Patent GB-969263-A (GB)
Title: Novel derivatives of thebaine and oripavine
Inventor: BENTLEY KENNETH WALTER
IPC: C07D489/12
Filed: 1962-03-02
Abstract: The invention comprises thebaine and oripuvine derivatives of the formula: <FORM:0969263/C1/1> where the symbol R represents a hydrogen atom or a methyl group or an acyl group CnH2n+1 CO- where n is an integer; R1 represents a hydrogen atom or an alkyl or alkenyl group containing 2 to 8 carbon atoms, a propargyl, cyclopropylmethyl, methylcyclopropyl methyl or dimethylcyclopropylmethyl group; R2 represents a hydrogen atom or an alkyl group of up to 3 carbon atoms or an aryl group and R3 represents a hydrogen atom, an alicyclic group of 5, 6 or 7 carbon atoms or an alkyl or alkenyl group of up to eight carbon atoms which may be substituted on carbon atoms 1 to 4 by an alicyclic; aryl, alkoxy, aryloxy or heterocyclic group containing oxygen such that when R represents a hydrogen atom or an acyl group or when R1 represents a hydrogen atom, a cyclopropylmethyl, methyl cyclopropylmethyl or a dimethylcyclopropylmethyl group, R3 does not contain the system -CHAryl or -CH-C=C attached directly to the carbon atom bearing the alcoholic hydroxyl group; and salts thereof with pharmaceutically acceptable acids.  The invention also includes a process for the preparation of compounds of the above general formula in which compounds of the above general formula where the group represented by symbol R3 does not contain the system -CHAryl or -CH-C=C linked directly to the carbon atoms bearing the alcoholic hydroxyl group and the symbols R and R1 represent methyl groups are treated with cyanogen bromide and the resulting N-cyano compound hydrolysed with an alkali metal hydroxide or alkoxide in a solvent to give a secondary amine of the above formula (R1 is H) which is converted to a tert. amine by treatment with an alkyl, alkenyl, cycloalkyl or propargyl halide or with an acyl halide followed by reduction of the resulting N-acyl compound with lithium aluminium hydride (when the hydrolysis is carried out at temperatures up to 180 DEG C. a product is obtained in which the symbol R represents a methyl group, and at temperatures above 180 DEG C. a product is obtained in which the symbol R represents a hydrogen atom); a process for the preparation compounds of the above general formula where the symbol R represents a methyl group and R1 represents one of n-propyl, isobutyl, alkyl, methylallyl, dimethylallyl and propargyl in which a compound of the general formula: <FORM:0969263/C1/2> is treated with a Grignard reagent R3MgX when the symbol X represents a halogen atom (in this process the reactants of the general formula immediately above wherein R is a methyl group, R1 is a n-propyl, isobutyl, allyl, methylallyl, dimethylallyl or propargyl group and R2 has the above significance may be prepared from the corresponding compounds in which R1 represents the methyl group by treatment with cyanogen bromide and the resulting N-cyano compound in which R1 is cyano is treated successively with dilute mineral acid, sodium nitrate and ammonia to form a secondary amine (R1 is hydrogen) and this compound is reacted with a n-propyl, isobutyl, allyl, methylallyl, dimethylallyl or propargyl halide); and processes for the preparation of the compounds of the first formula above wherein R represents CnH2n+1CO- (n is an integer) in which the corresponding compounds wherein R represents hydrogen are heated under reflux with the required acid anhydride and an alkali metal salt of the corresponding acid or are heated with an aqueous solution of an alkali metal hydroxide and a halide or anhydride of the required acid. Specifications 902,659 and 925,723 are referred to.