III. INDUSTRIAL PREPARATION 413 



A and li stM-\o to build \ip the jiyrimidinc rinp;, C and I) for tho ring 

 closure to the thiazole or thiazolium nucleus. .Mi tinee industrial sj^ntheses 

 use these fom* groups as stepping stones to the end product; in I'odd and 

 Bergel's synthesis the nitrogen for the thiazolium ring switches to group 

 ]\ wliit'h is then elongated to grouj) D. 



1. Group A, Two Carbon and Two Nitrogen Atoms 



The natural starting material for the left half of the pyrimidine ring is 

 NH 



acetamidine CH3 — C , which is easily available from acetonitrile in 



\ ■ . 



NH2 



two steps: the nitrile is converted to acetimino ether bj' etlumolic hj'drogen 

 chloride in the absence of water, the ether being converted to acetamidine 

 hydrochloride with ethanolic ammonia. Yield is 80 to 91 % in small 

 batches.-- Under optimal conditions, the yield may be raised to 95%. 

 Instead of acetamidine the acetimino ethyl ether can be used if amino 

 methjdene malonitrile-* serves as group B. The use of thioacetamide and 

 amino methylene malonitrile-* does not offer special advantages. Acetoni- 

 trile, the starting material, can be obtained from dimethylsulfate and 

 sodium cyanide. In this country it is available as a commercial item. 



2. Group B, Four Carbon Atoms and One or Two Amino Groups 



(4)C 



I 



(5)C— C 

 I (7) 

 (6)C 



The carbon skeleton with four carbon atoms permits quite a number of 

 variations. The chain of the carbon atoms 4, 5, and 7 can be provided by 

 the esters of ethoxypropionic acid, succinic acid, malonic acid, and malo- 

 nitrile; carbon atoms 6 is added in most of the cases by a formyl group, 

 either as such or as the methylene ether. The substitution in 7 may lead 

 to a halogen or to an amino group (synthesis of Todd and BergeP^). 



a. Indirect Introduciion of the Amino Group in the 4 Position 



Cline et al}^ start from ethoxypropionic ester (obtained from etliyl 

 acrylate by addition of ethanol with .sodium ethjdate) and convert it with 



" Organic Syntheses, Vol. 22, p. 5. John Wiley and Sons, New York, 1941. 



" O. Ilromatka, Merck & Co., U.S. Pat. 2,235,638 (March 18, 1941); Merck & Co., 



German Pat. 667,990 (November 24, 1938); F. IIonmann-La Roche and Co., .V. G., 



Briti.sh Pat. 486,414 (June 2, 1938). 

 " F. Hoffmann-La Roche and Co., A. G., British Pat. 546,624 (July 22, 1942). 

 " J. K. Cline, R. R. Williams, and J. Finkelsteiu, /. Am. Chem. Soc. 59, 1052 (1937). 



