The synthesis of 10-EDAM is as follows: 3-Methoxyallyl chloride (II) is prepared in situ by treatment of 1-methoxyallene (I) with an equivalent of HCl in ether at low temperature. The dianion of p-n-propylbenzoic acid is generated in THF at 0-5 C by lithium diisopropyl amide and subsequently alkylated with (II). The resulting 4-(p-carboxyphenyl)-1-methoxy-1-hexene (III) is brominated at pH 7-8 to give the alpha-bromoaldehyde acid (IV). Condensation with tetraaminopyrimidine in aqueous AcOH and subsequent in situ oxidation of the resultant dihydropteridine affords crystalline 10-ethyl-10-deaza-4-amino-4-desoxypteroic acid (V). Coupling of (V) with diethyl L-glutamate via the mixed anhydride method using isobutyl chloroformate affords the diethyl ester of 10-EDAM (VI). Following chromatographic purification on silica gel, the diester is saponified with 1N NaOH in methoxyethanol at room temperature to yield 10-EDAM.

The synthesis of 10-EDAM is as follows: 3-Methoxyallyl chloride (II) is prepared in situ by treatment of 1-methoxyallene (I) with an equivalent of HCl in ether at low temperature. The dianion of p-n-propylbenzoic acid is generated in THF at 0-5 C by lithium diisopropyl amide and subsequently alkylated with (II). The resulting 4-(p-carboxyphenyl)-1-methoxy-1-hexene (III) is brominated at pH 7-8 to give the alpha-bromoaldehyde acid (IV). Condensation with tetraaminopyrimidine in aqueous AcOH and subsequent in situ oxidation of the resultant dihydropteridine affords crystalline 10-ethyl-10-deaza-4-amino-4-desoxypteroic acid (V). Coupling of (V) with diethyl L-glutamate via the mixed anhydride method using isobutyl chloroformate affords the diethyl ester of 10-EDAM (VI). Following chromatographic purification on silica gel, the diester is saponified with 1N NaOH in methoxyethanol at room temperature to yield 10-EDAM.

A new synthesis for edatrexate has been described: The reaction of 2,4-diamino-6-(bromomethyl)pteridine (I) with tributylphosphine (II) in DMSO gives the corresponding phosphonium salt (III), which is condensed wtih 4-propionylbenzoic acid methyl ester (IV) by means of NaH in DMSO, affording 4-[1-(2,4-diaminopteridin-6-yl)-1-ethylvinyl]benzoic acid methyl ester (V). The hydrogenation of (V) with H2 and PtO2 in acetic acid gives 4-[1-(2,4-diamino-6,7-dihydropteridin-6-ylmethyl)propyl]benzoic acid methyl ester (VI), which, without isolation, is dehydrogenated with H2O2 in the same solvent yielding 4-[1-(2,4-diaminopteridin-6-ylmethyl)propyl]benzoic acid methyl ester (VII). The hydrolysis of (VII) with NaOH in DMSO - water affords the corresponding free acid (VIII), which is condensed with L-glutamic acid diethyl ester (IX) by means of isobutoxycarbonylchloride and triethylamine in DMF, giving edatrexate diethyl ester (X). Finally, this compound is hydrolyzed with NaOH in methanol.