III. INDUSTRIAL PREPARATION 123 



Kaiivr ;iii(l Schwyzcr" coiulensod 2 , 1 .•">-< i'iainiiH)-(>-liytlroxy])yiiiiii(liiio 

 with jilyccraldeliydc or diliydroxyacetone, gniiig a mixture of 2-amino-4- 

 hydroxy-()-liydro.\ymetliylpteridine and 2-amiiio-4-hydro\y-7-hydroxy- 

 methylpteridine. Reacted with p-amiiiobenzoylglutamic acid, the former 

 compound yielded P(iA. 



Uoclie Products Lts.^ obtained a patent for PC I A synthesitj by reacting 

 2-amino-4-hydroxy-6-hydroxymethylpteridine with thionyl chloride and 

 then treating the product with p-aminobenzoylghitamic acid, or hydro- 

 genating a mixture of pteridine and p-iiitrobenzoylglutamic acid. This 

 company subsequently obtained a series of patents on the synthesis of 

 P( JA and intermediate compounds, a few of which are listed.^ 



Hoffman-LaRoche Co.^'' condensed 2,4,5-triamino-6-hydroxypyrimidine 

 with a ketohexose and oxidized the 2-amino-4-hydroxy-6-tetrahydroxy- 

 butylpteridine which resulted with lead tetraacetate or another agent 

 capable of producing the glycol cleavage. The 2-amino-4-hydroxy-6-pter- 

 idylaldehyde that was formed was hydrogenated in an inert solvent or in 

 formic acid in the presence of p-aminobenzoylglutamic acid and a catalyst, 

 and PGA was obtained. Some formylpteroylglutamic acid was produced, 

 and this was converted to PGA by treatment with ammonia. Several of 

 the patents issued to this company are hsted." 



Forrest and Walker^- reacted glucose and fructose with 2,4,5-triamino-6- 

 hj'droxypyrimidine in the presence of hydrazine and obtained 2-amino-4- 

 hydroxy-6-D-arabotetrahydroxybutylpteridine; in the absence of hydrazine 

 he found 2-amino-4-hydroxy-7-D-arabotetrahydroxybutylpteridine. 



Uyeo and Mizukami^^ reported better yields when mercuric acetate was 

 used as a dehydration agent in Waller's method^ of synthesis. In a more 

 recent paper Uyeo et al}^ described a further modification of this method 

 of PGA synthesis. 



2,444,002, 2,444,005, 2,472,520, 2,500,296, 2,517,530, 2,520,479, 2,537,006, 2,547,519, 

 2,547,520, 2,568,597, 2,570,391, 2,570,392; British Pats. 12,491, 14,216, 24,564, 25,001, 

 25,002 (1948) ; 3,413, 631,494 (1949) ; 638,411, 638,480, 640,092 (1950) ; 644,913, 648,896, 

 650,276, 654,512, 655,771, 656,403, 657,902 (1951); 258,538 (1952). 



' P. Karrer and R. Schwyzer, Helv. Chim. Acta 31, 777 (1948). 



8 Roche Products Ltd., British Pats. 264,394, 630,751. 



» Roche Products Ltd., British Pats. 624,394, 628,305, 626,171 (1949); Belgium Pat. 

 481,230 (1948). 



>« HofTman-LaRoche and Co., British Pats. 626,171, 628,305; Roche Products Ltd., 

 British Pat. 631,516. 



'1 HotTman-LaRoche and Co., U. S. Pats. 2,487,393, 2,520,882; British Pats. 629,440 

 (1949); 657,254 (1951); 664,721 (1952); Swiss Pats. 253,838 (1948); 255,409, 258,141, 

 263,147 (1949); 263,281 (1950); 263,147 (1951); 268,328 (1952). 



'2 H. S. Forrest and J. Walker, /. Chem. Soc. 1949, 2077. 



'' S. Uyeo and S. Mizukami, Japan. J. Pharm. & Chem. 21, 237 (1949). 



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

 (1950). 



