SYNTHESIS 



In a fourth method,^ 2-amino-4-hy(iroxy-6-methylpteridine, 

 prepared by reduction of 2 - amino - 4 - hydroxy - 6 - pteridylmethyl 

 pyridinium iodide, was either brominated or chlorinated and the 

 product condensed with the diethyl ester of ^-aniinobenzoylglutamic 

 acid. 



All these and several similar methods were patented by the 

 American Cyanamid Co.® Thus in place of 2 : 3-dibromopropionalde- 

 hyde, there may be used 3-halogeno-2-isonitrosopropionaldehydes, 

 2:2: 3-trihalogeno-propionaldehydes, 2-halogeno-3-alkoxypropion- 

 aldehydes, 1:1- dihalogeno -2:3- epoxypropanes, 1:1:3- trihalo- 

 genoacetones or 2:2: 3-trihalogenoalkylaldehydes. In addition, a 

 patent was filed by the same company to cover the preparation of 

 pteroylglutamic acid from the corresponding diaminopteridine by 

 heating in an aqueous solvent under alkaline conditions, i : i-Dichloro- 

 acetone and i : i-dichloro-3-bromoacetone were used by F. E. King 

 and P. C. Spensley.' 



P. Karrer and R. Schwyzer ^ developed a new method of synthe- 

 sising pteroylglutamic acid, in which 2:4: 5-triamino-6-hydroxy- 

 pyrimidine was condensed with glyceraldehyde or dihydroxyacetone 

 giving a mixture of 2-amino-4-hydroxy-6-hydroxymethylpteridine and 

 2 -amino -4- hydroxy- 7-hydroxyme thy Ipteridine. The former gave 

 pteroylglutamic acid with ^-aminobenzoylglutamic acid. Reaction 

 of the pyrimidine with glyceraldehyde di-_/)-toluenesulphonate and 

 ^-aminobenzoylglutamic acid in presence of sodium iodide also yielded 

 pteroylglutamic acid. 



Roche Products Ltd.^ patented processes for the preparation of 

 pteroylglutamic acid by reacting 2-amino-4-hydroxy-6-hydroxy- 

 methylpteridine with thionyl chloride and then treating the product 

 with ^^-aminobenzoylglutamic acid, or by hydrogenating a mixture of 

 the pteridine and ;/)-nitrobenzoylglutamic acid. Hoffmann-La Roche 

 & Co.i<^ condensed 2:4: 5-triamino-6-hydroxy-pyrimidine with a 

 ketohexose and oxidised the resulting 2-amino-4-hydroxy-6-tetra- 

 hydroxybutylpteridine with lead tetra-acetate or some similar reagent 

 capable of effecting glycol cleavage. The 2-amino-4-hydroxy-6- 

 pteridylaldehyde so formed was hydrogenated in an inert solvent or 

 formic acid in presence of /)-aminobenzoylglutamic acid and a catalyst, 

 giving pteroylglutamic acid ; any formyl-pteroylglutamic acid pro- 

 duced at the same time was converted into pteroylglutamic acid 

 by treatment with ammonia. H. S. Forrest and J. Walker ^^ found 

 that in the presence of hydrazine, glucose and fructose reacted with 

 2:4: 5-triamino-6-hydroxypyrimidine to give 2-amino-4-hydroxy-6- 

 D-arabotetrahydroxybutylpteridine, whereas in the absence of hydra- 

 zine, 2-amino-4-hydroxy-7-D-arabotetrahydroxybutylpteridine was 

 formed. 



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