HU209921B - New process for producing disulfide-type derivatives of thiamine - Google Patents

Abstract

Prodn. of a disulphide form of thiamine or its deriv. comprises mixing of thiamine cpd. of formula (I) and organic thiosulphate of formula (II) with an alkali in aq. soln. In formulae, R1= opt. substd. alkyl or aralkyl; M= ammonium, alkali metal, or alkaline earth metal; R2= H, alkyl, aralkyl, or ester group. - Specifically the reaction system is satd. or super-satd. with NaCl or other inorganic salt; the alkali used is NaOH; (I) and (II) are added to an aq. soln. of alkali; alkali soln. is added to a mixed. aq. soln. of (I) and (II); the mixing is carried out by gradual addn.; and the reaction is seeded with crystals of target cpd.

Description

The present invention relates to a process for the preparation of disulfide-type thiamine derivatives which are useful inter alia for their therapeutic activity.

Numerous processes for the preparation of disulfide thiamine derivatives have been previously described. One of the typical processes, which comprises reacting an organic thiosulfate-type mercaptan-forming agent with a thiol-type thiamine derivative, is described in Japanese Patent Nos. 3,514,226 and 42-18,633 (Toku-Ko-Sho) and 61-225. Japanese Patent No. 170 (Toku-Kai-Sho).

However, these known methods have the following disadvantages, among other things; the process for the preparation of thiol-type thiamine, especially when the reaction is carried out in the presence of an aqueous solvent, results in a resinous product which makes it difficult to recover the product or, if the product may be obtained in crystalline form, extremely low yields.

The organic thiosulfate-type mercaptan-forming agent is readily prepared by reacting thiosulfate with an organic halide, such as a bromine compound. Therefore, mercaptan-forming agents prepared with such an organic halide are often used both on an experimental and an industrial scale. However, if this organic thiosulfate mercaptan-forming agent is used to prepare the disulfide thiamine derivative, the target compound cannot be obtained in significant yield.

On the other hand, a process for reacting thiosulfate with an alcohol sulfonic acid ester has also been proposed for the preparation of organic thiosulfate-type mercaptan forming agents, as disclosed in Japanese Patent Specification No. 40-23,786 (Toku-Ko-Sho). This agent is commonly used as one of the organic group delivery agents. For example, it is disclosed that this agent is used to prepare an asymmetric thiamine disulfide derivative by reaction with a thiol-type thiamine.

However, there is no disclosure that such an organic thiosulfate mercaptan-forming agent is used to prepare disulfide-type thiamine derivatives.

The process generally and conventionally used to prepare disulfide-type thiamine derivatives utilizes a two-phase system consisting of an organic solvent such as chloroform and water as the reaction medium for crystallization of the product in a stable form.

However, in the context of today's environmental contamination, the use of organic solvents is considered to be a source of many undesirable problems, such as disposal of waste water or harm to workers' health. The use of an organic solvent is also problematic from an industrial point of view, since equipment for the recovery of the organic solvent is also required.

As described above, in the conventional processes, the production process must include the step of producing a thiol-type thiamine. Therefore, especially when an aqueous solvent is used, these processes are far from being applicable on an industrial scale.

Furthermore, the yields of the known processes are unsatisfactory or the process is carried out using organic solvents which are environmentally harmful or require the installation of special equipment for the recovery of organic solvents in order to avoid environmental damage.

In view of the above, it has become desirable to develop a safe production process capable of producing high yields of stable disulfide thiamine derivatives.

To solve this problem, we have tried to react an organic thiosulfate derivative as a mercaptan-forming agent with thiamine hydrochloride and alkali, preferably by mixing them little by little, and found that very stable thiamine disulfide derivatives are obtained which are very pure and yield is very high.

It has also been found that when thiamine hydrochloride is reacted with an organic thiosulfate-type mercaptan, the yield of the reaction is greatly improved by the presence of an inorganic salt, such as sodium chloride, in the reaction mixture so that upon completion of the reaction mixture should be saturated.

More particularly, the present invention relates to the preparation of a disulfide-type thiamine or a derivative thereof represented by formula (I) wherein the compound is represented by formula (I) wherein R ¹ is C 1-6 alkyl optionally substituted by tetrahydrofuryl; In an aqueous solvent added with alkali, the alkali is preferably mixed with the other reactants gradually - M is an ammonium or alkali metal or alkaline earth metal atom - and (II) a compound of formula - wherein R ² represents a hydrogen atom or an ester residue.

The organic thiosulfate derivative mercaptan-forming agent used in the process of the invention can be prepared by reacting thiosulfate with an organic sulfonic acid ester of an alcohol. The organic sulfonic acid ester of the alcohol may be represented by the formula (I) wherein R ¹ is (C 1 -C 6) alkyl optionally substituted by tetrahydrofuryl; R 'is optionally substituted alkyl, aralkyl or aryl.

Alkyl groups substituted with R ^{1 are} typically straight or branched C 1 -C 6 groups. Examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or isopentyl.

The alkyl group represented by R 'may be lower alkyl, preferably C 1-6 alkyl, such as ethyl, propyl or isopropyl, more preferably C 2-4 alkyl.

The organic sulfonic acid ester of alcohols according to the invention is understood to mean, inter alia, a compound of the formula (Γ) in which R 'is lower alkyl, preferably methyl, the use of such a compound having the advantage that thiosul

Even in aqueous solution, its reaction with the wood is smooth, for example, the methanesulfonic acid ester of tetrahydrofururyl alcohol or the methanesulfonic acid ester of propyl alcohol.

The reaction of the organic sulfonic acid ester of alcohols with thiosulfate (e.g., an alkali metal salt such as a sodium or potassium salt, an ammonium salt or an alkaline earth metal salt such as a calcium or magnesium salt) can be carried out according to the invention. Ko-Sho).

In particular, the compound of formula (Γ) is reacted with 1-2 molar equivalents of thiosulfate in water or an aqueous organic solvent (such as alcohols or acetones) with stirring at 60-100 ° C.

The reaction is usually complete within 1-10 hours. The above reaction yields an organic thiosulfate derivative of the Formula I (wherein R ¹ is as defined above, M is an alkali metal, ammonium group, or alkaline earth metal).

The organic thiosulfate-type mercaptan generating agent of formula (I) may be prepared from an organic halide by the conventional method described above.

In the process of this invention, this compound of formula (I) is used as a mercaptan generating agent. The compound of formula (I) may be prepared after dissolution in water of the subsequent reaction after isolation from the reaction mixture, but generally the reaction mixture is employed as such or after removal of the organic solvent.

Another starting material for the process of the invention is the compound of formula ( ² ) wherein R ² is hydrogen or ester residue.

Residual examples of the ester include, but are not limited to, residues of optionally substituted lower aliphatic organic acids such as acetyl, propyl, β-aminopropionyl succionyl and alanyl, substituted oxycarbonyl groups such as ethoxycarbonyl, a carbamoyl group in which the nitrogen atom is optionally substituted or residues of inorganic acids such as phosphoric acid or sulfuric acid.

In the process of the present invention, crystals of the desired compound, the disulfide-type thiamine of formula (1) or its derivative, are obtained by mixing the compound of formula (I) and the compound of formula (Π) with an alkaline solution such as sodium hydroxide in preferably, it is gradual.

The compound of formula (II) may be added to the reaction system in the form of an aqueous solution or as a solid such as a powder or granule.

When used as an aqueous solution of the compound of formula (zes), the pH of the solution is preferably adjusted to 0.5-2.0 by the addition of an acid such as hydrochloric acid.

The mother liquor obtained by crystallization of the compound may also be used as the compound of formula (H). The compound of formula (II) can be prepared by methods known per se. In any process, the last step of which is crystallization, the mother liquor obtained after separation of the crystals can be used in the process of the invention to prepare disulfide-type thiamine or derivatives thereof. The mother liquor is preferably used after adjusting the pH as described above.

An example of a practical preparation of compounds of formula (Π) is the process outlined in Scheme 1 (wherein the substituents have the meanings given above).

This process can be carried out as described in Japanese Patent No. 26-3977 (Toku-Ko-Sho).

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

SUMMARY OF THE INVENTION The present invention relates to the preparation of the desired disulfide-type thiamine of formula (I) or a derivative thereof by reacting a compound of formula (I) with a compound of formula (II) by mixing with a base.

This mixing process is preferably carried out gradually. In order to effect a gradual mixing process, the compounds of formula (I) and (II) are brought into contact with the alkali gradually so that the reaction proceeds.

The process of the present invention may be carried out, but is not limited to, the following:

(1) gradually mixing a solution of a compound of formula (I) and (II) with an aqueous solvent mixed with an alkali, (2) a solution of a compound of the formula (I), a solution of a compound of formula (II) and (3) gradually mixing a solution of a compound of formula (I) and a solution of a compound of formula (II) in an alkaline solution.

Particularly advantageous for controlling the reaction is solution (2), in which case the pH of the reaction mixture can be maintained at a substantially constant level during the reaction. Therefore, the conditions for stirring the alkali are suitably controlled by the pH of the reaction system, the pH of the compounds of formulas I and II to be gradually mixed, and the stirring rate.

In solution (3), when a solution of a compound of formula (I) is premixed with a solution of a compound of formula (H), only the alkali solution is added to the desired compound. Therefore, the reaction can be easily controlled and is advantageous in industrial applications.

The aqueous solvent used in the process of the present invention is understood to mean water or a mixture of water and an organic solvent. Examples of such solvents are chloroform and methylene chloride.

The alkali is used in an amount of 3 or more equivalents, preferably 3.0 to 3.5 equivalents, relative to the compound of formula II.

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The reaction is preferably carried out at room temperature, 5 to 40 ° C.

The reaction is preferably conducted in an alkaline range at pH 9 or higher.

The final product is generally obtained in high yields, if the mixing is continued under the given conditions after completion of the mixing of the starting materials (aging).

The reaction time may conveniently be determined by the pH and temperature of the reaction mixture. The reaction time, including the aforementioned aging period, is 10-30 hours, preferably 20 hours, at pH 10, 3-7 hours, preferably 4-6 hours, at a reaction temperature of 20 + 2 ° C, at pH 9.5. 11 at 1.5-3 hours, preferably 1.5-2.5 hours and at pH 12-13 0.5-1.5 hours, preferably 0.5-1 hours, with the proviso that when the reaction temperature is increased the reaction time may be reduced accordingly.

Of the aforementioned pH ranges, the pH range of 10-11 is industrially preferred.

According to the solution of process (2), a particular embodiment is as follows:

In a reaction flask containing water, mix simultaneously and gradually, dropwise, the following components: 110 ml solution of the compound of formula I, 100 ml solution of the compound of the formula I and an alkaline solution. The stirring of the solution of the compound of the formula I is completed in 30 minutes and the solution of the compound of the formula II is completed in 20 minutes. In this case, the alkali is added so that the pH of the reaction mixture is 10 + 0.1 and the temperature of the reaction mixture is maintained at 20 ± 2 ° C.

After completion of the mixing, stirring was continued for another 3 hours at the same pH and temperature range while adjusting the addition of the alkali. Subsequently, stirring was continued for another 2 hours at the same pH and temperature range, while the addition of the alkali was adjusted to bring the pH of the reaction mixture to 11 ± 0.1. The addition of the alkali is then controlled so that the pH of the reaction mixture is 11.5 ± 0.1 and the reaction mixture is stirred for 0.5 hours at the same pH and temperature range to give the disulfide thiamine or derivative in high yield. The compound of formula (I) is mixed with the compound of formula (II) in a substantially equivalent ratio, or in a ratio in which the amount of the compound of formula (I) is more equivalent.

The compounds of formula (I) and (II) are preferably mixed in a ratio such that the molar ratio of the compound of formula (I) to the compound of formula (Π) is 1-1.5, more preferably 1.1-1.2 be.

The mixing is carried out at an optimum rate considering the pH and the temperature of the reaction mixture.

For example, when the pH of the reaction mixture is 10 to 0.1 and the reaction temperature is 20 ± 2 ° C, 110 ml of a 0.192 equivalent solution of the compound of formula I is added dropwise at a rate of 3.1 ml / min. 100 mL of a 0.167 equivalent solution was added dropwise at a rate of 4 mL / min.

Any conventional method of administering a limited amount of dosing may be employed. For example, a solution of a compound of formula (I) and a solution of a compound of formula (II) may be added dropwise to the reaction mixture through separate tube ends, a compound of formula (I) and a compound of formula (II) mixed in a mixing apparatus. or the compounds of formula (I) and (II) may be mixed in a spiral tube instead of a mixer.

Advantageously, a small amount of crystals of the desired compound is added as seed crystals to the reaction mixture, thereby accelerating the crystallization of the product. The amount of seed crystals is selected depending on the scale of the reaction system.

The yield of the reaction product is markedly improved by simple post-treatment by adding an inorganic salt, such as sodium chloride or potassium chloride, to the reaction mixture in an amount such that the solution is saturated or supersaturated. Otherwise, if the inorganic salt is not added at all or is added after the reaction is complete, the reaction product tends to form difficult to separate crystals from the reaction system.

After completion of the reaction, the crystalline product is collected by filtration, washed with, for example, water, ethanol or acetone, and dried to give the disulfide-type thiamine or its derivatives.

Furthermore, since, for example, chloroform, the final product is dissolved in an aqueous hydrochloric acid solution in the chloroform phase to transfer the final product to the aqueous phase, then the aqueous phase is separated, neutralized with alkali and the precipitated crystals are filtered off. The crystals were treated with water, acetone, etc. wash and dry to obtain the final product.

The invention will now be described, more specifically, by way of example with reference to the preferred embodiment.

Example 1

i) Preparation of Bunte Salt Solution A mixture of tetrahydrofurfuryl mesylate (g), sodium thiosulfate pentahydrate (54 g) and water (52 ml) was heated at 8590 ° C for 5 hours. The reaction mixture is then cooled and made up to 110 ml with water (hereinafter referred to simply as the Bunte salt).

ii) Preparation of a solution of thiamine hydrochloride

56.4 g of crystalline thiamine hydrochloride are made up to 110 ml with water.

iii) Disulfide formation

To a solution of 58.7 ml of a 30% w / w aqueous sodium hydroxide solution is added 1 g of seed crystals corresponding to the desired compound.

While stirring, add the previous 4

The Bunte salt solution described above is added and the thiamine hydrochloride solution is added at 15-20 ° C and the reaction is completed for 30 minutes.

After stirring for an additional 30 minutes, the precipitated crystals were suction filtered, washed with water, then with acetone, and then dried under vacuum. 51.1 g of thiamine (tetrahydrofurfuryl disulfide) (TTFD) are obtained. Yield 76.7% (theoretical yield calculated for thiamine hydrochloride, same for additional yield data).

138-140 ° C.

The purity of the product obtained was 97.2% by high performance liquid chromatography (HPLC).

The HPLC assay conditions are as follows: Column: nucleosyl C ₁₈ (5 μ)

Moving Bed: 0.005 M / 1 -C ₇ H ₁₅ S0 ₃ Na, 1%

Ac OH: CH ₃ OH: CH ₃ CN = 675: 195: 130. Column temperature: 50 ⁰ C.

Detection wavelength: UV 254 nm

Example 2

(i) Preparation of a solution of thiamine hydrochloride

56.4 g of thiamine hydrochloride are made up to 110 ml with water.

ii) Disulfide formation

To 58.7 ml of a 30% w / w aqueous sodium hydroxide solution are added 50 g of sodium chloride and 1 g of seed crystal (corresponding to the desired compound).

The resulting solution was stirred while 110 ml of the Bunte salt solution of Example 1 was added dropwise, and the above solution of thiamine hydrochloride was added dropwise at 20 + 2 ° C and the reaction was complete for 30 minutes.

The reaction mixture was stirred for an additional 30 minutes and worked up as described in Example 1. 51.0 g of the desired compound (TTFD) are obtained.

Yield 91.6%. M.p. 138140 ° C. The product was 99.0% pure by HPLC.

Example 3

(i) Preparation of a solution of thiamine hydrochloride

56.4 g of thiamine hydrochloride are made up to 100 ml with water and 35% by weight hydrochloric acid is added to adjust the pH to 0.6.

ii) Disulfide formation

To 58.7 ml of a 30% w / w aqueous sodium hydroxide solution is added 1 g of seed crystal (corresponding to the desired compound).

To the resulting solution was added dropwise the thiamine hydrochloride solution and 110 mL of the Bunte salt solution prepared in Example 1 dropwise with stirring, and the two reagents were added simultaneously.

The addition of thiamine hydrochloride is complete within 20 minutes and the Bunte saline solution takes 30 minutes. The mixture was then stirred for an additional 30 minutes and then stirred for 1 hour.

Example 4a. 61.9 g of the desired compound (TTFD) are obtained.

Yield 92.9%. 138-140 ° C.

The purity of the resulting compound was 98.2% by HPLC.

Example 4 To a stirred solution of sodium chloride (1 g) and seed crystal (1 g) in 37 ml of water was added dropwise with stirring 100 ml of thiamine hydrochloride solution prepared in Example 3 and 110 ml of Bunte obtained in Example 1. salt solution. Simultaneously, 40 wt.% Aqueous sodium hydroxide solution was added to the reaction mixture, maintaining its pH in the range of 11 ± 0.1.

The addition of the thiamine hydrochloride solution was completed in 20 minutes and the Bunte salt solution in 30 minutes.

The mixture was then stirred for a further 90 minutes and maintained at pH 11 + 0.1. The mixture was maintained at 20 + 2 ° C and worked up as in Example 1. 62.7 g of the desired compound (TMFD) are obtained.

Yield 94.1%. M.p. 138140 ° C. The purity of the product was 98.0% by HPLC.

Example 5 To 37 g of sodium chloride and 1 g of seed crystal corresponding to the target compound was added 37 ml of water. 100 ml of thiamine hydrochloride solution were prepared as described in Example 2 and 110 ml of Bunte salt were prepared as described in Example 1 and added dropwise to the above solution with stirring while the pH of the reaction mixture was 10 + 0, Keep it at 1.

The reaction mixture was maintained at 40 ± 2 ° C for 1 hour to add sodium hydroxide solution. The reaction mixture was then stirred at the same temperature for 30 minutes and worked up as described in Example 1. 60.2 g of the title compound (TIED) are obtained.

Yield 90.4%. M.p. 138140 ° C. The product was 97.3% pure by HPLC.

Example 6 To a mixture of 1 g of sodium chloride, 1 g of seed crystal of the target compound and 37 ml of water, 100 ml of the thiamin hydrochloride solution prepared in Example 3 and 110 ml of the Bunte salt prepared in Example 1 are added dropwise while stirring. and the pH of the mixture is maintained at 10 + 0.1 by the dropwise addition of 30% w / w sodium hydroxide.

The time needed for the administration of thiamine hydrochloride solution is 20 minutes and for Bunte saline solution 30 minutes. After the addition of the two solutions, the mixture was stirred for a further 3 hours while maintaining the pH at 10 ± 0.1, then for a further 2 hours at pH 11 + 0.1 and for a further 0.5 hours at pH 11, Stir at 5 ± 0.1 and adjust the pH of the solution to aqueous

EN 209 921 Β of sodium hydroxide solution. The temperature of the mixture was maintained at 20 ± 2 ° C.

The mixture is then worked up essentially as described in Example 1. 64.5 g of the target compound (TTFD) are obtained.

Yield 96.8%. M.p. 138140 ° C. The purity of the product was 99.00% by HPLC.

Example 7

To a mixture of 58.7 ml of 30% w / w aqueous sodium hydroxide, 50 g of sodium chloride and 1 g of seed crystal corresponding to the target compound was added 56.4 g of crystalline thiamine hydrochloride, while simultaneously dropping 110 ml of the Bunte prepared according to Example 1. salt solution, the addition takes 30 minutes.

The mixture was stirred for an additional 30 minutes and then worked up essentially as described in Example 1. 59.3 g of the target compound (TTFD) are obtained.

Yield 89.0%. M.p. 138140 ° C. The product was 97.9% pure by HPLC.

Example 8 Sodium chloride, 1 g of seed crystal of the target compound, 100 ml of thiamine hydrochloride solution prepared in Example 3 and 110 ml of Bunte salt solution prepared in Example 1 are mixed and mixed. Sodium hydroxide (30% w / w) was added dropwise to adjust the pH to 10.

Thiamine hydrochloride solution was added dropwise over 20 minutes, while Bunte saline solution was added dropwise over 30 minutes. After the addition of the two solutions, the reaction mixture was kept at pH = 10 ± 0.1 for 2 hours, at pH ± 11, 0.1 for 0.5 hours and at pH 5 ± 0.1 for 0.5 hours. solution. The temperature of the reaction mixture is maintained at 20 ± 2 ° C throughout the process.

The reaction mixture is then worked up essentially as described in Example 1. 61.6 g of the title compound (TIED) are obtained.

Yield 92.5%. M.p. 138140 ° C. The purity of the product was 98.5% by HPLC.

Example 9

To 2.8 parts of N- (2'-methyl-4'-amino-5'-pyrimidyl) methyl-4-methyl-5-p-oxyethylthiothiazolone was added 50 parts of water and 10 parts of concentrated hydrochloric acid. and the mixture is brought to a solution. Under ice-cooling and stirring, 9 parts of a 30% aqueous hydrogen peroxide solution are added dropwise. After completion of the reaction, aqueous barium chloride solution was added until the precipitation ceased. The precipitate is filtered off, the filtrate is concentrated, then mixed with ethanol and allowed to crystallize out. The resulting crystals were recrystallized from dilute alcohol. 10 parts of N- (2'-methyl-4'-amino-5'-pyrimidinyl) methyl-5-β-oxyethylthiazolium chloride are obtained in the form of hydrogen chloride (thiamine hydrochloride). . The product has a melting point of 250 ° C. (the term "part" means parts by weight.)

The filtrate from the above reaction mixture is used in the next step after the crystals of thiamine hydrochloride are recovered.

Add 37 g of water to 1 g of sodium chloride and 1 g of seed crystal corresponding to the target compound. Concentrated solution of the filtrate from crystallization of thiamine hydrochloride (56.4 g of thiamine hydrochloride) (120 mL) was added dropwise with stirring, while 110 mL of the Bunte salt solution prepared in Example 1 was added dropwise and during the addition, the pH of the mixture was maintained at 10 ± 0.1 by the addition of 30% w / w sodium hydroxide.

Adding thiamine hydrochloride solution takes 20 minutes and Bunte salt solution takes 30 minutes.

After the addition of the two solutions, the reaction mixture was further stirred for 3 hours at pH = 10 ± 0.1, for 2 hours at pH = 11 ± 0.1, and for 0.5 hours at pH 11.5 ± 0.1. values are provided by the addition of aqueous sodium hydroxide solution. The reaction temperature was maintained at 20 + 2 ⁰ C during this process.

The reaction mixture was worked up essentially as described in Example 1. 62.5 g of the target compound (TIED) are obtained.

Yield 93.8%. M.p. 138140 ° C. The purity of the product as determined by HPLC was 98.1%.

1. Comparative Example

To a solution of 56.4 g of crystalline thiamine hydrochloride in 140 ml of aqueous solution is added dropwise, with stirring at 15-20 ° C, 30 ml of a 30% by weight aqueous sodium hydroxide solution. The mixture was allowed to react for 30 minutes at the same temperature and a solution of the thiamine sodium salt of thiol was obtained.

To 110 ml of the Bunte salt solution described in Example 1, 25 g of sodium chloride and 220 ml of chloroform are added and the mixture is stirred for 30 minutes. A solution of the thiamine sodium salt of a thiol-type thiamine is added to the resulting solution while maintaining the temperature at 15-20 ° C, and the mixture is allowed to react.

After completion of the reaction, the reaction mixture is allowed to stand. The chloroform phase is separated, 120 ml of fresh chloroform is added to the remaining aqueous phase, and the chloroform phase is separated.

The chloroform phases were combined and extracted with 2 x 120 ml, then 80 ml of dilute hydrochloric acid. The extracts were combined and a solution of ammonia was added dropwise to the combined solution at 15-20 ° C with stirring to neutralize the precipitation of the crystals.

The precipitated white crystals are suction filtered and dried in vacuo at 50-60 ° C. Yield: 55.7 g TTFD.

Yield 83.6%. M.p. 138140 ° C. The purity of the product obtained by HPLC was 98.8%.

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2. Comparative Example

To 110 ml of the Bunte salt solution prepared in Example 1 is added 50 g of sodium chloride first, followed by 1 g of seed crystals corresponding to the target compound. A solution of the thiamine sodium salt of thiol type prepared essentially as described in Example 1 is added dropwise with vigorous stirring and the addition takes 50 minutes.

The mixture was reacted at 10 ° C and stirred vigorously for a further 30 minutes to complete the reaction.

The precipitated white crystals were suction filtered, washed with water and dried in vacuo. 48.6 g of TTFD are obtained. Yield 72.9%.

The product was found to be 88.2% pure by HPLC.

Industrial applicability

The process for the preparation of the disulfide-type thiamine or its derivatives according to the invention is simpler than the conventional processes, better than their yields and the organization of production, including quality control, and thus has significant industrial advantages.

In addition, the process is advantageous in that no organic solvent is added to the system. In this case, solvent recovery devices are not required, which also makes it advantageous to apply the process of the invention on an industrial scale.

Claims (11)

PATENT CLAIMS A process for the preparation of disulfide-type thiamines of the general formula (I) and derivatives thereof, in the following formula R 'is (C 1 -C 6) alkyl optionally substituted by tetrahydrofuryl, R ² is a hydrogen atom or an ester residue, characterized in that a compound of formula I wherein M is ammonium, an alkali metal or alkaline earth atom and R ¹ is as defined herein, and a compound of formula II wherein R ² are as defined as defined above with alkali in an aqueous solvent. Process according to claim 1, characterized in that the reaction is carried out in a reaction medium containing an inorganic salt, the solution being saturated or supersaturated. 3. A process according to claim 2 wherein the inorganic salt is sodium chloride. 4. A process according to claim 1 wherein the alkali is sodium hydroxide. The process of claim 1, wherein the compound of formula I wherein R ¹ and M are as defined in claim 1 is a compound of formula II wherein R ² is as defined in claim 1 - mixed in an aqueous solvent containing an alkali. 6. A process according to claim 1 wherein the compound of formula I wherein R ¹ and M are as defined in claim 1 and the compound of formula II wherein R ² is and alkaline in an aqueous solvent. The process of claim 1, wherein the aqueous solution of a compound of formula I wherein R ¹ and M are as defined in claim 1 and a compound of formula II wherein R ² is as defined in claim 1, comprising stirring an alkali solution. 8. Process according to any one of claims 1 to 3, characterized in that the reactants are mixed gradually. The process according to claim 1, wherein the reaction is carried out in a reaction mixture comprising seed crystals of the target compound. The process of claim 1, wherein a compound of formula (I) wherein R ¹ and M are as defined above and a compound of formula (Π) wherein R ² is as defined in claim 1 containing an inorganic salt and the seed crystals of the target compound. 11. The process of claim 1 wherein the mother liquor is retained after crystallization of the crystals of the compound of formula (II).