol and hydrogen chloride or sulfuric acid. After completion of the reaction, the whole reaction mixture is cooled, and the acidic reaction solution is separated from the resin,
The resin is washed with water to elute D-kilo-inositol remaining in the resin, and the obtained washing water containing the eluted D-kilo-inositol is combined with the reaction solution to form an acidic mixed solution. The acidic mixture was passed through a column packed with a basic ion exchange resin (OH ^- type) to obtain a neutral eluate containing D-kilo-inositol from the column, and then the eluate was concentrated. And producing crystals of D-kilo-inositol. 2. The method according to claim 1, wherein the hydrolysis of kasugamycin is carried out at a temperature of 50 to 98 ° C. for 6 to 40 hours under normal pressure. 3. The hydrolysis of kasugamycin is carried out under a pressure sufficient to inhibit boiling of water in the reaction mixture.
The method according to claim 1, which is performed at a temperature of 0 to 150 ° C for 1.0 to 10 hours. 4. The basic ion-exchange resins ^- a packed column of (OH type) D-km - after the step of Shutoku eluate neutral containing inositol, a packed column of said basic ion exchange resin The resin was washed with water, thereby eluting D-kilo-inositol remaining in the resin to obtain washing water containing the same. The washing water was combined with the neutral eluate containing D-kilo-inositol. The method according to claim 1, wherein the method further comprises a step of concentrating the combined mixture to precipitate crystals of D-chiro-inositol. 5. An aqueous solution of kasugamycin hydrochloride or sulphate is continuously introduced under warming conditions through a packed column of granules of strongly acidic ion exchange resin (H ⁺ type) and passed therethrough. To the strongly acidic functional groups of the strongly acidic ion exchange resin in the packed column in the form of an addition salt, and the resulting hydrogen chloride or sulfuric acid released from kasugamycin at a concentration of 0.05N to 0.5N. reaction and produced in the resin column effluent during and a kasugamycin under the action of the passing liquid flow down to hydrogen chloride or sulfuric acid through the column while in contact with strong acid ion-exchange resin bound kasugamycin was hydrolyzed A reaction for producing D-kilo-inositol occurs in parallel in the flow-through of the column, and D-kilo-inositol continuously flowing out of the column and chloride water Or Shutoku the effluent containing sulfuric acid as the reaction solution acidic and then the acidic reaction solution basic ion exchange resins ^- through a packed column of (OH type) exiting from the column D- km - inositol A neutral eluate was obtained, and the eluate was further concentrated to D-kilo-
D. depositing inositol crystals.
-A process for the production of kilo-inositol.