Syntheses Of Organic Impurities Of Anticoagulant Argatroban

Argatroban, a new type of thrombin inhibitors that binds thrombin activity sites reversibly, can be used in the anticoagulant therapy of acute stage of ischemic cerebral infarction. Argatroban has sixteen stereoisomers in theory because it processes four chiral carbon atoms in its structure. Since the presence of stereoisomer impurities severely affects the purity and quality of this drug it is indispensible to identify the impurities quantitatively in order to ensure the safety of patients’ medication. This work mainly focuses on the synthesis of the enantiomer impurity of argatroban, namely (2S,4S)-4-methyl-l-[N-[((R, S)-3-methyl-1,2,3,4-tetrahydro-8-quinolinyl) Sulfonyl]-D-arginyl]-2-piperidinecarboxylic acid that has not been reported hitherto. The synthetic procedure comprises two main parts. One is relevant to synthesis of ethyl (2S,4S)-4-methyl-2-piperidinecarboxylate wherein two stereocenters are established by use of (R)-(+)-1-Phenylethylamine as chiral auxiliary and asymmetric catalytic hydrogenation. The other is pertinent to amide coupling reaction between ethyl 4-methyl-2-piperidinecarboxylate and N-Boc-N’-nitro-D-Arg promoted by BOP condensating agent followed by removal of Boc protecting group on amine and subsequent reaction with 3-methyl-8-quinolinesulphonyl chloride. The final product was obtained by further catalytic hydrogenation and saponification reaction. The enantiomer impurity of argatroban obtained in the current method can meet the requirement as impurity reference for quality control of argatroban.