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Reinvestigation of the Synthesis of Ketanserin ( 5 ) and its Hydrochloride Salt ( 5.HCl ) via 3‐(2‐Chloroethyl)‐2,4‐(1 H ,3 H )‐quinazolinedione ( 2 ) or Dihydro‐5 H ‐oxazole(2,3‐ b )quinazolin‐5‐one ( 1 )
Author(s) -
Fakhraian Hossein,
Heydary Mehdi
Publication year - 2014
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.1897
Subject(s) - chemistry , piperidine , hydrochloride , chloroform , ethyl chloroformate , salt (chemistry) , oxazole , triethylamine , nuclear chemistry , free base , solvent , organic chemistry , medicinal chemistry
The synthesis of ketanserin ( 5 ) and its hydrochloride salt ( 5.HCl ) using respectively equimolar amounts of 3‐(2‐chloroethyl)‐2,4‐(1 H ,3 H )‐quinazolinedione ( 2 ) with 4‐(parafluorobenzoyl)piperidine ( 3 ) and dihydro‐5 H ‐oxazole(2,3‐ b )quinazolin‐5‐one ( 1 ) with hydrochloride salt of 4‐(parafluorobenzoyl)piperidine ( 3.HCl ) is reinvestigated. The one‐pot reaction of ethyl‐2‐aminobenzoate with ethyl chloroformate and ethanol amine has afforded 3‐(2‐chloroethyl)‐2,4‐(1 H ,3 H )‐quinazolinedione ( 2 ) (86%) that was then refluxed with 4‐(parafluorobenzoyl)piperidine ( 3 ) in ethyl methyl ketone in the presence of sodium carbonate to obtain free base of ketanserin (87%). In another attempt, a very pure hydrochloride salt of ketanserin ( 5.HCl ) was synthesized using equimolar amounts of dihydro‐5 H ‐oxazole(2,3‐ b )quinazolin‐5‐one ( 1 ) and hydrochloride salt of 4‐(parafluorobenzoyl)piperidine ( 3.HCl ) by a solvent‐less fusion method. Thus, under optimized conditions, 180°C and a reaction time of 30 min, the powder mixture was transformed into glassy crystals that were initially readily soluble in chloroform but were transformed afterwards over time (2 h) to white precipitates ( 5.HCl ) suspended in chloroform with a yield of 72%.