106 



PTEROYLGLUTAMIC ACID 



Numerous synthetic methods have subsequently been developed, the 

 large number of which is reflected in the many publications and patents in 

 this field. These procedures may be divided into two main categories: first, 

 those in which 2,4,5-triamino-6-hydroxypyrimidine (II) is condensed 

 simultaneously with a 3-carbon intermediate and p-aminobenzoylglutamic 

 acid; second, those in which a substituted pterin is first formed and then 

 coupled with an aromatic amine to give PGA. 



1. Simultaneous Condensation of Triaminopyrimidine, 3-Carbon 

 Intermediate, and Aromatic Amine 



The first method of synthesis, that of Waller et at}'' in which 2 , 3-dibromo- 

 propionaldehyde is used as the 3-carbon fragment, has already been de- 

 scribed. Examples of other 3-carbon systems which have been used are 

 given below. (X in the formula denotes chlorine or bromine. Reference 

 numbers are given in parentheses.) 



O 



H 



CH2X— C— CHO (36) 



0=C— C=C— COOH 



(37) 



X X 



(followed by decarboxyl- 

 ation) 



H OH 

 HO— C=C— CHO (34, 38-40) 



X— CH2— CX2— CHO (44) 







X— CH2— C— CHX2 (41-43 



CICH2— C— CHO 

 NOH 



(45) 



36 J. H. Mowat (to American Cyanamid Co.), U. S. Pat. 2,4.36,073 (Feb. 17, 1948). 

 " C. W. Waller and J. H. Boothe (to American Cyanamid Co.), U. S. Pat. 2,442,867 

 (June 8, 1948). 



38 R. B. Angier (to American Cyanamid Co.), U. S. Pat. 2,442,836 (June 8, 1948). 



39 R. B. Angier (to American Cyanamid Co.), U. S. Pat. 2,442,837 (June 8, 1948). 

 "R. B. Angier (to American Cyanamid Co.), U. S. Pat. 2,466,670 (Apr. 12, 1949). 

 " F. Weygand and V. Schmied-Kowarzik, Chem. Ber. 82, 333 (1949). 



^2 M. E. Hultquist and P. F. Dreisbach (to American Cyanamid Co.), U. S. Pat. 



2,443,165 (June 8, 1948). 

 "S. Uyeo, S. Mizukami, T. Kubota, and S. Takagi, J. Am. Chem. Soc. 72, 5339 



(1950). 

 **J. H. Boothe (to American Cyanamid Co.), U. S. Pat. 2,444,002 (June 22, 1948). 

 ^6D. B. Cosulich (to American Cyanamid Co.), U. S. Pat. 2,444,005 (June 22, 1948). 



