Requirements for large-scale synthesis of the potent antitumor drug 10-deazaminopterin have led to development of a facile synthesis of this compound and its 10-alkyl analogues. The lithium diisopropyl amide generated dianions of appropriate p-alkylbenzoic acids were alkylated with 3-methoxyallyl chloride. The resulting 4-(p-carboxyphenyl)-1-methoxy-1-butenes were brominated at pH 7-8 to afford the 2-bromo-4-(p-carboxyphenyl)butyraldehydes. Condensation with 2,4,5,6-tetraminopyrimidine and subsequent in situ oxidation of the resulting dihydropteridines yielded crystalline 10-alkyl-10-deaza-4-amino-4-deoxypteroic acids. The pteroic acids were coupled with diethyl glutamate via the mixed anhydride method, followed by saponification at room temperature, to give the target 10-deazaminopterins. The 10-alkyl compounds were approximately equipotent to 10-deazaminopterin as growth inhibitors of folate-dependent bacteria. Their abilities to inhibit Lactobacillus casei and L1210 derived dihydrofolate reductases were also similar. Transport properties in vitro were suggestive of an improved therapeutic index for the 10-alkyl analogues. Against L1210 in mice, the percent increase in life span at the LD10 dosage was +151% (methotrexate), +178% (10-deazaminopterin), +235% (10-methyl analogue), and +211% (10-ethyl analogue). 10,10-Dimethyl-10-deazaminopterin was less effective at an equimolar dosage, but the ILS at the maximum dose tested (72 mg/kg) was +135%. It was far less toxic than the other analogues possibly because of enhanced clearance.

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The synthesis of 2‐amino‐4‐hydroxy‐6‐amyl‐1,3,5‐triazanaphthalene (8) is described as a model sequence pertinent to preparation of 8‐deazafolic acid and its analogs. Condensation of 2‐acet‐amido‐4‐hydroxy‐6‐pyrimidinealdehyde (3) with dimethyl 2‐oxoheptylphosphonate afforded 1‐(2′‐acetamido‐4′‐hydroxy‐6′‐pyrimidinyl)‐1‐octene‐3‐one (4) as a key intermediate. Conversion of 4 to 1‐(2′‐amino‐4′‐hydroxy‐5′ ‐phenylazo‐6′ pyrimidinyl)‐3‐octanone (7) followed by reductive cyclization yielded 8 or its tetrahydro derivative (9).

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