Purine 7//-6-amino-7-methyl-, ring synthesi

Aminopterin and amethopterin are 4-amino analogues of folic acid (Fig. 11.5) and as such are potent inhibitors of the enzyme dihydrofolate reductase (EC 1.5.1.3) (Blakley, 1969). This enzyme catalyses the reduction of folic acid and dihydrofolic acid to tetrahy-drofolic acid which is the level of reduction of the active coenzyme involved in many different aspects of single carbon transfer. As is clear from Fig. 11.6, tetrahydrofolate is involved in the metabolism of (a) the amino acids glycine and methionine (b) the carbon atoms at positions 2 and 8 of the purine ring (c) the methyl group of thymidine and (d) indirectly in the synthesis of choline and histidine. 

The preparation of 9-niethyl and 9-butyl-2-hydroxy-8,9-dihydro-7H-purine-8-thione (XXVa Table 7) is somewhat unusual. Brown [45) has obtained these compounds from carbon disulfide and respectively f-methyl and 1 -butyl-5,6-diamino-1,2-dihydropyrimidin-2-one (XXIVa.). Evidently a shift of the alkyl group from the 3-N to the 9 N atom must occur during the ring closure. The structure of these two purines has been confirmed by their independent synthesis from 4-methylamino and 4-butylamino-5-amino-2-hydroxy pyrimidine. 

Compounds with a peri-fused imidazole ring to the purine ring 257 were only little studied. Their synthesis involved an intramolecular alkylation of 8-alkyl- or 8-aryl-9-(2-mesyloxyethyl)-l-methyl-purinediones 260b. The necessary intermediates 260b were achieved by hydrogenation of the 6-[2-(hydroxyethyl)-amino]-3-methyl-5-nitroso-pyrimidinedione 258 to 5-amino-6-[2-(hydroxyethyl)amino] compound 259 further reactions with the respective ortho-carboxylates and mesyl chloride gave 8-alkyl- or 8-aryl-9-(2-hydroxyethyl)-purinediones 260 or 261 (98CCC407) (Scheme 76). 

---