JP2685514B2 - Process for producing inorganic acid salt of disulfide type thiamine derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to an industrially advantageous method for producing an inorganic acid salt of a disulfide-type thiamine derivative known as active vitamin B ₁ .

2. Description of the Related Art Disulfide-type thiamine derivatives are basic substances and generally react with an inorganic acid to form a salt. For example, thiamine tetrahydrofurfuryl disulfide is commercialized as a monohydrochloride.

Until now, the method for producing the inorganic acid salt of the disulfide-type thiamine derivative has been to dissolve the raw material base in an organic solvent, then to treat with an acid, and after the completion of the reaction, concentrate the reaction solution and cool it to crystallize the salt. It is common to crystallize the salt by adding solvent 2 (poor solvent). For example, a method in which a raw material base is dissolved in an alcohol such as ethanol and then treated with an acid to form a salt (Japanese Examined Patent Publication No. 14-14390, Japanese Examined Patent Publication No. 41-1).
6174, Japanese Patent Publication No. 39-11387).

However, these methods are not necessarily industrially advantageous in terms of yield and product stability, in addition to complicated operations for recovering salts and solvents.

Structure of the invention The present inventors, as a result of studying a method for producing an inorganic acid salt of an industrially advantageous disulfide-type thiamine derivative,
We have established a manufacturing method that is easy to operate and has a high processing capacity and a high recovery rate of the formed inorganic acid salt.

That is, the present invention is to disperse a disulfide-type thiamine derivative in an organic solvent in which the disulfide-type thiamine derivative and the inorganic acid salt thereof are difficult to dissolve, and to act an inorganic acid on the suspension. It is a method of producing salt.

As the reaction solvent of the present invention, an organic solvent in which both the starting disulfide-type thiamine derivative and the target salt are insoluble is used. More preferably, the disulfide-type thiamine derivative is slightly soluble,
As the salt of the derivative, a salt having a lower solubility can be mentioned. Specifically, an organic solvent in which the solubility of the starting base and its salt (20 ° C.) is about 5 g or less, preferably about 2 g or less with respect to 100 ml of the solvent is used. For example, in the case of producing the hydrochloride thereof from thiaminetetrahydrofurfuryl disulfide, examples of the solvent include isopropanol and acetone, and acetone is particularly preferable. For other disulfide-type thiamine derivatives and salts thereof, the above-mentioned soluble organic solvent may be appropriately selected and used. However, the solvent used in the present invention must be a solvent which is inert to both the derivative and the salt, and examples of such solvents include ketones such as acetone, methyl ethyl ketone and cyclohexanone, and alcohols such as isopropanol and butanol. Examples thereof include ketones, and among them, ketones are preferable.

In the method of the present invention, first, the raw material base is suspended or dispersed in the above organic solvent. The concentration of the suspension / dispersion is usually about 50 to 150 parts by weight of the raw material base with respect to 100 parts by weight of the solvent. Next, an inorganic acid is added to such a suspension / dispersion liquid to cause a reaction. Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, phosphoric acid and the like. The solid form is added in the form of an aqueous solution. The amount of the acid used is 1 to 1.1 times mol with respect to 1 mol of the raw material base. When the acid is gradually added, heat is generated with the progress of the reaction, and the reaction solution temporarily becomes transparent. During the reaction, constantly cool it so that the reaction temperature does not rise above 30 ° C. In particular, after the reaction solution became transparent once, the reaction solution was gradually cooled to 10 to −
By keeping the temperature at 10 ° C, the generated inorganic salt can be completely precipitated as crystals. After the crystallization, if necessary, a solvent may be further added to improve the dispersed state of the crystals. The precipitated crystals can be collected by filtration, washed with water or acetone, and dried to obtain the desired inorganic acid salt of the disulfide-type thiamine derivative in a high yield.

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

Example 1 Preparation of Cyamine Tetrahydrofurfuryl Disulfide Hydrochloride Cyamine Tetrahydrofurfuryl Disulfide 56.8
g was added to 41 g of acetone with stirring to give a suspension, which was cooled to 0 ° C. When 15.3 g of 35% hydrochloric acid (molar ratio 1.03) was gradually added to this cooling liquid, the liquid temperature rose and became a transparent liquid. When the liquid was gradually cooled, white crystals were precipitated. The crystals were suction filtered and washed with acetone. After vacuum drying, 58.5 g (yield 94.4%) of the intended thiaminetetrahydrofurfuryl disulfide hydrochloride was obtained. This had an HPLC purity of 99.7% and a color tone of 0.072.

The HPLC purity and color tone were measured by the following methods.

HPLC column: Nucleosyl C ₁₈ (5μ) Mobile phase: 0.005MC ₇ H ₁₅ SO ₃ Na, 1% AcOH: CH ₃ OH: CH ₃ CN ＝ 675: 195: 130 Column temperature: 50 ℃ Detection wavelength: UV ₂₅₄ nm Color tone Dissolve 1 g of the target substance in 10 ml of 1 / 2N hydrochloric acid and measure A ₁ cm (400 nm).

Example 2 Preparation of Cyamine Tetrahydrofurfuryl Disulfide Hydrochloride Cyamine Tetrahydrofurfuryl Disulfide 56.8
g was added to 57 g of isopropanol with stirring to suspend, and the mixture was cooled to 0 ° C. 35% hydrochloric acid 16.5g (molar ratio 1.0
When 5) was gradually added, the reaction proceeded, the liquid temperature rose, and a transparent liquid was obtained. At this point, the reaction solution was cooled to precipitate white crystals. The crystals are suction-filtered, washed with isopropanol, and dried in vacuum to obtain the desired product, thiamin tetrahydrofurfuryl disulfide hydrochloride 5
9.0 g (yield 95.2%) was obtained. The purity and color tone of this product were as follows.

HPLC purity 99.5% Color 0.084 Example 3 Preparation of thiamin propyl disulfide hydrochloride 40 g thiamin propyl disulfide is added to 80 g acetone and cooled to 0 ° C. and suspended with stirring, to which 35%
Hydrochloric acid 12.2 g (molar ratio 1.04) was added.

The reaction solution once became a uniform solution, and then crystals were solidified and deposited. Cold acetone was added to this to solidify the crystals, which were then slurried, suction filtered, and washed with acetone. Cyamine propyl disulfide hydrochloride 40.8 when dried under vacuum
g (yield 92.5%) was obtained.

HPLC purity 99.5% Color 0.081 Comparative example 1 Cyamine tetrahydrofurfuryl disulfide 56.8
After dissolving g in 400 ml of methanol, 15.3 g of 35% hydrochloric acid
(Molar ratio 1.03) was gradually added and reacted. After completion of the reaction, 360 ml of methanol was distilled off under reduced pressure, the concentrated solution was suction filtered, washed with methanol and dried in vacuum to obtain the desired product, thiamin tetrahydrofurfuryl disulfide hydrochloride monohydrate 45.4 g (yield 70.2%) was obtained. The purity and color tone of this product were as follows.

HPLC purity 99.5% Color tone 0.078 Effect of the Invention According to the method of the present invention, the recovery operation of the inorganic acid salt and solvent of the disulfide-type thiamine derivative, which is the reaction product, is easy and the recovery rate is extremely high, and the purity thereof is high. Since it is also high, it is extremely useful as an industrial method for producing an inorganic acid salt of a disulfide type thiamine derivative.

Claims (2)

(57) [Claims] 1. A disulfide-type thiamine derivative and its inorganic acid salt are suspended in an organic solvent whose solubility (20 ° C.) is 5 g or less per 100 ml of solvent, and an inorganic acid is allowed to act on the suspension. A process for producing an inorganic acid salt of a disulfide-type thiamine derivative, which comprises: 2. The method according to claim 1, wherein the organic solvent is isopropanol or acetone.