Thiamine disulfide

Chemical Name N,N -[dithiobis[2-(2-hydroxyethyl)-1-methylvinylene] ] bis[N-[(4-amino-2-methyl-5-pyrimidinyl)methyl] formamide] 

20 parts by weight of thiamin are dissolved in 25 parts of water, a cold solution of 5 parts by weight of caustic soda in 25 parts of water added and the mixture oxidized with a solution of 2.4 parts by weight of caustic soda and 20 parts by weight of potassium ferric cyanide in 80 parts of water while stirring in the cold. The liquid is then evaporated to dryness and the resulting oxidation product extracted with warm butyl alcohol. 

The butyl-alcoholic solution is evaporated in vacuo and the residue dissolved with gentle heating in 25 parts by volume of methyl alcohol. 100 parts by volume of acetone are added, the solution filtered and further quantities of acetone added, whereupon crystallization sets in. Yield 12.2 parts by weight of the pure product, having the melting point 177° to 179°C. 

Warnat, K. U.S. Patent 2,458,453 January 4, 1949 assigned to Hoffmann-La Roche Inc. 

Chemical Name D-Threo-2,2-dichloro-N-[/3-hydroxy-Q -(hydroxymethyl)-p-methylsulfonyl-phenethyl] -acetamide 

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The thiol form (12) is susceptible to oxidation (see Fig. 2). Iodine treatment regenerates thiamine in good yield. Heating an aqueous solution at pH 8 in air gives rise to thiamine disulfide [67-16-3] (21), thiochrome (14), and other products (22). The disulfide is readily reduced to thiamine in vivo and is as biologically active. Other mixed disulfides, of interest as fat-soluble forms, are formed from thiamine, possibly via oxidative coupling to the thiol form (12). 

Heating thiamine disulfide (445) in triethylamine yields the A4-thiazoline-2-thione (446) as the main product. The reaction is probably initiated by the nucleophilic scission of the disulfide bond followed by liberation from one of the fragments of the sulfur which is responsible for the introduction of the thione group at the 2-position (Scheme 254) (68JCS(C)2871>. 

A small amount of thiamin is excreted in the urine unchanged, accounting for about 3% of a test dose, together with small amounts of thiamin monophosphate and thiamin diphosphate. As discussed in Section 6.5.1, this can be used to assess thiamin nutritional status. One of the major excretory products is thiochrome cyclization to thiochrome is the basis of the normal method of determining thiamin so, most reports of thiamin excretion are actually of thiamin plus thiochrome. In addition, small amounts of thiamin disulfide, formed by the oxidation of thiamin thiol, are also excreted. 

Figure 6.1. Thiamin and thiamin analogs, products of tliiaminolysis, and experimental antimetabolites. Relative molecular masses (M,) thiamin, 266.4 (chloride-hydrochloride, 337.3) thiamin monophosphate, 345.3 thiamin diphosphate, 425.3 thiamin triphosphate, 505.3 thiochrome, 262.3 thiamin thiol, 282.4 (oxidizes to thiamin disulfide, 562.7) oxythiamin, 301.8 and pyrithiamin, 420.2.

Yasuo. H. and Yoneda N., Aminomethyla-tion of thiantine disulfides and formation of cyclobismcthylenethiamine from N-amino-methylated thiamine disulfide, Chem. Phiirm. Bull. Tokyo, 24. 1128, 1976. 

Volvert, M.L., Seyen, S., Piette, M., et al. (2008) Benfotiamine, a synthetic S-acyl thiamine derivative, has different mechanisms of action and a different pharmacological profile than lipid-soluble thiamine disulfide derivatives. BMC Pharmacol. 8, 10. 

Partial protection from scurvy in guinea pigs provided by a-lipoic acid (R22) is probably due to the preservations of small residual amounts of ascorbic acid in the diet. Ascorbic acid has similar effects on riboflavin-(T4) and thiamine-deficient (T3) rats. The temporary improvements are the result of the reduction of thiamine disulfide to nutritionally active forms (B3). 

B3. B hidi, Z. G., Weight increase in the rat due to thiamine disulfide activation by ascorbic acid. Internat. Rev. Vitamin Research 80, 305-322 (1960). 

Komata, Y, Inaoka, M., Kaneko, A., and Fujie, T. (1992). In vitro percutaneous absorption of thiamine disulfide from a mixture of propylene glycol and fatty acid, J. Pharm. Sci., 81 744-746. 

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