Synthesis Of CCR5 Antagonist TAK-779 As An Anti-HIV Lead Compound

Acquired immune deficiency syndrome (AIDS) is a disease of the human immune system caused by the human immunodeficiency virus (HIV), which is now a pandemic, retarding economic growth and destroying human capital.The compound TAK-779 was a new small-molecule CCR5 antagonist with highly efficient anti-HIV-1 activity, which was optimized by Takeda Pharmaceuticals Co., Ltd. Japan. Although this drug was put on hold due to liver toxicity concerns, it was still very important, since it would be helpful in research and development of other lead compounds by group replacement and modification.Based on a large amount of references, a synthetic route of TAK-779 was chosen.The target compound TAK-779 was obtained by condensation of two key intermediates, the carboxylic acid 11 and the aniline 13, followed by quaternary ammoniation and ion-exchanges.The key intermediate, carboxylic acid 11 was prepared from the starting material bromobenzene, via 10 steps, including Friedel-Crafts acylation, hydrolysis, selective reduction, intramolecularly Friedel-Crafts acylation, Suzuki coupling reaction, methoxycarbonylation, reduction, hydrolysis, sulfonylation, elimination and hydrolysis. The other key intermediate, aniline 13 was given via amination and reduction of nitro derivates, using (4-nitrophenyl)methanamine as the starting material.The total yield was 3.3%. And the structures of all the intermediates and products were determined by LC-MS and1H-NMR.