ANEURINE (thiamine) 



synthesis of the pyrimidine half from acetamidine and formyl-succinic 

 ester as follows : 



NH2 CHO Nr=CH 



II II 

 CH3 . C + CH . CH2 . COOC2H5 > CH3 . C C . CH2 . COOC2H5 > 



II I ' li II 



NH COOCaHg N— C . OH 



N=CH N=CH 



CH3 . C C . CHj . COOC2H6 ^ CH3 . C C . CH2 . CONH2 > 



II II II II 



N— C . CI N— C . NH^ 



N=CH n=zk:h 



II II 



CH3 . C C . CH2 .NHa > CH3 . C C . CH^Br 



II II II II 



N— C . NH2 N— C . NH2 



They synthesised the thiazole half by condensing 3-bromo-3-aceto- 

 propyl acetate with barium thiocyanate to give 2-hydroxy-5-^- 

 hydroxyethyl-4-methyl- thiazole from which the hydroxyl group was 

 removed by chlorination, followed by reduction. The product was 

 condensed with 4-amino-5-bromomethyl-2-methyl-p5n-imidine, giving 

 aneurine bromide hydrobromide. 



The I.G. patents based on this work cover, not only the direct 

 coupling of the thiazole half and the pyrimidine half, but also the 

 preparation of aneurine from the thioformamidomethyl-pyrimidine. 

 One group of patents ^^ covers the preparation of pyrimidine com- 

 pounds by combining acetamidine with a great variety of formyl- 

 and alkoxjmiethylene-acetic esters and acetonitriles substituted by a 

 group convertible into the aminomethyl group. 



The preparation of the thiazole compound by Andersag and 

 Westphal's barium thiocyanate method was the subject of another 

 patent, 28 which mentions incidentally the preparation of the necessary 

 3-bromo-3-acetopropyl alcohol esters. The final stage of the synthesis 

 was described in another patent, ^^ which includes both the direct 

 coupling of the two halves and the condensation of 4-amino-2-methyl- 

 5-thioformamidomethyl-pyrimidine with y-aceto-y-bromopropyl ben- 

 zoate. 



A variant of the LG. method of preparing the pyrimidine half of 

 the molecule was described by Chinoin,^^ who condensed alkoxyme- 

 thylene-cyanoacetic esters with a base such as acetamidine to form the 

 intermediate a-cyano-j3-amidino-acrylic acid which, on heating with 

 water or acidulated water, yielded the amino-pyrimidine : 



20 



