Patent GB-1381661-A (GB)
Title: 3,2-benzoxazepine derivatives
IPC: C07D267/14
Filed: 1972-02-28
Abstract: 1381661 1,2,4,5-Tetrahydro-3,2-benzoxazepines GRUPPO LEPETIT SpA 28 Feb 1972 [18 March 1971 20 Jan 1972] 9026/72 Heading C2C Novel 1,2,4,5 - tetrahydro - 3,2 - benzoxazepines of the general formula wherein R is a hydrogen atom or C 1-4  alkyl group, R 1  is a hydrogen atom or C 1-4  alkyl, C 3-5  alkenyl, C 1-4  hydroxyalkyl, carbamoyloxy- C 1-4  alkyl (optionally substituted), acyl, amidino or carbamoyl (optionally mono- or disubstituted) group and R 2  is a hydrogen or halogen atom or nitro, amino or acylamino group and is in the 7- or 8- position, and pharmaceutically acceptable acid addition salts thereof are prepared (a) when R 1  is a hydrogen atom, by alkaline hydrolysis of the corresponding compound in which R 1  is an alkoxycarbonyl group; (b) when R 1  is a carbamoyl group, by treatment of the product of (a) with sodium cyanate and hydrogen chloride; (c) when R 1  is an alkyl group, by alkylation of the product of (a); (d) when R 1  is a carbamoyloxyalkyl group, by treatment of the corresponding compound in which R 1  is a hydroxyalkyl group with sodium cyanate and hydrogen chloride; (e) when R 1  is a 2-hydroxyethyl group, by reaction of the product of (a) with ethylene oxide; (f) when R 1  is an amidino group, by reaction of the product of (a) with cyanamido; (g) when R 1  is a substituted carbamoyl group, by reaction of the product of (a) with a substituted carbamoyl chloride; (h) when R 1  is an acyl group, by acylation of the product of (a) with an acid chloride; (i) when R 1  is a substituted carbamoyl group, by reaction of the corresponding compound in which R 1  is a chlorocarbonyl group with an amine; (j) when R 1  is a substituted carbamoyl group, by reaction of the product of (a) with an isocyanate; (k) when R 1  is an acyl group and R 2  is a nitro group, by nitration of the corresponding compound in which R 2  is a hydrogen atom; (1) when R 1  is a hydrogen atom, by acid hydrolysis of the corresponding compound in which R 1  is an acyl group; (m) when R 2  is an amino group, by catalytic hydrogenation of the corresponding compound in which R 2  is a nitro group; (n) when R 2  is an acylamino group, by acylation of the product of (m) with an acid chloride; and (o) when R 2  is a chlorine atom, by diazotization of the product of (m), followed by treatment with acidic CuCl; followed optionally by salification of the product. 1,2,4,5-Tetrahydro-3,4-benzoxazepines of the first general formula above wherein R 1  is an alkoxycarbonyl group are prepared by cyclization of an O - (o - halomethylphenethyl) - N- (alkoxy- or aralkoxycarbonyl) - hydroxylamine of the general formula wherein R 3  is an alkyl group, with a strong base. O - (o - Bromomethylphenethyl) - N - ethoxycarbonylhydroxylamine is prepared by catalytic hydrogenation of o-(2-bromoethyl)-benzaldehyde, treatment of the resulting o-hydroxymethylphenethyl bromide with acetic anhydride, reaction of the resulting o-acetoxymethylphenethyl bromide with N-hydroxy-urethane (potassium salt), alkaline hydrolysis of the resulting O - (o - acetoxymethylphenethyl) - N - ethoxycarbonyl-hydroxylamine and treatment of the resulting O - (o - hydroxymethylphenethyl) - N- ethoxycarbonyl-hydroxylamine with hydrogen bromide. O - [o - (1 - Chloroethyl) - phenethyl]- N - ethoxycarbonyl - hydroxylamine is prepared by reaction of o-(2-bromoethyl)-benzaldehyde with methyl magnesium iodide in ether, followed by the addition of aq. NH 4 Cl, reaction of the resulting o-(l-hydroxyethyl)-phenethyl bromide with N-hydroxy-urethane (potassium salt) and treatment of the resulting O - [o - (1 - hydroxyethyl)-phenethyl]-N- ethoxy - carbonyl - hydroxylamine with hydrogen chloride. 1,2,4,5 - Tetrahydro - 3,2 - benzoxazepines of the first general formula above wherein R 1  is a chlorocarbonyl group are prepared by reaction of the corresponding compound in which R 1  is a hydrogen atom with phosgene. Pharmaceutical compositions having antiinflammatory, hypnotic, sedative and myorelaxing activity comprise, as active ingredient, a novel 1,2,4,5-tetrahydro-3,2-benzoxazepine of the first general formula above or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable carrier.