Hydrochloric Acid → 2,4-Diaminopyrido[2,3-d]pyrimidine-6-carbonitrile

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Referring now to Scheme I, compounds 3 and 4 were prepared by reported procedures, which proved to be readily adaptable to large-scale preparations. The reductive dechlorination Steps to give 5 and 6 were done in DMF--MeOH (N,N-dimethylformamide-methyl alcohol) solution containing 5% Pd on BaCO3. This method differs slightly from the reported conversion of 3 to 5, which was done in DMF using PdCl2 with Et3N (triethylamine) serving as the HCl scavenger. Annelation of the 2,4-diaminopyrimidine moiety by treatment of 5 and 6 with guanidine in refluxing EtOH (ethyl alcohol) followed. 2,4-Diaminopyrido[2,3-d]pyrimidine-6-carbonitrile (7) was obtained in 95% yield; starting 5 was no longer present in the reaction mixture after 24 hours according to TLC. The 5-methyl congener 8 formed less readily. Even after 5 days, some 6 was still present, but the unchanged material was easily removed during isolation of 8 in acceptable (58%) yield. Reductive condensation of 7 with diethyl N-(4-aminobenzoyl)-L-glutamate in 70% AcOH (acetic acid) solution in the presence of Raney Ni was done using a procedure similar to that reported for the reductive amination of the corresponding aldehyde. The procedure was adapted from the reported general method for the preparation of quinazoline (5,8-dideaza) analogues of AMT. The diethyl ester 9 thus formed proved to be identical with the sample previously reported. The reductive condensation was then applied to 8 to give the diethyl ester of the corresponding 5-methyl compound 10. The esters 9 and 10 were then hydrolyzed to give 5-dAMT (11) and 5-Me-5-dAMT (12). The methyl compound 12 was methylated at N10 to give 5-methyl-5-deazamethotrexate (5-Me-5-dMTX, 20).

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