Synthesis of a novel 5-deaza-5-thia analogue of tetrahydrofolic acid, N-(p-{[(2-amino-6,7-dihydro-4-oxo-3H,8H-pyrimido[5,4-b][1,4]thiazin-6-yl)methyl]amino}benzoyl)glutamic acid

Abstract

N-(p-{[(2-Amino-6,7-dihydro-4-oxo-3H,8H-pyrimido[5,4-b][1,4]thiazin-6-yl)methyl]amino}benzoyl)glutamic acid 4, a deaza-this analogue of tetrahydrofolic acid, was first synthesised as a diastereoisomeric mixture by the thermal condensation of 5-bromo-6-chloroisocytosine 6 with diethyl N-{p-[(3-amino-2-mercaptopropyl)amino]benzoyl}glutamate 5bvia the aliphatic S–N-type Smiles rearrangement in ethanolic pH 7 phosphate buffer solution followed by smooth alkaline hydrolysis of the ester protecting group.