Syntheses of R and S isomers of AF-DX 384, a selective antagonist of muscarinic M-2 receptors

Enantiomers of 5,11-dihydro-11-[2-[2-[(N,N-dipropylaminomethyl)piperidin-1- yl]ethylamino]-carabonyl]-6H-pyrido[2,3- b][1,4]benzodiazepin-6-one (AF-DX 384) 1, have been synthesized from (S)-(+) and (R)-(-)-2-[N,N-dipropylamino methyl]piperidine 4. The enantiomeric excess of 1 has been determined by ca pillary electrophoresis by using the alpha-highly sulphated cyclodextrin (a lpha-HSCD) as chiral selector within the running electrolyte. (S)-(+)-(4) w as prepared from (S)-(-)-pipecolic acid in a 4-step procedure (overall yiel d: 30%, ee: 99%) and (R)-(-)-AF-DX 384 from (R)-(+)-pipecolic acid. The (R) -(-) isomer exhibited in vitro a 23-fold higher affinity than its enantiome r (S)-(+) towards muscarinic receptors of subtype 2. (C) 2000 Published by Elsevier Science Ltd. All rights reserved.