Patent GB-1136214-A (GB)
Title: Thebaine and oripavine derivatives
Inventor: BENTLEY KENNETH WALTER
IPC: C07D489/12
Filed: 1965-06-15
Abstract: 1,136,214. Thebaine and oripavine derivatives. RECKITT & SONS Ltd. 10 June, 1966 [15 June, 1965], No. 25289/65. Heading C2C. Novel thebaine and oripavine derivatives of the general formula wherein R represents a hydrogen atom, a methyl group, the group C n H 2n+1 CO-in which n is an integer from 1 to 3 inclusive, benzoyl or nicotinoyl; R 1  represents a hydrogen atom, an alkyl, alkenyl or alkynyl group containing up to 8 carbon atoms or an alicyclic substituted methyl group in which the total number of carbon atoms is from 4 to 8; R 2  represents a hydrogen atom, an alkyl or alkenyl group containing up to 3 carbon atoms, or an aryl group; R 3  represents a hydrogen atom, an alicyclic group containing 4 to 8 carbon atoms, an alkyl, alkenyl or alkynyl group containing up to 8 carbon atoms which may be substituted on the carbon atoms numbered 1 to 4 (the carbon atom numbered 1 being adjacent to the carbon atom bearing the alcoholic hydroxy group) by an alicyclic, aryl, alkoxy, aryloxy or heterocyclic group containing oxygen, provided that when R represents a hydrogen atom, R 3  and R 2  do not contain the systems -CH- aryl and attached directly to the carbon atom bearing the alcoholic hydroxy group, and salts thereof with pharmaceutically acceptable anions are prepared by any of the following methods (a) Catalytic hydrogenation of a 6,14 endethenotetrahydro-thebaine and oripavine derivatives of the formula (b) Catalytic hydrogenation of a 6,14-endetheno - 7 - acyltetrahydrothebaine of the formula and reaction of the resulting 6,14-endethenotetrahydrothebaine with a Grignard reagent or organo-lithium compound comprising R 3  linked to a metal atom, conversion into the corresponding oripavine derivative followed by O- acylation, or N-demethylation and N-alkylation, e.g. by reaction with an alkyl, alkenyl or alkynyl halide, or with an acyl halide followed by reduction. (c) Reaction of a thebaine or oripavine derivative of the first general formula wherein R 1  is a methyl group with a cyanogen halide and removal of the cyano group from the resulting N-cyano compound by hydrolysis to give the corresponding northebaine or nororipavine derivative, followed by optional alkylation or acylation and reduction of the resulting amide with lithium aluminium hydride to give a thebaine or oripavine derivative of the first general formula wherein R 1  is not hydrogen or a methyl group. (d) Reaction of a thebaine or oripavine derivative of the first general formula wherein R 1  is a methyl group with dimethyl or diethyl azodicarboxylate to give a methylene-bis-compound of the formula followed by reaction with an alkyl halide containing R 1  (other than hydrogen or a methyl group). (e) When R is an acyl, benzoyl or nicotinoyl group, by esterification of the phenolic hydroxyl group in any thebaine or oripavine derivative of the first general formula above wherein R is a hydrogen atom. (f) N-alkylation or -acylation of a 6,14- endethenotetrahydronorthebaine derivative of the formula wherein ALK represents an alkyl group, obtained by hydrogenation of the corresponding 6,14 - endetheno-tetrahydronorthebaine derivative, followed in either case by reduction with lithium aluminium hydride to give a 6,14- endethenotetrahydronorthebaine derivative of the first general formula above wherein R 2  and R 3  are hydrogen atoms and R is a methyl group; (g) Hydrolysis of a compound of the first general formula above wherein R is a methyl group to the corresponding compound in which R is a hydrogen atom; (h) N-Demethylation of a compound of the formula followed optionally by acid addition salt formation. 7 - Acetyl - 6,14 - endoetheno - tetrahydronorthebaine hydrochloride is prepared by hydrogenation and alkaline hydrolysis of the corresponding N-cyano compound to give N-formyl- 7 - acetyl-6,14- endoethenotetrahydronorthebaine, followed by acid hydrolysis.