Synthesis of the penta‐glutamyl derivative of N ‐[4‐[ N ‐[3‐(2,4‐diamino‐1,6‐dihydro‐6‐oxo‐5‐pyrimidinyl)‐propyl]amino]benzoyl]‐L‐glutamic acid (5‐DACTHF). An acyclic analogue of tetrahydrofolic acid

The penta‐glutamyl derivative of N ‐[4‐[ N ‐[3‐(2,4‐diamino‐1,6‐dihydro‐6‐oxo‐5‐pyrimidinyl)propyl]amino]‐benzoyl)‐L‐glutamic acid (1, 5‐DACTHF, 543U76) was synthesized by a convergent route. L‐γ‐Glutamyl‐L‐γ‐glutamyl‐L‐γ‐glutamyl‐L‐γ‐glutamyl‐L‐γ‐glutamyl‐L‐glutamic acid heptakis t ‐butyl ester ( 20 ) was prepared in ten steps from L‐glutamic acid di‐ t ‐butyl ester and N ‐(benzyloxycarbonyl)‐L‐glutamic acid α‐t ‐butyl ester. 4‐[ N ‐[3‐(2,4‐Diamino‐1,6‐dihydro‐6‐oxo‐5‐pyrimidinyl)propyl]trifluoroacetamido]benzoic acid ( 6 ), which was synthesized from pyrimidinylpropionaldehyde 3 in three steps, was condensed with 20 , followed by deprotection to provide N ‐[4‐[ N ‐[3‐(2,4‐diamino‐1,6‐dihydro‐6‐oxo‐5‐pyrimidinyl)propyl]amino]benzoyl]‐L‐γ‐glutamyl‐L‐γ‐glutamyl‐L‐γ‐glutamyl‐L‐γ‐glutamyl‐L‐γ‐glutamyl‐L‐glutamic acid ( 2 ). Hexaglutamate 2 is a potent inhibitor of glycinamide ribonucleotide transformylase.