Patent GB-1164672-A (GB)
Title: Novel Derivatives of Thebaine and Oripavine, their Pharmaceutically Acceptable Salts, and to processes of their production
Inventor: MAYOR PHILIP ARTHUR
IPC: C07D489/12
Filed: 1967-03-31
Abstract: 1,164,672. Thebaine and oripavine derivatives. RECKITT & SONS Ltd. 26 March, 1968 [31 March, 1967], No. 14948/67. Heading C2C. The invention comprises compounds of the formula wherein Y represents the ethero or the ethano group, R represents a methyl group or a hydrogen atom; R<SP>1</SP> represents a hydrogen atom, an alkyl or alkenyl group of up to 3 carbon atoms, a phenyl or a tolyl group; R<SP>2</SP> represents a cycloalkyl group of 5 to 7 carbon atoms, an alkyl or alkenyl group of up to 8 carbon atoms, a benzyl or a phenethyl group; R<SP>3</SP> represents a hydrogen atom, an alkyl group of up to 5 carbon atoms, allyl, methallyl, dimethylallyl, crotyl or propargyl group, or a cycloalkyl methyl group of 4 to 6 carbon atoms, R<SP>4</SP> represents a phenyl group, a tolyl group, a cycloalkyl group of 5 to 7 carbon atoms, an alkyl or alkenyl group of up to 5 carbon atoms, a propargyl group, a benzyl or a phenethyl group; and a process for preparation of compounds of the formula in which R, R<SP>1</SP>, R<SP>2</SP>, R<SP>4</SP> and Y are as defined above and in which R<SP>5</SP> represents an alkyl group of up to 5 carbon atoms, an allyl, methylallyl, dimethylallyl or crotyl group or a cycloalkyl methyl group of 4 to 6 carbon atoms, by reacting a compound of the formula wherein R<SP>5</SP>, Y and R are as defined above, Q is one of the radicals wherein R<SP>1</SP> and R<SP>2</SP> are as defined above and where Alk represents an alkyl group of up to 5 carbon atoms and Z represents the anion from an acid, with a Grignard reagent R<SP>4</SP>MgX or an organo lithium compound R<SP>4</SP>Li where R<SP>4</SP> is as defined above and X is a halogen atom. The bases in which R is methyl and R<SP>3</SP> is cyano may be prepared from those in which R<SP>3</SP> is methyl by treatment with cyanogen bromide. The bases in which R is methyl and R<SP>3</SP> is hydrogen may be prepared from those in which R<SP>3</SP> is cyano by alkaline hydrolysis in a solvent at a temperature of about 150-170 C. Compounds in which R and R<SP>3</SP> are both hydrogen can be prepared by carrying out this hydrolysis at a temperature above 180 C. The bases of the invention claimed in which R<SP>3</SP> is alkyl, alkenyl or alkynyl may also be prepared from those in which R is hydrogen by treatment with the appropriate alkyl, alkenyl or alkynyl halides. The bases in which R<SP>3</SP> is alkyl, alkenyl, alkynyl or cycloalkyl methyl can fulther be prepared from bases in which R<SP>3</SP> is hydrogen by acylation with the appropriate acid chloride or anhydride followed by reduction of the resulting amide with lithium aluminium hydride. The bases in which R is hydrogen and R<SP>3</SP> is other than cyano can be prepared from the corresponding bases in which R is methyl by heating with an alkali metal hydroxide or alkoxide in a solvent at a temperature above 180 C. Pharmaceutical compositions of the above compounds having analgesic and antitussive activity may be administered orally.