ANEURINE (thiamine) 



CaH.O . CH2 . CH, . COOCaH^ ^■^^^^'^\ CaH.O . CH^ . CH . COOC^Hs !!^ii£1^5!^J 



I 

 CHO 



N=C . OH N=C . CI 



CH3.C C.CH2.OC2H, ^^ CH3.C C.CH^.OC.H^ -— ^ 



II II il II 



N— CH N— CH 



N=C . NH2 N=C . NH2 



II HBr I I 



CH3 . C C . CH2 . OCaHg — > CH3 . C C . CHaBr 



II II 11 II 



N— CH N— CH 



The final product, in the form of its hydro bromide, was reacted 

 with 5-^-hydroxyethyl-4-methyl-thiazole, obtained by E. R. Buchman * 

 from a-aceto-y-butyrolactone by the following series of reactions : 



CHj— CH, 



CH3 . CO . CHa . COOC2H5 — . CH, . CO . CH . CHa . CH2 — i 



O 



L 



CH3 . CO . CCl . CH2 . CH2 ^'^' °^^ > CH3 . CO . CHCl . CHa . CH2OH 



io L 



Aneurine bromide hydrobromide was formed and this was con- 

 verted into the chloride hydrochloride by shaking with silver chloride. 

 Attempts to prepare the pyrimidine half by other methods ^ such as 

 by Curtius, Hoffman or Loessen degradations of the appropriate 

 derivatives of 4-hydroxy-2-methyl-pyrimidine-5-acetic acid (obtained 

 from hydroxymethyl malonic ester) were not very successful. 



The method of Williams et al. has been adopted for the large scale 

 manufacture of vitamin B^ by Merck & Co., Rahway, and a large 

 number of patents have been filed in this country, in the U.S.A. and 

 elsewhere to protect this process. The first group ^ describes the 

 preparation of halogenated acetopropyl alcohols, esters and similar 

 derivatives, which are required in the synthesis of the thiazole half, 

 by halogenation of acetopropyl alcohol or the appropriate derivative 

 or by hydrolysis and decarboxylation of halogenated a-aceto-y- 

 butyrolactone. The second group,'' comprising a single patent, 

 protects the condensation of halogenated acetopropyl alcohol with 

 thioformamide to give 4-alkyl-5-hydroxyalkyl thiazoles. The third 

 group 8 covers the condensation of acetamidine with a-formyl-^- 

 ethoxypropionic ester to give 5-ethoxymethyl-4-hydroxy-2-methyl- 

 pyrimidine, and the preparation from this compound of the 



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