An improved synthesis of piperazino-piperidine based CCR5 antagonists with flexible variation on pharmacophore sites

An improved and efficient synthetic route towards piperidino-piperazine based CCR5 antagonists was developed. The new approach was flexible for introducing various substitutents in the pharmacophore sites via Grignard reagent addition and reductive amination. L-Amino acids were used as a chiral pool to introduce and then induce the desired stereochemistries, meanwhile rendering the variable substitution. The efficient construction of the piperazino-piperidine nucleus was achieved in a highly convergent manner with a key building block of N-1-Boc-4-substituent-4-aminopiperidine, exhibiting significant advantages in terms of concise synthetic route and environmental-friendly reagents over the previously described stepwise synthesis, in which a modified Strecker reaction was involved with highly toxic reagents such as diethylaluminum cyanide. (C) 2004 Elsevier Ltd. All rights reserved.