SYNTHESIS 



corresponding 4 -halogeno- derivatives and thence the 4-araino- 

 compound. The preparation of the 2-methyl-5-halogenomethyl-4- 

 amino-pyrimidine is also described. 



The last group ^ covers the formation of aneurine by condensation 

 of 5-^-hydroxyethyl-4-methyl-thiazole with 4-amino-5-bromomethyl-2- 

 methyl-pyrimidine or with 5-alkyloxyniethyl-2-methyl-4-amino- 

 pyrimidine, or with (4-amino-2-methyl-pyrimidyl-5-)-bromoacetic acid. 



5-^-Hydroxyethyl-4-methylthiazole has also been prepared by 

 reducing ethyl 4-methylthiazole-5-acetate with lithium aluminium 

 hydride, the ester being prepared by the reaction of ethyl a-bromo- 

 laevulinate with thiof ormamide. ^'^ 



British Method 



The method of synthesis discovered by Todd et al. differs in one 

 important respect from that of Williams : the thiazole ring is formed 

 as the last stage of the synthesis, being produced by the action of 

 3-aceto-3-chloro-propyl alcohol on the appropriate thioformamido- 

 methyl-pyrimidine. The preparation of such thioformamido com- 

 pounds was first described by Todd et al.}^ who showed that 5-amino- 

 pyrimidine yielded the corresponding thioformyl derivative on treat- 

 ment with a solution of potassium dithioformate ; the reaction does not 

 occur with 2-, 4- or 6-amino-pyrimidine. By reacting 4-amino-6-ethyl- 

 5-thioformamido-pyrimidine with 3-aceto-3-chloro-propyl alcohol, 

 an isomer of anemrine was obtained, identical with the compound 

 represented by Williams' first formula (page 13). The fact that it 

 was biologically inactive helped towards the rejection of this formula. 

 Potassium dithioformate was subsequently used by A. R. Todd and 

 F. Bergel ^^ to prepare aneurine itself, the complete series of reactions 

 being as follows : 



NH2 QHjO.OC N=C.OH N=C.C1 



I I I II II 

 CH3.C + C.CN >CH3.C C.CN ^CHj.C C . CN ► 



II II II II II II 

 NH CaHjO— CH N— CH N— CH 



N=C.NH2 N=C.NH3 ^ N=C . NH, 



II II II 



CH3.C C.CN ^CHa.C C.CHa.NHa > CH3 . C C . CH^ . NH . CSH 



II II II II 11 II 



N— CH N— CH N— CH 



y Aneurine 



In an alternative process, acetamidine was coupled, not with 

 ethoxymethylene-cyanacetic ester, but with ethoxymethylene-malonic 

 2 17 



