Dibenz- -l,4-oxazepine

Synonyms Loxapine hydrochloride Loxapine succinate 2-Chloro-ll-(4-methylpiperazin-l-yl)dibenz[l,4]oxazepine Oxilapine Loxitane... 

Choi, D.D. and Landis, W.G., A review of toxicologic studies on dibenz-l,4-oxazepine (CR), U.S. Army Chemical Systems Laboratory, Edgewood Arsenal, MD, 1982. 

Upshall, D.G., 1974. The effects of dibenz ( l 4-oxazepine (CR) upon rat and rabbit embryonic development. Toxicol. Appl. Pharmacol. 24, 301—311. Upshall D.G., 1977. Riot control smokes lung absorption and metabolism of peripheral sensory irritants. In Duncan, W., Leonard, B.J. (Eds.), Qin. Toxicol Excerpta Medica, Amsterdam, pp. 121—129. 

RCAs are peripheral chemosensory irritants that target the eyes, airways and/or skin. The 1997 CWC defines them as Any chemical not listed in a Schedule, which can produce rapidly in humans sensory irritation or disabling physical effects which disappear within a short time following termination of exposure . Use for riot control purposes is permitted under the CWC, but not for military harassment, and stocks of RCAs must be declared. Most of the major RCAs [CN, CS and dibenz[/),/]-l,4-oxazepine (CR) Scheme 1.8] are low volatility solids and, unless they are used in solution in a spray, they need to be aerosolised for efficient use, for example using pyrotechnic munitions or dispersed as micronised powders. 

Dibenz[6,/][l,4]oxazepin-ll(10//)-ones 4 are formed in near quantitative yield by cycli-zation of aryl 2-isocyanatophenyl ethers 3 in the presence of aluminum trichloride. Exact yields were not reported.40... 

The cyclization of imines 7, induced by the isopropyloxycarbonyloxy radical (i-PrOC02). obtained by homolytic cleavage of diisopropyl peroxydicarbonate, leads to dibenz[6,/][l,4]-oxazepines 8, accompanied by traces of biphenyls and benzoxazoles.424... 

Dibenz[6,/][l,4]oxazepines are reduced to the 10,11-dihydro compounds 1 by catalytic hydrogenation in the presence of palladium on charcoal and a trace of Raney nickel.44... 

Ballantyne, B. The acute mammalian toxicology of dibenz(b,f)-l,4-oxazepine. Toxicology 8 347-379, 1977. 

Dibenz[6,/][l,4]oxazepines, which have intense lachrymatory and skin irritant properties, can be prepared in high yield by the Bischler-Napieralsky-type cyclization of A7-(2-phenoxyphenyl)formamides (76JCS(P1) 1279). 

Chemical Name 2-Chloro-ll-(l-piperazinyl)dibenz[b,f][l,4]oxazepine Common Name -Structural Formula ... 

A mixture of 10 g of the above piperazine carboxylate ester, 8 g of phosphorus pentoxide and 20 ml of phosphorus oxychloride is heated under reflux for about 1 day, diluted with 100 ml each of chloroform and benzene and quenched with 200 g of ice. The mixture is made basic with 10% sodium hydroxide. The organic layer is isolated and extracted with 150 ml of dilute hydrochloric acid. The product is precipitated from the aqueous layer by addition of 10% sodium hydroxide, extracted with benzene and dried over potassium carbonate. Recrystallization from benzene-petroleum ether gives 2-chloro-ll-(l-piperazinyl)dibenz[b,f][l,4]oxazepine which melts at 175°C to 176°C. 

This crude product is dissolved in 100 ml of dilute hydrochloric acid, the acid solution is extracted with ether, and the aqueous layer is made basic with sodium hydroxide solution (3N) in the presence of ether (approximately 250 ml). The ether layer is separated, dried over potassium hydroxide and evaporated to a white solid. Additional purification by repeating the formation of the hydrochloric acid salt and reprecipitation of the base is carried out. When purified in this manner, followed by drying at 80°C in vacuo over phosphorus pentoxide, 2-chloro-ll-(4-methyl-l-piperazinyl)dibenz[b,f] [l,4]oxazepine, MP 109° to 111°C, is obtained. 

The lactam derivative dibenz[h/]l 4-oxazepin-ll-(lOH)-one is a primary metabolic product of metabolism and a direct precursor of the urinary hydroxylated metabolites. In rats, the lactam, a dihydro-CR metabolite, an amino alcohol of CR, and an arene oxide are metabolites in CR degradation. In the rat, the major mechanism for elimination is sulfate conjugation and biliary excretion to a limited extent. Phase I metabolism by microsomal mixed fimction oxidases involves reduction of CR to the amino alcohol, oxidation to form the lactam ring, and hydroxylation to form the hydroxylactams. Phase II conjugation reactions sulfate the hydroxylactam intermediates for renal elimination. Amino alcohol intermediates are conjugated with glucuro-nide for biliary secretion. 

Blain, P.G. (2003). Tear gases and irritant incapacitants 1-chloroacetophenone, 2-chlorobenzylidene malononitrile and dibenz[B,F]-l,4-oxazepine. Toxicol. Rev. 22 100-10. 

Kumar, P., Vijayaraghavan, R., Pant, S.C., Sachan, A.S., Malhotra, R.C. (1995). Effect of inhaled aerosol of 1-chloroacetophenone (CN) and dibenz (b,f)-l,4-oxazepine (CR) on lung mechanics and pulmonary surfactants inrats. Plum. Exp. Toxicol. 14 404-9. 

Lundy, P.M., McKay, D.H. (1975). Mechanism of the cardiovascular activity of dibenz [b,f][l,4] oxazepine (CR) in cats. Suffield Technical Paper 438. Defence Research Establishment, Ralston, Alberta, Canada. 

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