WO1992012138A1 - Procede de production d'un derive bisulfure de thiamine - Google Patents

Procede de production d'un derive bisulfure de thiamine Download PDF

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Publication number
WO1992012138A1
WO1992012138A1 PCT/JP1990/001742 JP9001742W WO9212138A1 WO 1992012138 A1 WO1992012138 A1 WO 1992012138A1 JP 9001742 W JP9001742 W JP 9001742W WO 9212138 A1 WO9212138 A1 WO 9212138A1
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Prior art keywords
general formula
solution
compound represented
reaction
same
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English (en)
Japanese (ja)
Inventor
Katsuji Shimizu
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Takeda Pharmaceutical Co Ltd
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Takeda Chemical Industries Ltd
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Priority to PCT/JP1990/001742 priority Critical patent/WO1992012138A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a novel method for producing a disulfide-type thiamine or a derivative thereof useful for medicines and the like.
  • 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.
  • 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.
  • 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.
  • a water-soluble solvent such as chloroform is used as a reaction solvent.
  • a two-phase system is used.
  • 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 could't do.
  • 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.
  • organic thiosulfate compound as a merkato stimulus
  • 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.
  • the present invention has a general formula
  • 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.
  • 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 1 represents alkyl or aralkyl which may be g-substituted
  • R ' represents alkyl, aralkyl or aryl which may be E-substituted.
  • the alkyl represented by R 1 a straight- ⁇ or branched charcoal vegetable number 1-6 is normally used.
  • alkyl groups such as isobutyl, pentyl, isopentyl and the like.
  • 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.
  • aralkyl groups such as benzyl and phenyl can be exemplified.
  • 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
  • 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.
  • 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.
  • 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.
  • aralkyl groups such as benzyl and phenyl can be used.
  • aryl groups include aryl groups such as phenyl.
  • These groups may also have an appropriate substituent.
  • substituents include halogens such as nitrogen and bromine, and alkyl groups such as methyl, ethyl, propyl, and isobrole.
  • 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.
  • 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 ( ⁇ ). And react with stirring.
  • the reaction is usually completed in 1 to 10 hours.
  • 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.
  • organic thiosulfate merkabut agent (I) can also be obtained from an organic halide compound as in the above-mentioned conventional method.
  • 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.
  • 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.
  • the ester include lower aliphatic organic acid residues which may have fi conversion, such as acetyl, propyl, 5-aminopropionyl, succinoyl.
  • examples thereof include an inorganic acid residue such as phosphoric acid and sulfuric acid, which may have a substituent on nitrogen.
  • 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. ⁇ 3 ⁇ 4 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.
  • an acid such as hydrochloric acid is added to adjust the pH to 0.5-2.0. It is preferable to keep the range.
  • a crystallized mother used to obtain the crystal may be used.
  • Compound ( ⁇ ) 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.
  • a specific production method of the compound (II) for example, a production method represented by the following formula can be mentioned. ce ⁇ , -3 ⁇ 4 U cy: C H, +
  • This method can be carried out, for example, according to the method described in JP-B-26-37977.
  • any reactor may be used as long as it is generally used for a chemical reaction.
  • sodium hydroxide, a hydroxide reactor and the like are used.
  • 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 ( ⁇ ) into contact with an alkali to promote the reaction.
  • 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 ( ⁇ ) to be gradually mixed, and the mixing speed.
  • 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 ( ⁇ ) 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.
  • the reaction time may be appropriately selected according to the pH of the reaction solution and the temperature.
  • the reaction should be performed for 5 to 11 hours at 119.5 for 10 to 30 hours, preferably 20 hours, and ⁇ 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.
  • the reaction temperature is raised, the rush can be shortened accordingly.
  • the range of pH 10 to 11 is industrially preferable.
  • reaction model is shown by reaction method (1) as follows.
  • the mixture is stirred for about 3 o'clock under the same ⁇ and temperature conditions, while controlling the addition of aluminum.
  • the addition of Al 2 O 3 so that the reaction solution becomes ⁇ ⁇ 11 ⁇ 0, 1, simmer for about 2 hours at the same ⁇ ⁇ and temperature.
  • 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.
  • 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.
  • the amount of addition may be appropriately determined depending on the size of the reaction system.
  • 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.
  • the resulting product may be a zirconia crystal from which it is difficult to obtain a product.
  • 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.
  • the target material 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.
  • 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 ⁇ m (hereinafter simply referred to as Bunte salt).
  • a mixed solution is prepared by adding seed (19) 19 to 58.7 ml of a 30% by weight aqueous sodium hydroxide solution.
  • the measurement conditions for HP LC are as follows.
  • This product had an HP LC purity of 98.2%.
  • Example 2 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.
  • TTF D target product
  • This product had an HP LC purity of 98.0%.
  • 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.
  • 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.
  • Example 1 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 ?.
  • This product had an HP LC concentration of 97.9%.
  • 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.
  • the product had an HP LC purity of 98.5%.
  • N- (2'-Methyl-4'-Amino-birimidyl 5 ')-Methyl-4'-Methyl-15' ⁇ -Oxyxethyl-thiothiazolone 8. 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.
  • the siaamine clay solution was added dropwise over 20 minutes, and the Bunte salt solution was added dropwise over 30 minutes.
  • 3 hours while maintaining DH10 ⁇ 0.1, 2 hours at ⁇ 11 ⁇ 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.
  • 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.
  • 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.
  • the product had an HP LC purity of 98.8%.
  • the reaction was carried out at 10 and the reaction was completed under vigorous stirring for another 30 minutes.
  • 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.
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention se rapporte à un procédé industriellement avantageux, qui sert à produire une thiamine de forme bisulfure ou son dérivé et qui consiste à cet effet à mélanger un composé représenté par la formule générale R1SSO3M (où R1 représente un groupe alkyle ou aralkyle éventuellement substitué, et M représente un ammonium, un métal alcalin ou un métal de terres alcalines) et un composé représenté par la formule générale (I) (où R2 représente un hydrogène, un alkyle, un aralkyle ou un reste d'ester) avec un alcali dans un solvant aqueux.
PCT/JP1990/001742 1990-12-28 1990-12-28 Procede de production d'un derive bisulfure de thiamine Ceased WO1992012138A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/JP1990/001742 WO1992012138A1 (fr) 1990-12-28 1990-12-28 Procede de production d'un derive bisulfure de thiamine

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP1990/001742 WO1992012138A1 (fr) 1990-12-28 1990-12-28 Procede de production d'un derive bisulfure de thiamine

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WO1992012138A1 true WO1992012138A1 (fr) 1992-07-23

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103387573A (zh) * 2012-05-08 2013-11-13 江苏兄弟维生素有限公司 一种盐酸硫胺的制备工艺

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3544574A (en) * 1967-03-03 1970-12-01 Takeda Chemical Industries Ltd Thiamine halophenylalkyl disulfides
JPS61225170A (ja) * 1985-03-29 1986-10-06 Osaka Soda Co Ltd ジスルフイド型ビタミンｂ↓１またはその誘導体の製法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3544574A (en) * 1967-03-03 1970-12-01 Takeda Chemical Industries Ltd Thiamine halophenylalkyl disulfides
JPS61225170A (ja) * 1985-03-29 1986-10-06 Osaka Soda Co Ltd ジスルフイド型ビタミンｂ↓１またはその誘導体の製法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103387573A (zh) * 2012-05-08 2013-11-13 江苏兄弟维生素有限公司 一种盐酸硫胺的制备工艺

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