Parallel synthesis of Levetiracetam (Keppraź) and its analogs via an Ugi-RCM strategy


Guobin Miao,, Ying Kan, Chi Le, Vivek Joshi, Ruhui Qiu, Libing Yu, and Carmen Baldino. Chemistry Department, ArQule, Inc, 19 Presidential Way, Woburn, MA 01801
As part of our continued efforts to develop protocols for parallel synthesis of bioactive small molecules for drug discovery, we have recently developed a synthetic strategy using the tandem Ugi/Ring closing metathesis (RCM) sequence to construct the pyrrolidone scaffold, which has been known as an attractive pharmacophoric motif in medicinal chemistry.  This method allows the use of readily available acrylic acid, and diversity elements of ketones, aldehydes and isocynides.  To demonstrate its utility, parallel synthesis of Levetiractam (Keppraź, alpha-ethyl-2-oxopyrrolidine acetamide, 1), a drug on the market developed by UCB for add-on treatment of refractory partial seizures, and its diverse analogs, have been achieved.