Total Synthesis of Methotrexate-γ-TRIS-Fatty Acid Conjugates

Abstract

Several routes for the regiospecific synthesis of lipophilic γ-conjugates of methotrexate are described. Coupling of methotrexate-α-tert-butyl ester with glycyl-TRIS-(mono-/di-/tri-)palmitate followed by trifluoroacetic acid cleavage of the α-protection afforded the target methotrexate-γ-glycyl-TRIS-(mono-/di-/tri-)palmitate derivatives. Methotrexate-α-benzyl-γ-glycyl-TRIS-tripalmitate was prepared but no method was found to selectively cleave the α-ester. A method where the diaminopteridinylmethyl moiety was attached last was successful, but was low yielding in the final step. Coupling of 4-amino-4-deoxy-N¹⁰-methylpteroic acid with glutamoyl-γ-glycyl-TRIS-palmitate derivatives efficiently afforded the desired conjugates.