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Unprecedented Formation of 2‐Chloro‐5‐(2‐chlorobenzyl)‐4,5,6,7‐tetrahydrothieno[3,2‐c]pyridine 5‐oxide via Oxidation‐Chlorination Reaction Using Oxone: A Combination of Synthesis and 1D‐2D NMR Studies
Author(s) -
Krake Everaldo F.,
Baumann Wolfgang
Publication year - 2019
Publication title -
chemistryselect
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.437
H-Index - 34
ISSN - 2365-6549
DOI - 10.1002/slct.201903556
Subject(s) - chemistry , prodrug , thienopyridine , pyridine , pyridine n oxide , medicinal chemistry , combinatorial chemistry , biochemistry , aspirin , clopidogrel
Ticlopidine hydrochloride ( 1⋅HCl , Ticlid™) is a prodrug that, through bioactivation by cytochrome P450 (CYP), interacts with the P2Y 12 receptor ADP inhibiting platelet aggregation. This prodrug mediated by a multistep biochemical process led to the formation of active metabolic intermediates. In this work, an eco‐friendly and efficient protocol for the formation of 2‐chloroticlopidine ( 2 ) using 1⋅HCl and oxone in aqueous methanol media via an unprecedented formation of reactive thienopyridine intermediate 2‐chloro‐5‐(2‐chlorobenzyl)‐4,5,6,7‐tetrahydrothieno[3,2‐c]pyridine 5‐oxide ( 4 ) was developed. The key to success of 4 is the oxidation of tertiary amines to N ‐oxides, followed by mono‐chlorination at the 2‐position of the thiophene ring by oxidation of the chloride counterion of this prodrug. In addition, we use the 1D and 2D NMR techniques as a tool to monitor reaction progress, and for assigning the signals of all compounds involved, especially for the novel thienopyridine 4 .