{Author}: Xueqing Zhao, Fei Li , Weiping Zhuang, Xiaowen Xue, Jingming Zhou，Dongsheng Fang

{Journal}: Organic Process Research & Development

{Year}: 2010

{Volume}: 14

{Issue}: 2

{Pages}: 346-350

{Abstract}: A new synthetic method for nolatrexed dihydrochloride (thymitaq) has been developed. The synthesis was accomplished in three steps featuring the direct conversion of the starting 4-bromo-5-methylisatin into the methyl anthranilate by potassium peroxydisulfate/sodium methoxide. In the final Ullmann reaction potassium carbonate was employed in place of sodium hydride, and the amount of copper catalysts was significantly reduced. Moreover, sodium sulfide solution was utilized to efficiently remove copper under approximately neutral conditions instead of hydrogen sulfide/methanol under strongly acidic conditions. By means of these modifications, nolatrexed dihydrochloride was ensured to be prepared in good yield and high purity.