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Nucleophilic addition of 2‐, 3‐, or 4‐[2‐(methylamino)ethyl]pyridine to the aziridine, 7‐methyl‐7‐azabicyclo[4.1.0]heptane
Author(s) -
Rees David C.
Publication year - 1990
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.5570270206
Subject(s) - chemistry , ethylamine , pyridine , aziridine , nucleophile , medicinal chemistry , derivative (finance) , heptane , toluene , ring (chemistry) , stereochemistry , organic chemistry , financial economics , economics , catalysis
The synthesis of trans ‐(±)‐ N ‐methyl‐ N ‐[2‐[methyl[2‐(3‐pyridyl)ethyl]amino]cyclohexyl]‐4‐benzofuranacetamide dihydrochloride, 1 which is a 3‐[2‐(methylamino)ethyl]pyridyl derivative of the kappa opioid analgesic trans ‐(±)‐ N ‐methyl‐ N ‐[2‐(1‐pyrrolidinyl)cyclohexyl]benzofuran‐4‐acetamide monohydrochloride, 2 is described. The key intermediate is trans ‐(±)‐ N,N' ‐dimethyl‐ N ‐[2‐(3‐pyridyl)ethyl]‐1,2‐cyclohexanediamine, 9 which is formed by nucleophilic addition of 3‐[2‐(methylamino)ethyl]pyridine 6 to the aziridine, 7‐methyl‐7‐azabicyclo[4.1.0]heptane, 4 . During attempts to prepare the 2‐ or 4‐isomeric pyridyl derivatives of 1 it was discovered that both 2‐ or 4‐[2‐(methylamino)ethyl]pyridine, 5 or 7 are converted to N ‐methyl‐ N,N ‐di‐[2‐(2‐pyridyl)ethylamine] 11 and N ‐methyl‐ N,N ‐di[2‐(4‐pyridyl)ethylamine] 13 respectively by refluxing in toluene in the presence of ammonium chloride. The 3‐isomer, 6 is unchanged after treatment under identical conditions. Careful control of the reaction conditions enabled the aziridine 4 to be ring opened with the pyridyl amines 5 or 7 to give the 1,2‐diamines trans ‐(±)‐ N,N ′‐dimethyl‐ N ‐[2‐(2‐pyridyl)ethyl]‐1,2‐cyclohexanediamine, 8 or trans ‐(±)‐ N,N ′‐dimethyl‐ N ‐[2‐(4‐pyridyl)ethyl]‐1,2‐cyclohexane diamine 10 respectively.