JPH03128363A - Preparation of disulfide type thiamine derivative - Google Patents

Abstract

PURPOSE:To simply prepare the subject stable compound in a high yield and in a high purity useful for drugs, etc., by gradually mixing and reacting an organic thiosulfate salt and an alkali preferably in the presence of an inorganic salt. CONSTITUTION:A compound of formula I [R<1> is alkali or aralkyl which may be substituted; M is ammonium or alkali(ne earth) metal] is gradually mixed and reacted with a compound of formula II (R<2> is H, alkyl, aralkyl or ester residue) and an alkali (e.g. NaOH) in an aqueous solution to prepare the subject compound. The addition of an inorganic salt (e.g. NaCl) to the reaction solution in such an amount as to be saturated with the inorganic salt after the reaction improves remarkably the reaction yield. As the reaction method, a mixture of the compounds of formulas I and II may be gradually mixed with the alkali solution or the alkali solution may be mixed with the mixed solutions, but the three components are preferably gradually mixed with each other.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a novel method for producing disulfide-type thiamines or derivatives thereof useful for pharmaceuticals and the like.

Regarding the conventional method for producing disulfide-type thiamine derivatives,
Many methods have been known so far.

As a representative method, a method has been proposed in which a thiol-type thiamine derivative is treated with an organic thiosulfate-type mercaptizing agent (Japanese Patent Publication No. 35-14226; Japanese Patent Publication No. 42-18633).
．． JP-A-6L-225170).

This conventional method requires a step to produce thiol-type thiamine, and especially when the reaction is carried out in the presence of an aqueous solvent, the product becomes a candy-like substance that is difficult to recover. Even if it could be obtained by crystallization, the yield was quite low.

An organic thiosulfate type mercaptizing agent can be easily obtained by reacting an organic halide (for example, a bromine compound) with a thiosulfate. For this reason, both in the laboratory and industrially, mercaptating agents made exclusively from organic halides are often used. However, this method for producing disulfide-type thiamine derivatives using an organic thiosulfate-type mercaptizing agent has not been able to obtain the target product in a very high yield.

On the other hand, as a method for producing organic thiosulfate-type mercaptizing agents, a method has also been proposed in which thiosulfate is reacted with a sulfonic acid ester of alcohols (Japanese Patent Publication No. 4 O-
23786). This product is generally used as one of the reagents for introducing an organic thio group, and it is described that an asymmetric thiamine disulfide derivative can be obtained by reacting with, for example, a thiol-type thiamine.

However, no report has been found on the production of disulfide-type thiamine derivatives using this organic thiosulfate-type mercaptizing agent.

In addition, in the production method of disulfide-type thiamine derivatives that has been widely used, a two-phase system of water and an organic solvent such as chloroform is used as the reaction solvent in order to stably separate and crystallize the product. .

However, in light of recent environmental pollution problems, the use of organic solvents is often undesirable for industrial production, such as wastewater treatment problems and worker health problems. Further, if organic solvents are used industrially, there are problems such as the need for equipment for recovering the solvents.

Problems to be Solved by the Invention As mentioned above, the prior art requires a step to obtain a thiol-type thiamine during the production process, or in particular uses an aqueous solvent. This cannot be said to be a manufacturing method like that.

Therefore, it is desired to develop a safe production method that can obtain stable disulfide-type thiamine with good yield.

Means for Solving the Problems In order to solve the above-mentioned problems, the present inventors used an organic thiosulfate compound as a mercaptizing agent and gradually mixed it with thiamine hydrochloride and an alkali.
When the reaction was carried out, it was found that extremely stable and highly pure thiamine disulfide derivatives were obtained in high yield.

The present inventors further discovered that when reacting thiamine hydrochloride with an organic thiosulfate type mercaptizing agent, an inorganic salt such as common salt is present in the reaction solution in an amount such that the inorganic salt is saturated at the end of the reaction. It was discovered that the reaction yield was further improved dramatically.

That is, the present invention has the following formula: ] Compounds represented by the general formula % formula % alkyl group.

Indicates an aralkyl group or an ester residue. ] The present invention relates to a method for producing a disulfide-type thiamine or a derivative thereof, which comprises mixing a compound represented by the following formula with an alkali little by little in an aqueous solvent.

The mercaptizing agent for an organic thiosulfate compound used in the present invention can be obtained by reacting an organic sulfonic acid ester of alcohol with a thiosulfate.

Organic sulfonic acid esters of alcohols are represented by the general formula %() (wherein R1 represents an optionally substituted alkyl or aralkyl, and R″ represents an optionally substituted alkyl, aralkyl, or aryl). be able to.

As the alkyl represented by R1, a linear or branched alkyl having 1 to 6 carbon atoms is usually used. Examples include alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and impentyl.

Further, as the aralkyl, those in which an aromatic group (carbocyclic ring system or heterocyclic ring system) is substituted with a lower alkyl group having 1 to 4 carbon atoms are used. For example, aralkyl groups such as benzyl and phenethyl can be mentioned.

These alkyl and aralkyl groups include amino, carboxyl, hydroxy, acylamino groups such as acetylamino, benzoylamino, benzenesulfonylamino, toluenesulfonylamino, etc., such as methoxyamino, ethoxyamino, propoxyamino, impropoxyamino, butoxyamino alkoxyamino groups such as methylthio, ethylthio, propylthio, butylthio, acylthio groups such as acetylthio, benzoylthio, benzenesulfonylthio, etc., such as acetyloxy, benzenesulfonyloxy,
Acyloxy groups such as toluenesulfonyloxy, alkoxy groups such as methoxy, ethoxy, propoxy, impropoxy, butoxy, or alkoxycarbonyl groups in which these alkoxy groups are bonded to carboxyl groups, or foreign groups such as furyl and tetrahydrofuryl groups. It may be replaced with an annular replacement valve or the like.

Further, as the alkyl group represented by Rl, for example, a lower alkyl group such as ethyl, propyl, H-soprovil, etc. is used, preferably an alkyl group having 1 to 6 carbon atoms, more preferably 2 to 4 carbon atoms.

As the aralkyl group, one in which an aromatic group (carbocyclic ring system or heterocyclic ring system) is substituted with a lower alkyl group having 1 to 4 carbon atoms is used. For example, aralkyl groups such as benzyl and phenethyl can be mentioned.

Furthermore, examples of the aryl group include aryl groups such as phenyl.

These groups may have appropriate substituents, and examples of the substituents include halogens such as chlorine and bromine, and alkyl groups such as methyl, ethyl, propyl, and isopropyl.

Among such organic sulfonic acid esters of alcohols used in the present invention, esters in which R' is lower alkyl, especially methyl, have the advantage that the reaction with thiosulfate proceeds smoothly even in an aqueous solution. Examples of these include methanesulfonic acid ester of tetrahydrofurfuryl alcohol and methanesulfonic acid ester of furovyl alcohol.

Organic sulfonic acid esters and thiosulfates of alcohols (
For example, reactions with alkali metal salts such as sodium and potassium, ammonium salts, alkaline earth metal salts such as calcium and magnesium,
The method described in Japanese Patent No. 86 may be used.

That is, in water or an aqueous organic solvent (organic solvents include alcohols, acetones, etc.), approximately 1 to 2 times the mole of thiosulfate is added to compound (I'), and 60 to 100
The reaction is carried out under stirring at °C.

The reaction is usually completed in 1 to 10 hours.

This reaction produces an organic thiosulfate compound represented by the general formula % (Rl has the same meaning as above, M represents an alkali metal, ammonium or alkaline earth metal).

Furthermore, the organic thiosulfate type mercapto agent (1) can also be obtained from an organic halide as in the conventional method described above.

In the present invention, this compound (1) is used as a mercaptating agent.

Compound (1) can be once isolated from the reaction solution and dissolved in water for the next reaction, but usually the reaction solution is used as is or the reaction solution is used after removing the organic solvent. be able to.

The other raw material used in the present invention has the general formula: [R8 represents hydrogen, an alkyl group, an aralkyl group, or an ester residue. ] It can be expressed as

The alkyl group and aralkyl group represented by R2 are the same as R1 described above.

Further, as an ester residue, for example, acetyl.

Lower aliphatic organic acid residues that may have substituents such as propyl, β-aminopropionyl, succinoyl, alanyl, substituted oxycarbonyl such as ethoxycarbonyl, carbamoyl that may have a substituent on nitrogen ,
Alternatively, inorganic acid residues such as phosphoric acid and sulfuric acid can be mentioned.

In the production method of the present invention, compound (I) and compound (
By gradually mixing II) with an alkaline solution such as sodium hydroxide in an aqueous solvent, crystals of the target compound, disulfide-type thiamine, or a derivative thereof can be obtained.

Compound (II) may be added as it is as an aqueous solution or a solid, for example, powder.

When compound (n) is used in an aqueous solution, it is preferable to add an acid such as hydrochloric acid to adjust the pH to a range of 0.5 to 2.0.

The alkali used in the present invention may be any alkali commonly used in chemical reactions, such as sodium hydroxide and potassium hydroxide.

In the present invention, the above-mentioned compound (1) and (I[) are mixed with an alkali to react with each other to obtain the desired disulfide-type thiamine or its derivative.

This mixing operation is preferably carried out gradually.

The purpose of such gradual mixing is to bring compounds (1) and (■) into contact with the alkali little by little to advance the reaction.

Examples of this method include, but are not limited to, the following methods.

■ Compound (I) and (
Gradually mix the solution II).

(2) Gradually mix the three solutions of compounds (I) and (n) and an alkaline solution.

(2) Gradually mix an alkaline solution into the mixed solution of compounds (I) and (n).

In particular, in the case of (2), it is possible to keep the pH of the reaction solution constant to some extent from the start of the reaction to the end of the reaction, which is a preferable method in terms of reaction control. Therefore, mixing of alkali is required to react with pH 8 and gradually mixing of compound (I) and (
It is determined appropriately depending on the pH and mixing speed of II).

In addition, in the case of (■), if a mixed solution of compounds (I) and (■) is prepared in advance, the desired product can be obtained simply by mixing the alkaline solution, which facilitates reaction control and facilitates industrial implementation. It's advantageous.

The aqueous solvent used in the present invention refers to water or a mixed solvent of water and an organic solvent. At this time, examples of organic solvents that can be used include chloroform and methylene chloride.

It is sufficient that the equivalent ratio of alkali/compound (n) is 3 or more, but it is preferably in the range of 3.0 to 3.5.

The reaction temperature may be around room temperature, about 5 to 40°C.

The reaction is preferably carried out in an alkaline region at a pH of 9.0 or higher.

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

The reaction time may be appropriately selected within a suitable range depending on the pH and temperature of the reaction solution. Including the above aging time, when the reaction is normally carried out at a temperature of 20±2°C, the reaction solution has a pH of 9,
5 for 10-30 hours, preferably 20 hours, pH 1O for 3-7 hours, preferably 4-6 hours, pH 11 for 1.5 hours.
~3 hours, preferably 1.5-2.5 hours, pH 12~
The reaction is carried out at 0.13° C. for 5 to 1.5 hours, preferably 0.5 to 1 hour. However, if the reaction temperature is increased, the reaction time can be shortened accordingly.

Among these, a pH range of 10 to 11 is industrially preferable.

Specifically, if the reaction model is shown using reaction method (2), it is as follows.

110 ml of compound (1) solution, loOmQ of compound (I[) solution, and alkaline solution are simultaneously gradually mixed (dropped) into 37- water in the reaction vessel. Mixing of the compound (I) solution is completed in 30 minutes, and mixing of the compound (If) solution is completed in 20 minutes. At this time, the pH of the reaction solution was 1O±0. The mixing of the alkali is controlled so that the temperature is maintained at 20±2°C.

After the mixing is completed, stirring is continued for about 3 hours under the same pH and temperature conditions while controlling the addition of alkali. Thereafter, while controlling the addition of alkali so that the reaction solution has a pH of 11=1:0.1, it is stirred for about 2 hours under the same pH and temperature conditions. Further, by controlling the addition of alkali so that the reaction solution has a pH of 41.5 ± 0.1 and stirring at the same pH and temperature conditions for about 0.5 hours, disulfide-type thiamine or its derivatives can be obtained in high yield. is obtained.

Compound (I) and (I[) are mixed in approximately equivalent amounts or in such an extent that compound (I) is in an equivalent ratio.

Preferably, compound (I)/(It) is 1-1°5
The molar ratio is more preferably in the range of 1.1-1.2 molar ratio.

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

For example, the pH of the reaction solution is 1O±0.11, the degree of reaction is 20
At ±2°C, 0.192 equivalents of (I) 110m are
, 1 d/win and 0.167 equivalents of (II)10
0- dropwise at a speed of 4 m/mrn.

Any commonly used method may be used to mix the ingredients little by little. For example, there is a method in which a solution of compounds (1) and (II) is dropped into a reaction vessel from separate nozzles, or a method in which (1) and (II) are mixed and stirred using a stirring device and the mixed solution is immediately added. There are methods such as introducing the mixture into a reaction vessel and mixing using a spiral tube instead of a stirring device.

Further, it is desirable to add a small amount of crystals of the target compound as seed crystals to the reaction solution in advance, since this promotes crystallization of the product. The amount added may be appropriately selected depending on the size of the reaction system.

In addition, inorganic salts such as common salt (e.g. sodium chloride,
If potassium chloride, etc.) is present in an amount that saturates or supersaturates the yield of the reactant, the yield of the reactant will be dramatically improved and a product that can be easily worked up will be obtained.

Note that if an inorganic salt is not added or if an inorganic salt is added after the reaction, the product may form crystals that are difficult to obtain.

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

In addition, when using chloroform, etc., the target substance dissolves in the chloroform layer, so after adding hydrochloric acid water and transferring the target substance to the aqueous layer, the aqueous layer is separated, neutralized with alkali, Filter the precipitated crystals. Next, the desired product is obtained by washing with water, acetone, etc. and drying.

Effects of the Invention The method for producing disulfide-type thiamine or its derivatives according to the present invention is much simpler than conventional methods, and is extremely industrially advantageous in terms of improved production volume and easy production control such as quality. This is an advantageous method.

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

X Number of Ships The present invention will be described in more detail below with reference to Examples.

[Example 11 1) Preparation of Bunte salt solution 36 g of tetrahydrofurfuryl mesylate, 54 g of sodium thiosulfate pentahydrate, and 52 g of water were added,
The reaction was allowed to proceed at ~90'C for 5 hours with stirring. After cooling, water was added to adjust the liquid volume to 110 - (hereinafter simply referred to as Bunte salt).

Ii) Preparation of thiamine hydrochloride solution 56.4 g of thiamine hydrochloride crystals were added to 110 g of water.
− was prepared.

1ii) Disulfidation Then, 30% by weight aqueous sodium hydroxide solution 58.7-
A mixed solution is prepared by adding seed crystals (of the desired product) 19 to the mixture.

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

After further stirring for 30 minutes, the precipitated crystals were suction filtered, and then
After washing with water and acetone, drying in vacuum, thiamine tetrahydrofurfuryl disulfide (TTFD) 3
4.8g was obtained.

Yield: 76.7% (theoretical yield based on thiamine hydrochloride: the same applies hereinafter). The purity by HPLC of a product with a melting point of 138 to 140° was 97.2%.

Note that the HPLC measurement conditions are as follows.

Column: Nucleosil C4 (5μ) Mobile phase: 0.
005M-C, H, 6S O, Na, 1% AcoH:
CH30H: CH, CN-675: 195: 1
30°C Lamb temperature: 50°C Detection wavelength: UV 254nm [Example 2] I) Preparation of thiamine hydrochloride solution Water was added to 56.4 g of thiamine hydrochloride to prepare a solution of 110°C.

U) Disulfidation Prepare a mixed solution by adding 50 g of sodium chloride and 1 g of seed crystals (of the desired product) to 58.7 d of a 30% by weight aqueous sodium hydroxide solution.

While stirring the mixture, add the same Bunte salt solution 1 as in Example 1.
10- and the above thiamine hydrochloride solution at 20±2℃ for 30 minutes.
They were mixed dropwise at the same time and allowed to react over a period of minutes.

After further stirring for 30 minutes, the mixture was treated in the same manner as in Example 1 to obtain the desired product (TTFD) 41.59.

Yield 91.6% Melting point 138-140'0 HPLC purity of this product was 99.0%.

[Example 31 1) Preparation of thiamine hydrochloride solution Water is added to 56.4 g of thiamine hydrochloride to make it 100-, and 35% by weight of hydrochloric acid is added to adjust the pH to 0.6.

ij) Disulfidation: Prepare a mixed solution by adding 50 g of sodium chloride and 1 g of seed crystals (of the desired product) to 58.7 d of a 30% by weight aqueous sodium hydroxide solution.

While stirring the mixed solution, the thiamine hydrochloride solution and the same Bunte salt solution 110- as in Example 1 are simultaneously added dropwise and mixed.

Thiamine hydrochloride solution for 20 minutes, Bunte salt solution for 30 minutes.
Example 1
The product was treated in the same manner as above to obtain 61.9 g of the target product (TTFD).

Yield 92.9% Melting point 138-140℃ HP of this product
LC purity was 98.2%.

[Example 4] 50 g of sodium chloride and 1 g of seed crystals (of the desired product),
While stirring the aqueous solution of water 37-, thiamine hydrochloride solution 100- produced in the same manner as in Example 3 and Bunte's salt solution 110- as in Example 1 were simultaneously added dropwise and mixed, and at the same time, 40% by weight sodium hydroxide was added. The pH of the reaction solution is 1.
It was added dropwise so that the amount was 1±0.1.

Thiamine hydrochloride solution for 20 minutes, Bunte salt solution for 30 minutes.
Drip over a minute.

After the addition was completed, the mixture was stirred for 90 minutes while maintaining the pH at 11±0.1. The temperature at this time was maintained at 20±2°C. Thereafter, the target product (TTFD) 62 was processed in the same manner as in Example 1.
．． 7g was obtained.

Yield 94.1% Melting point 138-140' (! HPLC purity of this product was 98.0%.

[Example 51 Water 37- was added to sodium chloride 509 and 1 g of seed crystals (object), and while stirring, thiamine hydrochloride solution 100- produced in the same manner as in Example 2 and Bunte as in Example 1 were added. While dropping the salt solution 110-, a 40% by weight sodium hydroxide solution was added so that the pH of the reaction solution was 1o±0.1.

The reaction temperature at that time was 40±2°C. The time for dropping the sodium hydroxide solution was 1 hour. After that, at the same temperature,
After stirring for a minute, the same treatment as in Example 1 was carried out to obtain the desired product (TTF
D) 41.19 was obtained.

Yield 90.4% HP of product with melting point 138-140°
LC purity was 97.3%.

[Example 6] 50 g of sodium chloride, 19 seed crystals (object), and 37 g of water
While stirring mQ, 100 mQ of thiamine hydrochloride solution prepared in the same manner as in Example 3 and 110 m12 in Bunte's salt solution prepared in the same manner as in Example 1 were simultaneously added dropwise and mixed, and at the same time, 30% by weight sodium hydroxide was added. The aqueous solution was added dropwise so that the pH of the reaction solution was 0.01.

Thiamine hydrochloride solution for 20 minutes, Bunte salt solution for 30 minutes.
It was added dropwise over a period of minutes. Furthermore, after the completion of dropping both, the pH was adjusted to 1.
o: pH 11±0.1 for 3 hours while maintaining I=O, l
The mixture was stirred for 2 hours at pH 11.5±0.1 for 0.5 hour while adjusting with an aqueous sodium hydroxide solution. At this time, the temperature was maintained at 20±2°C.

Thereafter, in the same manner as in Example 1, the target object (TTFD) 6
4.59 was obtained.

Yield: 96.8% Melting point = 138-140'0 The HPLC purity of this product was 99.0%.

[Example 7J While stirring a mixture of 58.7 d of a 30% by weight aqueous sodium hydroxide solution, 50 g of sodium chloride, and Ig of seed crystals (target object), 56.4 d of crystals of thiamine hydrochloride were added.
9 and the same Bunte salt solution 110- as in Example 1 were simultaneously added dropwise over 30 minutes, stirred for an additional 30 minutes, and then treated in the same manner as in Example 1 to obtain 59.3 g of the target product (TTFD).
I got it.

Yield 89.0% Melting point 138-140'0 HPLC purity of this product was 97.9%.

[Comparative Example 11 Crystals of thiamine hydrochloride 56.4! ? Aqueous solution 14 containing
56 d of 30% by weight aqueous sodium hydroxide solution was added to
Add it dropwise over 30 minutes while stirring at 5-20' (!).
The reaction was further continued for 30 minutes at the same temperature to obtain a sodium salt solution of thiol-type thiamine.

Next, 259 grams of sodium chloride and 220 grams of chloroform were added to 110 grams of the Bunte salt solution described in Example 1 and stirred for 30 minutes.

While maintaining this liquid at 15 to 20°C, a sodium salt solution of thiol-type thiamine was added under stirring to cause a reaction.

After the reaction is completed, the reaction solution is allowed to stand, the chloroform layer is separated, and chloroform 12 (ltf2) is newly added to the remaining aqueous layer, which is separated in the same manner.

Combine the chloroform layers and dilute with dilute hydrochloric acid 120- and 80-
Extract once. The extract was neutralized by dropping ammonia solution under stirring at 15 to 20°C to precipitate crystals.

After suction filtering the precipitated white crystals and washing with water, 50 to 60
Vacuum drying at °C gave a TTFD of 55.79.

Yield 83.6% Melting point 138-140'c HPLC purity of this product was 98.8%.

[Comparative Example 2] 50 g of sodium chloride and seed crystals (of the target product) were added in advance to Bunte's salt solution 110- produced in the same manner as in Example 1.
A sodium salt solution of thiol-type thiamine prepared in the same manner as in Comparative Example 1 was added dropwise thereto over 50 minutes with strong stirring.

The reaction was carried out under io'c and the reaction was completed under strong stirring for an additional 30 minutes.

The precipitated white crystals were suction-filtered, washed with water, and dried under vacuum to obtain 48.6 g of TTFD.

Yield 72.9% HPLC purity was 88.2%.

Claims (1)

[Claims] 1) General formula R^1SSO_3M [R^1 is an optionally substituted alkyl group or aralkyl group, M represents ammonium, an alkali metal, or an alkaline earth metal. ] Compounds represented by the general formula [▲Mathematical formulas, chemical formulas, tables, etc. are available▼]2Cl^- [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 following with an alkali in an aqueous solvent. 2) The production method according to claim 1), characterized in that the reaction is carried out in a system in which the inorganic salt is present in a saturated or supersaturated state. 3) The manufacturing method according to claim 2), wherein the inorganic salt is sodium chloride. 4) The manufacturing method according to claim 1), wherein the alkali is sodium hydroxide. 5) General formula R^1SS in aqueous solvent mixed with alkali
O_3M [R^1 and M are the same as above. ] and the general formula [▲There are mathematical formulas, chemical formulas, tables, etc.▼]2Cl^- [R^2 indicates the same as above. ] The manufacturing method according to claim 1), characterized in that a compound represented by the above is mixed. 6) General formula R^1SSO_3M [R^1 and M are the same as above. ] and the general formula [▲There are mathematical formulas, chemical formulas, tables, etc.▼]2Cl^- [R^2 indicates the same as above. ] The manufacturing method according to claim 1), characterized in that the compound represented by these and an alkali are mixed in an aqueous solvent. 7) General formula R^1SSO_3M [R^1 and M are the same as above. ] and the general formula [% formula] 2Cl^- [R^2 represents the same group as above. ] The manufacturing method according to claim 1, characterized in that an alkaline solution is mixed into an aqueous solvent mixed with a compound represented by the following. 8) Claim 1) characterized in that the mixing operation is carried out gradually.
to 7) the manufacturing method described above.