WHI-05

Chemical Name: 3'-Azido-5-bromo-5'-O-[4-methoxyphenoxy[1-(methoxycarbonyl)ethylamino]phosphoryl]-3'-deoxy-6-methoxy-5,6-dihydrothymidine
项目整合开发状态: Preclinical
项目研究机构: Parker Hughes Institute (Originator), Paradigm Pharmaceuticals (Not Determined)
合成路线:Treatment of 4-bromophenol (I) with phosphoryl chloride gave p-bromophenyl phosphoro- dichloridate (II),which was condensed with alanine methyl ester (III) to furnish alaninyl phosphorochloridate (IV).Further coupling of (IV) with 3'-azidothimidine (V) in the presence of N-methylimidazole afforded phosphate (VI).Then,addition of methyl hypobromite,(prepared from bromine and MeOH) provided the title compound as a diastereomeric mixture.

合成路线:In a related procedure,methyl hypobromite was added to 3'-azidothimidine (V) in MeOH,and the resulting mixture of diastereomeric 5-bromo-6-methoxypyrimidines (VII) and (VIII) was separated by column chromatography.Both the (5R,6R)- and the (5S,6S)-isomers (VII) and (VIII) were then coupled to phosphorochloridate (IV) to yield the title compound as seperated enantiomers.

合成路线:The reaction of 4-methoxyphenol (I) with POCl3 and triethylamine in ethyl ether gives the dichlorophosphate (II),which is condensed with alanine methyl ester (III) by means of triethylamine in dichloromethane yielding the amide (IV).The condensation of (IV) with azidothymidine (V) by means of N-methylimidazole (NMI) in THF affords the 5'-phosphate derivative (VI),which is finally treated with methyl hypobromite (Br2 in methanol).