416 THIAMINE 



duced*" to 2-methyl-4-amino-5-aminomethylpyrimidine, the last step in 

 this group for their synthesis. 



Not satisfied with the results, Todd and Bergel found a much better 

 ring closure with ethyl ethoxymethylene malonate and acetamidine in 

 presence of 1 mole of sodium ethylate; the ring is closed with a yield of GO %. 



NH2 COOEt N=C— OH 



II II 



CH3— C + C— COOEt -> CH3— C C— COOEt 



II II II II 



NH CHOEt N— CH 



After the replacement of the hydroxyl group by chlorine (yield 65 %), 

 the 4-chloro compound is treated with concentrated aqueous ammonia at 

 room temperature. 



The yield of amination is 65 %, and the following dehydration of the 

 amide to the nitrile yields 50 %. The hydrogenation to the diamine is done 

 as above. 



Starting from acetonitrile, ethyl cyanoacetate, or malonate and ethyl 

 orthoformate, both methods of Todd and Bergel have eight steps. The 

 yields of the second method w^ere promising, but both methods were aban- 

 doned when still better ways became available. 



Andersag and Westphal's procedure^^ is interesting in that they could 

 perform a Hofmann degradation in the pyrimidine series, a reaction W'hich 

 the American and British workers had tried without success. The condensa- 

 tion of acetamidine with ethyl formyl succinate in hot alcoholic solution 

 gives ethyl 2-methyl-4-hydroxypyrimidyl[5]acetic ester, which is converted 

 via the 4-chloro compound to 2-methyl-4-aminopyrimidyl[5]acetamide. 



This amide is treated with an ice-cold aqueous solution of bromine in 2.5 

 A'^ potassium hydroxide and heated, yielding 2-methyl-4-amino-5-amino- 

 methylpyrimidine in a nearly quantitative yield. The diamide dihydro- 

 chloride is then treated with a hot solution of sodium nitrite to remove the 

 amino group in the 7 position, and the resulting 2-methyl-4-amino-5-hy- 

 hydroxymethylpyrimidine is converted with hydrogen bromide in acetic 

 acid to 2-methyl-4-amino-5-bromomethylpyrimidine dihydrobromide. As 

 with the exception of the Hofmann degradation no yields are given for the 

 nine different steps, it is not possible to evaluate the method. It seems that 

 the I. G. Farbenindustrie has not used it technically. 



h. Direct Introduction of the Amino Group in the 4 Position 



If ethyl a-cyano-jS-acetamidinoacrylate (Todd and BergeP^) is not treated 

 with alkali but heated in water (with or without a slight amount of acid), 

 the ring closes in a different way, the carbon atom of the cyano group enter- 

 ing the ring and leaving the carbothoxy group untou died. 



