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Synthesis of optically active af‐(1‐Ethyl‐3‐methylhexahydro‐1,3‐diazin‐5‐yl)‐ and N ‐(1‐Ethyl‐5‐methyloctahydro‐1,5‐diazocin‐3‐yl)pyridine‐3‐carboxamides
Author(s) -
Hirokawa Yoshimi,
Yamazaki Hiroshi,
Kato Shiro
Publication year - 2002
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.5570390417
Subject(s) - chemistry , ethyl ester , yield (engineering) , pyridine , receptor , lithium aluminium hydride , ethyl acetate , stereochemistry , medicinal chemistry , organic chemistry , biochemistry , materials science , metallurgy
As part of the structure‐activity relationship of the dopamine D 2 and serotonin 5‐HT 3 receptors antagonist 1, which is a clinical candidate with a broad antiemetic activity, the synthesis and dopamine D 2 and serotonin 5‐HT 3 receptors binding affinity of ( R )‐5‐bromo‐ N ‐(1‐ethyl‐3‐methylhexahydro‐1,3‐diazin‐5‐yl)‐ and ( R )‐5‐bromo‐ N ‐(1‐ethyl‐5‐methyloctahydro‐1,5‐diazocin‐3‐yl)‐2‐methoxy‐6‐methylaminopyridine‐3‐carboxam‐ides ( 2 and 3 ) are described. Treatment of 1‐ethyl‐2‐( p ‐toluenesulfonyl)amino‐3‐methylaminopropane dihy‐drochloride ( 4a ) with paraformaldehyde and successive deprotection gave the 5‐aminohexahydro‐1,3‐diazine 6 in excellent yield. 3‐Amino‐1‐ethyl‐5‐methyloctahydro‐1,5‐diazocine ( 15 ) was prepared from 2‐(benzyloxycarbonyl)amino‐3‐[[ N ‐( tert ‐butoxycarbonyl)‐ N ‐methyl]amino]‐1‐ethylaminopropane ( 9 ) through the intramolecular amidation of ( R )‐3‐[ N ‐[(2‐benzyloxycarbonylamino‐3‐methylamino)propyl]‐ N ‐ethyl]aminopropionic acid trifluoroacetate ( 12 ), followed by lithium aluminum hydride reduction of the resulting 6‐oxo‐1‐ethyl‐5‐methyloctahydrodiazocine ( 13 ) in 41% yield. Reaction of the amines 6 and 15 with 5‐bromo‐2‐methoxy‐6‐methylaminopyridine‐3‐carboxylic acid furnished the desired 2 and 3 , which showed much less potent affinity for dopamine D 2 receptors than 1 .