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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
Author(s) -
Styles Virgil L.,
Kelley James L.
Publication year - 1990
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.5570270654
Subject(s) - chemistry , glutamic acid , benzoic acid , derivative (finance) , stereochemistry , amino acid , medicinal chemistry , organic chemistry , biochemistry , financial economics , economics
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.