Synthesis of Allopurinol

There are several ways of synthesising allopurinol.

              The first reaction scheme⁷ is shown below:

             The hydrolysis of the nitrile group of 3-amino-4-cyanopyrazole (VI) with concentrated sulfuric acid gave 3-amino-4-pyrazolecarboxamide (X) isolated as the sulfate in greater than 80% yield. This sulfate when heated with formamide gave an excellent yield of 4-hydroxypyrazolo(3,4-d)pyrimidine (XIV), allopurinol which is the analog of hypoxanthine.

             Preparation of 4-hydroxypyrazolo(3,4-d)pyrimidine (XIV).  75 g. of the sulfate salt of 3-amino-4-pyrazolecarboxamide (X) and 200 ml. of C.P.formamide were heated at 180-190ƒC for 45 minutes.  The cooled solution was diluted with one litre of cold water and filtered to yield 48.0 g. of XIV.  An analytical sample was obtained by recrystallization of the crude product from water.

Anal. Calcd. for C₅H₄N₄O:  C, 44.1;   H,  2.94;  N, 41.2.

Found: C, 44.3;  H, 3.0;  N, 41.1.

              The second reaction scheme⁶ below shows diazotization of allopurinols, which is purine antagonists in the 1-n-triazolo[d] pyrimidine series, obtained by the requisite 4,5-diaminopyrimidines

              Analogs of guanine, adenine, xanthine and hypoxanthine, in which a nitrogen replaced a carbon atom of the corresponding purine, were prepared by this general method.  The pyrimidine intermediate required for the synthesis of the hypoxanthine analog was obtained by refluxing an aquoeus solution of 2-thio-4,5-diamino-6-hydroxypyrimidine with Raney nickel catalyst.