Synthesis of stereoisomers of antithrombotic nipecotamides.
The stereoisomers of alpha,alpha'-bis[3-(N,N-diethylcarbamoyl)-piperidino]-p-xylene (1) were synthesized. Rac ethyl nipecotate was resolved by diastereomeric (-)-D- and (+)-L-tartrate salt formation. The enantiomeric esters were hydrolyzed to the corresponding nipecotic acids, which were then converted into t-BOC derivatives. Treatment of the latter with diethylamine/isobutyl chloroformate and removal of the t-BOC protecting group afforded (R)- and (S)-N,N-diethylnipecotamides. Condensation of the latter with alpha,alpha'-dibromo-p-xylene gave (R,R)- and (S,S)-1. The meso-diastereomer was obtained by stereospecific synthesis in addition to our earlier procedure involving fractional crystallization of the diastereomeric mixture obtained by synthesis. The latter was resolved earlier into 1A, 1B, and 1C using chiral high-performance liquid chromatography (HPLC). Based on the stereospecific synthesis now achieved, 1A and 1B are assigned the configurations, (R,R) and (S,S) respectively, and 1C is assigned the meso configuration. The (R,S) structure of the latter is also confirmed by X-ray crystallography.
Zheng
X
X
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee, Memphis 38163, USA.
Day
C
C
Gollamudi
R
R
D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D009557:Nipecotic Acids / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism
D005343:Fibrinolytic Agents; D009557:Nipecotic Acids