Patent GB-1479241-A (GB)
Title: 10,11-dihydro-10-piperazinyl-dibenz(b,f)oxepins methods for their preparation and compositions containing them
IPC: C07D405/12
Filed: 1975-01-03
Abstract: 1479241 10,11-Dihydro-10-piperazyl-oxyines F HOFFMANN-LA ROCHE & CO AG 3 Jan 1975 [4 Jan 1974] 241/75 Heading C2C Novel compounds I and their salts in which R is a C 1-6 alkyl, C 3-6  alkenyl or C 3-6.  0 alkaryl group (which may be substituted by cyano, hydroxy or C 2-18  alkanoyloxy when R is other than methyl and in which unsaturation does not take place at the 1-position) or a group in which X is O, S, NH, CH 2  or C 1-6  alkylimino Y is an ethylene or propylene group optionally substituted by C 1-6  alkyl and m is 0 or 1, one of R 1  and R 2  is-H, and the other is halogen, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  alkylthio, CF 3  or OH and one of R 3  and R 4  is H and the other is H, halogen, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  alkylthio, CF, or OH are prepared by (i) reacting a compound II in which Z is a leaving atom or group and R<SP>1</SP> 1 , R<SP>1</SP> 2 , R<SP>1</SP> 3  and R<SP>1</SP> 4  have the values of R 1  to R 4  respectively and in addition any hydroxy group present may be protected, with an R substituted piperazine (2) reducing the corresponding #<SP>10,11</SP> compound in which any hydroxy group R 1  to R 4  may be protected or (3) introducing a group R into a compound V in a manner known per se. Compounds I (R=an alkanoyloxy substituted C 1-6  alkyl, C 3-6  alkenyl or C 3-6  alkynyl group) are prepared by esterifying the corresponding hydroxy substituted compound in which compound any hydroxy group R 1  to R 4  may be protected. Compounds I (R = C 1-6  alkyl or hydroxy C 1-6  alkyl) are prepared by reducing a compound VII in which R 5  is C 1-6  alkanoyl, hydroxy C 1-6  alkanoyl or (C 1-6  alkoxy) carbonyl. Compounds V are prepared by reacting an R<SP>1</SP> 1 , R<SP>1</SP> 2 , R<SP>1</SP> 3 , R<SP>1</SP> 4  substituted 10,11-dehydro-10-oxo-oxepine (XVI) with ethyl piperazinocarboxylate reducing the 10,11-double bond and decarboxylating. Compounds II (Z = C1) are prepared by reducing a compound XVI to the 10-ol and chlorinating. Compounds XVI (R<SP>1</SP> 1  or R<SP>1</SP> 2 =Me, Cl, MeO, R<SP>1</SP> 3  or R<SP>1</SP> 4 =Me, Cl, F, MeS, CF), are prepared by reacting an Me or Cl substituted 2-iodobenzoic acid with an Me, F or Cl substituted phenol and submitting the resultant 2-phenoxybenzoic acid to the standard homologation procedure to form the corresponding phenyl-acetic acid which is cyclized. Compounds XVI (R<SP>1</SP> 1 =F, Cl, Br) are prepared reduction of the nitro-derivative to an amine, diazotisation and reaction with NaBF 4 , CuCl or CuBr. 8-Fluoro- 10,11 - dihydro - 2 - nitro - oxepin - 10 - one is prepared by reacting 4-fluorophenol with 2- chloro-5-nitro benzaldehyde and treating the 2 - (p - fluorophenoxy) - 5 - nitro - benzaldehyde formed with acetylglycine in AC 2 O to give 2- (p - fluorophenoxy)- 5 - nitro - phenylpyruvic acid which is decarboxylated to the phenylacetic acid and cyclized. Me and MeO substituted 2-iodo-benzoic acids are prepared by diazotisation and iodination of the corresponding arthranilic acid. Compounds I have CNS depressant and neuroleptic properties and form with a carrier a pharmaceutical composition which may be administered orally, parenterally or rectally.