WO1992012138A1

WO1992012138A1 - Process for producing disulfide derivative of thiamine

Info

Publication number: WO1992012138A1
Application number: PCT/JP1990/001742
Authority: WO
Inventors: Katsuji Shimizu
Original assignee: Takeda Chemical Industries, Ltd.
Priority date: 1990-12-28
Filing date: 1990-12-28
Publication date: 1992-07-23

Abstract

An industrially advantageous process for producing a thiamine of disulfide form or its derivative, which comprises mixing a compound of the general formula R1SSO3M (wherein R1 represents an optionally substituted alkyl or aralkyl group, and M represents ammonium, alkali metal or alkaline earth metal) and a compound of general formula (I) (wherein R2 represents hydrogen, alkyl, aralkyl or ester residue) with an alkali in an aqueous solvent.

Description

Harm

Disulfide-type samine

^ Technical field

The present invention relates to a novel method for producing a disulfide-type thiamine or a derivative thereof useful for medicines and the like.

Background art

Many methods have been known for producing disulfide-type thiamine derivatives.

As a typical example, a method is proposed in which a thiosulfate-type melamine derivative is allowed to act on a thiol-type thiamine derivative (Japanese Patent Publication No. 35 1 4 2 26, Japanese Patent Publication No. 4 18-33) Japanese Patent Application Laid-Open (JP-A) No. 61-2522170).

This conventional method requires a process for producing a thiol-type thiamine.In particular, when the reaction is carried out in the presence of an aqueous solvent, the product becomes a candy and is difficult to recover. Even if it was obtained as ft, it had the S point that the yield was quite good.

An organic thioacid mercury butting agent is exposed to S by causing thioacid to act on an organic halide (for example, a bromo compound). For this reason, a merkabuting agent is often used solely and industrially, exclusively from the tangled haptic compound of ::. However, the method of producing a disulfide-type thiamine conductor using this organic thio-W acid-rich mercaptolating agent failed to obtain a target product in a very high yield.

On the other hand, a method for producing thioic acid: a method for producing an organic thioic acid: mercaptotizing agent, wherein thiosulfuric acid is allowed to act on a sulfonate of alcohols (Japanese Patent Publication No. 40-237886). It is described that this is generally used as one of the reagents for introducing an organic thio group, and it can be reacted with, for example, a thiol-type thiamine to obtain an asymmetric thyamine disulfide BI conductor.

However, there is no report of producing a disulfide-type sineamine SI conductor using the organic thiosulfuric acid-rich mercaptotizing agent.

In addition, in the conventional method for producing disulfide-type thiamine ^ conductors, in order to stably separate and antagonize the product, a water-soluble solvent such as chloroform is used as a reaction solvent. A two-phase system is used.

However, from the viewpoint of recent environmental pollution, the use of organic solvents is often unfavorable for industrial production due to wastewater treatment problems and worker health concerns. In addition, if an organic solvent is used industrially, there is a problem that equipment for collecting the solvent is required. Disclosure of the invention

As described above, the conventional technology requires a step of obtaining a thiol-type thiamine during the production process, and in particular, when using an aqueous solvent, what is a production method that can be applied to industrial religion? It was something I couldn't do.

Therefore, there is a demand for the development of a safe production method capable of obtaining a stable disulfide-type thiamine with a good yield.

In order to solve the above-mentioned problems, the present inventors used an organic thiosulfate compound as a merkato stimulus, and reacted the thiosulfate compound by gradually combining it with thiamine clay and alkali. However, they have found that extremely stable, highly pure thiamine disulfide conductor can be obtained in high yield.

The present inventors have found that when reacting a thiamine clay with a thiosulfate-type mercaptotizing agent, the reaction wave is subjected to a filtration such as a filtration method such as an inorganic salt at the end of the reaction. It has been found that the reaction yield can be further dramatically improved if it is present in an amount.

That is, the present invention has a general formula

R ^ S OaM (I)

[R ¹ represents an alkyl or aralkyl group which may be removed, M represents ammonium, an alkali metal or an alkaline earth metal, and a compound represented by the general formula and

[R ² represents a hydrogen, alkyl, aralkyl or ester group. A method for producing a disulfide-type thiamine or a derivative thereof, which is characterized in that a compound represented by the formula: The merkabutation of an organic thiosulfate compound used in the present invention can be obtained by reacting an alcoholic sulfonic acid ester with a thiosulfate. The sulfonic acid ester of alkenyl is of the general formula

R then OS 0 ₂ -R '(Ι')

(In the formula, R ¹ represents alkyl or aralkyl which may be g-substituted, and R 'represents alkyl, aralkyl or aryl which may be E-substituted.)

Can be represented by

The alkyl represented by R ^1, a straight-鍰状or branched charcoal vegetable number 1-6 is normally used. For example, methyl, ethyl, propyl, isopropyl, butyl, Examples include alkyl groups such as isobutyl, pentyl, isopentyl and the like.

As the aralkyl, those obtained by substituting a lower group (carbon ring system or ring system) with a lower alkyl group having 1 to 4 carbon atoms are used. For example, aralkyl groups such as benzyl and phenyl can be exemplified.

These alkyl groups and aralkyl groups include amino, carboxyl, and hydroxy, for example, acetylamino, benzoylamino, benzenesulfonylamino, toluenesulfonylamino, and other acylamino groups such as methoxyamino, ethoxyamino, bu-poxyamino, and isopropoxy. Alkoxyamino groups such as amino and butoxyamino; alkylthio groups such as methylthio, ethylthio, propylthio and butylthio; and acylthio groups such as acetylthio, benzoylthio and benzenesulfonylthio; acetyloxy, benzenesulfonyloxy and toluenesulfonyloxy; An alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy or the like; It may be substituted with a heterocyclic substituent such as an alkoxycarbonyl group or a furyl group or a tetrahydrofuryl group bonded to a sil group.

As the alkyl group represented by R ′, for example, a lower alkyl group of ethyl, butyl pill, and isopropyl koto, preferably an alkyl group of 1 to 6 carbon atoms, and preferably an alkyl group of 2 to 4 carbon atoms for S Is done.

As the aralkyl group, an aromatic group (a carbocyclic or heterocyclic system) obtained by scooping a lower alkyl group having 1 to 4 carbon atoms or the like is used. For example, aralkyl groups such as benzyl and phenyl can be used.

Further, examples of aryl groups include aryl groups such as phenyl.

These groups may also have an appropriate substituent. Examples of the substituent include halogens such as nitrogen and bromine, and alkyl groups such as methyl, ethyl, propyl, and isobrole.

Among the rubbery sulfonic acid esters of alcohols used in the present invention, esters in which R 'is a lower alkyl, particularly methyl, have the advantage that the reaction with thiosulfate proceeds smoothly even in water. Examples of such a substance include methanesulfonic acid ester of tetrahydrofurfuryl alcohol and methanesulfonic acid ester of propyl alcohol.

The reaction between the sulfonic acid ester of alcohols and thiosulfate (for example, sodium chloride, sodium salt, potassium salt, ammonium salt, calcium salt, magnesium salt, etc.) For example, the method may be performed by using the method described in Japanese Patent Publication No. 40-23776. That is, in water or an aqueous nucleated solvent (such as alcohols and acetates as organic solvents), thiosulfate was also added at about 1 to 2 times the molar amount of the compound (Γ). And react with stirring.

The reaction is usually completed in 1 to 10 hours.

The general formula

R ^l SSO _s M (I)

(R ¹ is as defined above, M is Al-metal, Al-Zuium or Al-earth metal)

A thiosulfate compound represented by the formula is formed.

Further, the organic thiosulfate merkabut agent (I) can also be obtained from an organic halide compound as in the above-mentioned conventional method.

In the present invention, this compound (I) is used as a merbutating agent.

Compound (I) can be once isolated from the reaction solution and dissolved in water for the next reaction, but the reaction solution is usually used as it is or the organic solvent is removed from the reaction. Can be used.

The other raw material used in the present invention is represented by the general formula

| H, C CBsOS ¹

2C

[R ² represents hydrogen, an alkyl group, an aralkyl group or an ester residue. ].

Alkyl and Ararukiru group represented by R * have the same meanings as R ¹ above. Examples of the ester include lower aliphatic organic acid residues which may have fi conversion, such as acetyl, propyl, 5-aminopropionyl, succinoyl. Aranyl, substituted oxycarbonyl such as ethoxycarbonyl, and the like. Examples thereof include an inorganic acid residue such as phosphoric acid and sulfuric acid, which may have a substituent on nitrogen. one

In the production method of the present invention, the compound (I) and the compound (III) are gradually combined with an alkali coating such as sodium hydroxide in an aqueous solvent to thereby provide a diso-no-reactive thyamine or a target compound of the present invention.轱 ¾ of the conductor can be obtained.

The compound (10 may be added in the form of an aqueous solution or a solid, for example, a powdery substance as it is. When the compound (H) is used in an aqueous solution, an acid such as hydrochloric acid is added to adjust the pH to 0.5-2.0. It is preferable to keep the range.

As the compound (母), a crystallized mother used to obtain the crystal may be used. Compound (Π ) Itself may be produced by any known method.In any of the methods, the crystallization is carried out as the final step, and the base mother liquor for the separation of the target substance is used in the present invention. Can be used for the production method of disulfide-type thiamine or a derivative thereof. It is preferable that the crystallization matrix used be adjusted in pH as described above. As a specific production method of the compound (II), for example, a production method represented by the following formula can be mentioned. ce Η, -¾ U cy: _C H, +

(Each symbol is as defined above.)

This method can be carried out, for example, according to the method described in JP-B-26-37977.

As the reactor used in the present invention, any reactor may be used as long as it is generally used for a chemical reaction. For example, sodium hydroxide, a hydroxide reactor and the like are used. In the present invention, the above-mentioned compounds (I) and (II) are mixed with an alkali to be reacted to obtain a disulfide-type thiamine as a target substance or a derivative thereof.

This mixing operation is preferably performed gradually. The purpose of the gradual mixing in this way is to gradually bring the compounds (I) and (接触) into contact with an alkali to promote the reaction.

As this method, for example, the following method can be used, but it is not limited to this.

(1) The compound (ι> and-(n solutions are also gradually mixed with the alkali-mixed aqueous solvent.

(2) Slowly mix the three kinds of solutions of the compounds (I) and (B) and the alkaline solution.

③ Slowly mix the alkaline solution into the mixed solution of compounds (I) and (Π). In particular, in the case of (2), the pH of the reaction solution can be kept to some extent from the start to the end of the reaction, which is a preferable method for reaction control. Therefore, the mixing of the alkali is determined by the pH to be reacted, the pH of the compounds (I) and (π) to be gradually mixed, and the mixing speed.

In the case of (3), if a mixed solution of the compounds (∑) and (Π) is prepared in advance, the desired product can be obtained only by mixing the alkali solution, which makes the reaction control easy and industrially possible. It is advantageous for implementation. The aqueous solvent used in the present invention refers to water or a mixed solvent of water and an organic solvent. At this time, usable organic solvents include black form and methylene chloride. It is sufficient if the equivalent ratio of the alkali Z compound (Π) is 3 or more, but it is preferably in the range of 3.0 to 3.5.

The reaction temperature may be around 5 to 40 and around room temperature.

The reaction is preferably carried out at pH 9.0 or higher in the alkaline region.

Usually, even after the mixing of the raw materials is completed, by controlling the stirring operation under a certain condition (aging), a reaction product can be obtained in a high yield.

The reaction time may be appropriately selected according to the pH of the reaction solution and the temperature. In general, if the reaction is carried out at a reaction degree of 20 ± 2, including the above-mentioned ripening, the reaction should be performed for 5 to 11 hours at 119.5 for 10 to 30 hours, preferably 20 hours, and ρΗΙΟ for 3 to 7 hours. The reaction is carried out preferably for 4 to 6 hours, at pH 11 for 1.5 to 3 hours, preferably for 1.5 to 2.5 hours, and at pH 1.2 to 13 for 0.5 to 1.5 hours, preferably 0.5 to 1 hour. Will be However, if the reaction temperature is raised, the rush can be shortened accordingly.

Among them, the range of pH 10 to 11 is industrially preferable.

Specifically, the reaction model is shown by reaction method (1) as follows.

110 compounds (I solution, 10 ° C solution of compound (π) and an aqueous solution are simultaneously slowly mixed (dropped) with 37o water in the reaction vessel. Compound (I) solution is 30 minutes compound ([pi) solution terminates the mixture at 20 minutes閱. at this time, the p H is 10 ± 0.1 in the reaction mixture, the temperature is that unload control the mixing of alkali to maintain the 20 ± 2 _beta

After mixing is completed, the mixture is stirred for about 3 o'clock under the same ρΗ and temperature conditions, while controlling the addition of aluminum. After that, while controlling the addition of Al 2 O 3 so that the reaction solution becomes ρ Η 11 ± 0, 1, simmer for about 2 hours at the same ρ Η and temperature. Further, while controlling the addition of alkali so that the reaction solution becomes 1.5 ± 0 * 1, the reaction is carried out for about 0.5 hours under the same DH and temperature conditions, so that the disulfide-type samine or its disulfide is obtained in high yield. A conductor is obtained.

Mixing of the compounds (I) and (II) is carried out in such an amount that the equivalent ratio of the compound (I) is substantially or slightly equivalent.

Preferably, the compound (I) / (H) is in the range of 1 to L5, more preferably in the range of 1.1 to L.2 molar ratio.

The mixing speed may be set at an optimum speed based on the pH and temperature of the reaction solution.

For example, if the pH of the reaction solution is 10 ± 0.1 and the reaction temperature is 20 ± 2, 0.192 equivalent of (I) 11051 is 3.101 / 81 ^ and 0.167 equivalent of (11) IO OBI is 4 al / ain. It is performed by dripping at a speed of. Any method can be used as long as it is generally used. For example, a method of dropping a solution of the compounds (I) and (III) into the reaction vessel from separate nozzles or the like into the reaction vessel, or mixing and stirring (I) and (III) with a stirrer and immediately mixing There are a method of introducing the liquid into a reaction vessel, and a method of mixing using a spiral tube instead of a stirring device.

In addition, it is desirable to add a small amount of crystals of the target compound as seed crystals to the reaction solution in advance so as to promote crystallization of the product. The amount of addition may be appropriately determined depending on the size of the reaction system.

In addition, the presence of inorganic salts such as sodium chloride (eg, sodium chloride, potassium chloride, etc.) during the reaction in the form of S that saturates or supersaturates greatly increases the yield of the reaction product, and facilitates post-treatment. Things are obtained.

If inorganic salts are not added, or if an inorganic salt is added after the reaction, the resulting product may be a zirconia crystal from which it is difficult to obtain a product.

After completion of the reaction, the resulting crystals are passed through, washed with, for example, water, ethanol, acetone, or the like, and dried to obtain disulfide-type thiamine or a derivative thereof.

In addition, when the target material is dissolved in the black mouth form layer, the target material dissolves in the black mouth form layer. Neutralize and filter out the precipitated crystals. Next, it is washed with water, acetone, etc., and dried to obtain the desired product.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described more specifically by way of examples.

[Example 1〗

i) Production of Bunchi clay solution

Tetrahydrofurfuryl mesylate 36 <6> f and sodium thiosulfate pentahydrate 54 <4> s water 52 <2> l1 were added, and the mixture was reacted at 85-90 with stirring for 5 hours. After cooling, water was added to adjust the liquid volume to 11 µm (hereinafter simply referred to as Bunte salt).

ii) Production of thiamine citrate solution

Crystals of Siamin Clay Clay 5 6.49 were added to water to make 11 O ml.

m) Disulfide

Next, a mixed solution is prepared by adding seed (19) 19 to 58.7 ml of a 30% by weight aqueous sodium hydroxide solution.

While stirring the mixture, the Bunte salt solution and the thiamine hydrochloride solution were added dropwise at 15 to 20 over 30 minutes to react.

Another 30 minutes! After stirring, the precipitated crystals are suctioned, then washed with water and acetone. The reaction was carried out and dried in vacuo to give thiamine tetrahydrofurfuryl disulfide (TT FD) 51.19.

Yield 76.7% (theoretical yield based on siamine hydrochloride: the same applies hereinafter)

138-140 ° C

Its purity by HPLC was 97.2%.

The measurement conditions for HP LC are as follows.

Column: Nucleosil C ₁₈ (5 / i)

Mobile layer: 0.005MC ₇ H ₁₅ SO ₃ fia, l¾AcOH: CH ₃ OH: CH ₃ CN =

675: 195: 130

Column temperature: 50. C

Detection wavelength: UV 254nm

[Example 2]

i) Preparation of thiamine hydrochloride solution

Water is added to thiamine hydrochloride 56.4 ₉ to adjust to 11 Oml.

ii) Disulfide conversion

Sodium chloride 509 and seed crystals in 58.7 ml of 30% by weight aqueous sodium hydroxide solution

(Target product) Prepare a mixture to which 19 was added.

While stirring the mixture, 11 Oml of the same Bunte salt solution as in Example 1 and the above siamine hydrochloride solution were simultaneously dropped and mixed at 20 ± 2 ° C. for 30 minutes to cause a reaction. After further stirring for 30 minutes, the mixture was treated in the same manner as in Example 1 to obtain the desired product (TTFD) 61.09.

Yield 91.6% Melting point 138-140 ° C

The HPLC purity of this product was 99.0%.

[Example 3] 1.

i) Preparation of thiamine hydrochloride solution

Water is added to 56.4? Of thiamine hydrochloride to make up to 100ml, and then 35wt% hydrochloric acid is added to adjust the pH to 0.6.

ii) Disulfide conversion

Prepare a mixture of 58.7 ml of a 30% by weight aqueous sodium hydroxide solution and 50 g of sodium chloride and 1? Of a seed crystal (the target substance).

While the mixture is being stirred, 110 ml of the siamine hydrochloride solution and 110 ml of the same Bunte salt solution as in Example 1 are simultaneously dropped and mixed.

After dropping the siaamine hydrochloride solution in 20 minutes and the Bunte salt solution in 30 minutes, the mixture was stirred for 30 minutes and treated in the same manner as in Example 1 to obtain the target product (TTFD) 61.9 ?.

New Yield 92.9% Melting point 138-140 ° C

This product had an HP LC purity of 98.2%.

[Example 4]

While stirring an aqueous solution of sodium chloride 509 and seed crystal (the target substance) 19 and 37 ml of water, 100 ml of a thiamine hydrochloride solution prepared by the same method as in Example 3 and 110 ml of a Bunte salt solution as in Example 1 At the same time, and at the same time, a 40% by weight sodium hydroxide solution was added dropwise so that the reaction solution had a pH of 1 ± 0.1.

Drop the siaamine hydrochloride solution dropwise over 20 minutes and the Bunte salt solution over 30 minutes. After the addition was completed, the mixture was stirred for 90 minutes while maintaining the pH at 1 ± 0.1. At this time, the temperature was kept at 20 ± 2 ° C. Thereafter, the same treatment as in Example 1 was carried out to obtain a target product (TTF D) 62.79.

Yield 94.1% Melting point 138-140 ° C

This product had an HP LC purity of 98.0%.

[Example 5]

37 ml of water was added to 50 ml of sodium chloride and 1 seed crystal (of the target substance), and while stirring, 100 ml of the siamin hydrochloride solution produced by the same method as in Example 2 and 110 ml of the same Bunte salt solution as in Example 1 were added. While dropping, a 40% by weight sodium hydroxide solution was added so that the reaction solution became ρΗ10 ± 0.1.

At that time, the reaction temperature was 40 ± 2 ° C, and the dropping time of the sodium hydroxide solution was 1 hour. Thereafter, the mixture was stirred at the same temperature for 30 minutes and treated in the same manner as in Example 1 to obtain the target product (TTFD) 60.2.

Yield 90.4% Melting point 138-140 ° C

The HPLC purity of this product was 97.3%.

[Example 6]

While stirring 50 g of sodium chloride, seed crystals (target substance) 19 and 37 ml of water, 100 ml of the thiamine hydrochloride solution produced by the same method as in Example 3 and 110 ml of the Bunte salt solution produced by the same method as in Example 1 while stirring. Were added dropwise at the same time, and at the same time, a 30% by weight aqueous sodium hydroxide solution was added dropwise so that the reaction solution had a pH of 10 ± 0: 1. The siaamine hydrochloride solution was added dropwise over 20 minutes and the Bunte salt solution over 30 minutes. After completion of the addition, the mixture was stirred for 3 hours while maintaining the pH at 0 ± 0.1, for 2 hours at a pH of 0.1, and for 0.5 hour at a pH of 11.5 ± 0.1, while adjusting with an aqueous sodium hydroxide solution. At this time, the temperature was kept at 20 ± 2 ° C.

Thereafter, in the same manner as in Example 1, the target product (TTFD) 64.5 was obtained.

Yield 96.8% Melting point 138-140 ° C

The HPLC purity of this product was 99.0%.

镦

new [Example 7]

To a 58.7 ml of a 30% by weight aqueous solution of sodium hydroxide, sodium chloride 50 * and seed crystal (target substance) 1-were added. 110 ml of the same Bunte salt solution as in Example 1 was simultaneously added dropwise for 30 minutes, and the mixture was further stirred for 30 minutes, and then treated in the same manner as in Example 1 to obtain the desired product (TTFD) 59-3 ?.

Yield 89.0% Toshiki 138 ~: L40

This product had an HP LC concentration of 97.9%.

[Jeongjeon 8]

Sodium hainide 50 s, Seed crystal (target) lg, Thiaamine hydrochloride dissolved wave manufactured by the same method as in Example S 10 Oal. Bunte salt 110 Bl manufactured by the same method as in Example 1 was mixed.样A 30% by weight aqueous solution of sodium hydroxide was added to the mixed solution, and the mixture was added dropwise so as to have a pH of 10.

The Siamin HCl clay coating was added dropwise over 20 minutes, and the Bunte salt solution was added dropwise over 30 minutes. After the addition of both, the pH was maintained at 10 ± 0.1 for 3 hours, the pH at 0.1 for 2 hours, the pH at 11.5 ± 0, 0.5 for 0.5 hours, while adjusting with aqueous sodium hydroxide. Stirred. At this time, the S degree was kept at 20 ± 2 throughout.

Thereafter, in the same manner as in Example 1, 61.6 g of the target product (TTFD) was obtained.

Yield 92.596 points 138 ~ 140

The product had an HP LC purity of 98.5%.

[Example 9]

N- (2'-Methyl-4'-Amino-birimidyl 5 ')-Methyl-4'-Methyl-15' ^-Oxyxethyl-thiothiazolone 2. 8 parts with 50 parts of water and 10 parts of concentrated acid Dissolve and add 9% of 30% hydrogen peroxide under ice-cooling with stirring, and after anti-JK, add the water solubility of barium hanide until precipitation is no longer possible. Precipitate and remove the filtrate. When ethanol is mixed, crystals precipitate. When this is recrystallized from dilute ethanol, the hydrochloride salt of N- (2'-methyl-4'-amino-birimidyl 5 ')-methyl-4-methyl-5-1 / 5-oxexetyl-thiazolym chloride at sensitivity 250 (Siamin hydrochloride clay) 10 parts are obtained. (In the above, the parts indicate heavy :! parts.) In this way, while a ziamine ½ 酸 ¾ 粽 is obtained, a thiamine clay clay S out narrow is also used in the lower E step.

Add 37 g of water to 50 g of sodium chloride and 1 g of seed crystals (the target substance), and add 12 Oml (56.4 g as siamine hydrochloride) of the concentrated filtrate of thiamine hydrochloride crystallization filtrate while stirring and add the same mixture as in Example 1. The Bunte salt solution 11 OBI produced by the above method was simultaneously dropped and mixed, and at the same time, the reaction solution was added with a 30% by weight aqueous sodium hydroxide solution at pH 10 ± 0. Shen down to become one.

The siaamine clay solution was added dropwise over 20 minutes, and the Bunte salt solution was added dropwise over 30 minutes. In addition, after completion of both ports, 3 hours while maintaining DH10 ± 0.1, 2 hours at ρΗ11 ± 0,1 and 0.5 hours at pHl 5 ± 0.1, and haze with aqueous sodium hydroxide solution We stirred while knotting. At this time, the temperature was kept at 20 ± 2 throughout.

Then, in the same manner as in Example 1, 62.5 g of the target product (TTFD) was obtained.

Yield 93.8% Melting point 138 ~ 140

The HPLC bluntness of this product was 98.1%.

[Comparative Example 1]

To 140 nl of an aqueous solution containing thiamine hydrochloride crystals 56., 30% by weight of sodium hydroxide aqueous solution 56B1 was added dropwise with stirring at 15 to 20 over 30 minutes, and the reaction was continued at the same temperature for 30 minutes. A sodium salt solution of the thiol-type thiamine was obtained.

Next, 25 l of sodium chloride and 220 al of chloroform were added to 11 OBI of Bunte clay coating 11 described in Example 1, and the mixture was stirred for 30 minutes.

While maintaining this wave at 15 to 20, a sodium salt solution of thiol-type samine was added and stirred to carry out the reaction.

After the reaction is completed, the reaction wave is quenched, the form layer of the mouth is collected, and 12 Oml of form is newly added to the remaining aqueous layer, and the mixture is similarly collected.

Combine the p-form layers and extract twice with 120 ml of dilute hydrochloric acid and 8 OBI. The extract is

The mixture was neutralized by dropwise addition of an ammonia solution with stirring at 15 to 20 to precipitate crystals. The deposited right-colored crystals were suctioned, washed with water, and vacuum-dried at 50 to 60 to yield TTFD55.7.

Yield 83.6% »Point 138 ~ 140

The product had an HP LC purity of 98.8%.

[Comparative example 2]

Bunte clay solution prepared in the same manner as in Example 1 And a seed crystal (of the desired product) 19 were added thereto, and a sodium salt solution of thiol-type samine prepared in the same manner as in Comparative Example 1 was dropped over 50 minutes under vigorous stirring.

The reaction was carried out at 10 and the reaction was completed under vigorous stirring for another 30 minutes.

After suctioning out the precipitated white crystal, it was washed with water and dried under vacuum to obtain 48.6% of TTFD.

72.9% yield

The HPLC purity of this product was 88.2%. Sedentary availability

INDUSTRIAL APPLICABILITY The method for producing a disulfide-type thiamine or a derivative thereof according to the present invention is extremely industrially advantageous because the steps are simplified as compared with the conventional method, and the production control such as improvement of the production amount and quality is easy. Is the way.

In addition, the method can be carried out in a system that does not use an organic solvent. In that case, equipment such as solvent recovery is unnecessary, and the method is suitable for carrying out on an industrial level.

Claims

Range of sought

1) General formula

R! SSOe

[R ¹ represents an optionally substituted alkyl group or aralkyl group, and M represents ammonium, alkali metal or alkaline earth metal. ]

And a compound represented by the general formula

[R ² represents hydrogen. An alkyl group, an aralkyl group, or an ester residue. ] A method for producing a disulfide-type thiamine or a derivative thereof, which comprises mixing a compound represented by the formula

2) The production method according to claim 1), wherein the inorganic salt is reacted in a system in which the inorganic salt is in a saturated state or a saturated state.

3) The method according to claim 2, wherein the inorganic salt is sodium chloride.

4) The method according to claim 1, wherein the alkali is sodium hydroxide.

5) The general formula in an aqueous solvent mixed with Al

R »S SOsM

[R ¹ and M are the same as above. ]

And a compound represented by the general formula

[R ² is the same as above. ]

Claim 1) manufacturing method _c 6 according) formula for the mixing and in compound represented by the Toku徼

R ^X S S0 ₃ M

[R ¹ and M are the same as above. ]

And a compound represented by the general formula WO 92/12138 _ 1-PCT / JP90 / 01742

[R ² is the same as above. ]

The method according to claim 1, wherein the compound represented by the formula (1) and an alcohol are mixed in an aqueous solvent.

7) —General formula

R】 SSO _s M

[R ¹ and M are the same as above. ]

And a compound represented by the general formula

[R ² represents the same group as described above. Three

2. The method according to claim 1, wherein the solution is combined with an aqueous solution mixed with the compound represented by formula (1).

8) The method according to any one of claims 1) to 7), wherein the mixing operation is performed gradually.

9) The method according to claim 12, wherein the reaction is carried out in a system in which seed crystals of the target compound are present.

10) In the presence of an inorganic salt and seed crystals of the target compound, the general formula

R ^J SS OsM

[R ¹ and M agree with the above. ] And the general formula

[R ² represents the same group as described above. The method according to claim 1), wherein mixing the alkali solution with an aqueous solvent mixed with the compound of formula (1) is desired.

11) General formula

2. The process according to claim 1, wherein a crystallization mother liquor is used for obtaining crystals of the compound represented by the formula (1).