N-dealkylation of tertiary amines

Claim 2

A PROCESS FOR THE MONO N-DEALKYLATION OF TERTIARY AMINES SELECTED FROM THE GROUP CONSISTING OF N,N-DIMETHYL-LOWER ALKYLAMINE, N-METHYL-DI-LOWER ALKYLAMINE, N-METHYL-DICYCLOHEXYLAMINO, N,N-DIMETHYLCYCLOHEXYLAMINE, N,N-DIETHYLCYCLOHEXYLAMINE, N,N-DIMETHYLBENZYLAMINE, HORDENINE, NMETHYLPYRROLIDINE, N-ETHYL-N-ETHYLPYRROLIDINE, NICOTINE, NMETHYLPIPERIDINE, PIPERIDINE, ARECOLINE, MEPERIDINE, TROPINE, ATROPINE, HYOSCYAMINE, SCOPOLAMINE, COCANE, TROPACOCANE, MORPHINE, CODEINE, O3 ,O6-DIACETYLMORPHINE, THEBINE, NMETHYLMORPHINANS DIHYDROCODENIONES, DIHYDROMORPHINONES, 6,14-ENDO-ETHANOMORPHINES, ERYTHROMYCIN AND TETRACYCLINE, WHICH COMPRISES THE STEPS OF REPLACING THE N-ALKYL GROUP OR ONE OF THE N-ALKYL GROUPS OF SAID TERITARY AMINE BY A VINYLOXYCARBONYL GROUP BY REACTION OF SAID TERITARY AMINE WITH A SOURCE OF VINYLOXYCARBONYL GROUPS SELECTED FROM VINYL HALOFORMATES TO THEREBY FROM A VINYLOXYCARBONYL AMIDE OF THE CORRESPONDING SECONDARY AMINE AND THEREAFTER CLEAVING SAID VINYLOXYCARBONYL AMIDE UNDER MILD ACIDIC CONDITIONS WITH A HYDROHALIC ACID AND A HYDROXYLIC REAGENT SELECTED FROM THE GROUP CONSISTING OF WATER, A LOWER CARBOXYLIC ACID AND A LOWER ALKANOL TO SPLIT OFF SAID VINYLOXYCARBONYL GROUP FROM THE AMINO N ATOM AND OBTAIN THE CORRESPONDING SECONDARY AMINO OR HYDROHALIDE SALT THEREOF.

Claim 3

The process of claim 1 wherein said source of vinyloxycarbonyl groups is vinyl chloroformate.

Claim 4

The process of claim 1 wherein said reaction of said tertiary amine with said source of vinyloxycarbonyl groups is carried out by combining said tertiary amine with an excess of said source of vinyloxycarbonyl groups in an inert organic solvent maintained at a temperature within the range of from about -40*C to about 0*C, then allowing the mixture to warm to room temperature, and thereafter heating said mixture at reflux for a period ranging from about 30 minutes to about 20 hours to complete formation of said vinyloxycarbonyl amide and/or to facilitate removal of volatile by-products.

Claim 5

The process of claim 1 wherein said reaction of said tertiary amine with said source of vinyloxycarbonyl groups is carried out in the presence of a proton scavenger which is more basic than said tertiary amine and less reactive than said tertiary amine toward said source of vinyloxycarbonyl groups so as to effect removal of any acid liberated during said reaction.

Claim 6

The process of claim 4 wherein said proton scavenger is selected from the group consisting of 1,8-bis-(dimethylamino)-naphthalene and N-alkyldicyclohexylamines.

Claim 7

The process of claim 4 wherein said tertiary amine is in the form of an acid salt thereof.

Claim 8

The process of claim 4 wherein at least one of the groups remaining attached to the amino N atom of said tertiary amine throughout the process is a group initially having alcoholic or phenolic hydroxyl group substituents, and the reaction of said tertiary amine with said source of vinyloxycarbonyl groups also forms vinyloxycarbonyl ester groups at the hydroxyl sites.

Claim 9

The process of claim 7 wherein subsequent to said splitting off of said vinyloxycarbonyl group from said amino N atom, the resulting secondary amine or hydrohalide salt thereof is modified by attachment of another tertiary amine-forming substituent to said amino N atom, and thereafter said vinyloxycarbonyl ester groups are reconverted to hydroxyl groups by treatment under basic conditions with aqueous of alcoholic base or under strong acidic conditions with aqueous or alcoholic acid.

Claim 10

The process of claim 1 wherein said hydrohalic acid is selected from the group consisting of HCl and HBr and the hydroxylic reagent is an alcohol selected from the group consisting of methanol and ethanol.

Claim 11

In a process for the N-substituent modification of a tertiary amine selected from the group consisting of N-N-dimethyl-lower alkylamine, N-methyl-di-lower alkylamine, N-methyl-dicyclohexylamine, N,N-dimethylcyclohexylamine, N,N-diethylcyclohexylamine, N,N-dimethylbenzylamine, hordenine, N-methylpyrrolidine, N-ethylpyrrolidine, nicotine, N-methylpiperidine, N-ethylpiperidine, arecoline, meperidine, tropine, atropine, hyoscyamine, scopolamine, cocaine, tropacocaine, morphine, codeine, O3,O6-diacetylmorphine, thebaine, N-methylmorphinans, dihydrocodeinones, dihydromorphinones, 6,14-endo-ethanomorphines, erythromycin and tetracycline, comprising the steps of mono N-dealkylating said tertiary amine to form a secondary amine and thereafter modifying said secondary amine by attachment of another tertiary amine-forming substituent to the amino N atom, the improvement which comprises the steps of effecting said N-dealkylation by replacing the N-alkyl group or one of the N-alkyl groups of said starting tertiary amine by a vinyloxycarbonyl group by reaction of said tertiary amine with a source of vinyloxycarbonyl groups selected from vinyl haloformates to thereby form a vinyloxycarbonyl amide of the secondary amine, and thereafter cleaving said vinyloxycarbonyl amide under mild acidic conditions with a hydrohalic acid and a hydroxylic reagent selected from the group consisting of water, a lower carboxylic acid and a lOwer alkanol to split off said vinyloxycarbonyl group from the amino N atom and obtain the secondary amine or hydrohalide salt thereof.

Claim 12

In a process for the N-substituent modification of a tertiary amine selected from the group consisting of N-N-dimethyl-lower alkylamine, N-methyl-di-lower alkylamine, N-methyl-dicyclohexylamine, N,N-dimethylcyclohexylamine, N,N-diethylcyclohexylamine, N,N-dimethylbenzylamine, hordenine, N-methylpyrrolidine, N-ethylpyrrolidine, nicotine, N-methylpiperidine, N-ethylpiperidine, arecoline, meperidine, tropine, atropine, hyoscyamine, scopolamine, cocaine, tropacocaine, morphine, codeine, O3,O6-diacetylmorphine, thebaine, N-methylmorphinans, dihydrocodeinones, dihydromorphinones, 6,14-endo-ethanomorphines, erythromycin and tetracycline, comprising the steps of mono N-dealkylating said tertiary amine to form a secondary amine and thereafter modifying said secondary amine by attachment of another tertiary amine-forming substituent to the amino N atom, the improvement which comprises the steps of effecting said N-dealkylation by replacing the N-alkyl group or one of the N-alkyl groups of said starting tertiary amine by a vinyloxycarbonyl group by reaction of said tertiary amine with a source of vinyloxycarbonyl groups selected from vinyl haloformates to thereby form a vinyloxycarbonyl amide of the secondary amine, and thereafter cleaving said vinyloxycarbonyl amide under mild acidic conditions with a hydrohalic acid and a hydroxylic reagent selected from the group consisting of water, a lower carboxylic acid and a lOwer alkanol to split off said vinyloxycarbonyl group from the amino N atom and obtain the secondary amine or hydrohalide salt thereof.

Claim 13

The process of claim 10 wherein said source of vinyloxycarbonyl groups is vinyl chloroformate.

Claim 14

The process of claim 10 wherein at least one of the groups remaining attached to the amino N atom of said starting tertiary amine throughout the process is a group initially having alcoholic and/or phenolic hydroxyl group substituents which are protected by lower alkanoyl or lower alkenoyl protecting groups stable to mild acidic conditions during the splitting off of said vinyloxycarbonyl group from the amino N atom and stable during the attachment of said other tertiary amine-forming substituent to the amino N atom.

Claim 15

The process of claim 12 wherein said protecting groups protecting said alcoholic and/or phenolic hydroxyl groups are vinyloxycarbonyl groups.

Claim 16

The process of claim 13 wherein said protection of said alcoholic and/or phenolic hydroxyl groups with vinyloxycarbonyl groups and said replacement of the N-alkyl group in said starting tertiary amine by a vinyloxycarbonyl group are simultaneously effected by treatment of said starting tertiary amine containing free alcoholic and/or phenolic hydroxyl groups with an excess of vinyl chloroformate and a proton scavenger in an insert solvent, said proton scavenger being more basic than said starting tertiary amine and less reactive than said starting tertiary amine toward said vinyl chloroformate so as to effect removal of any acid liberated during the resulting reaction.

Claim 17

The process of claim 14 wherein said proton scavenger is selected from the group consisting of 1,8-bis-(dimethylamino)-naphthalene and N-alkyldicyclohexylamines.

Claim 18

The process of claim 13 wherein subsequent to attachment of said other tertiary amine-forming substituent to the amino N atom, said vinyloxycarbonyl groups protecting said alcoholic and/or phenolic hydroxyl groups are replaced by hydrogen to give the free alcoholic and/or phenolic hydroxyl groups by treatment under basic conditions with aqueous or alcoholic base or under strong acidic conditions with aqueous or alcholic acid.

Claim 19

A process for the synthesis of nalorphine from morphine which comprises the stepps of reacting morphine with vinyl chloroformate in the presence of a proton scavenger which is more basic than said morphine and less reactive than said morphine toward said vinyl chloroformate so as to effect removal of any acid liberated during said reaction and to obtain N,O,O-tri(vinyloxycarbonyl)-normorphine, treating said N,O,O-tri(vinyloxycarbonyl)-normorphine under mild acidic conditions with a hydrobolic acid and a hydroxylic reagent selected from the group consisting of water, a lower carboxylic acid and a lower alkanol to split off the vinyloxycarbonyl group froom the amino N atom and obtain the hydrohalide salt of O,O-di(vinyloxycarbonyl)-normorphine, neutralizing said hydrohalide salt and N-allylating the neutralized product by reaction with an allyl halide to obtain O,O-di(vinyloxycarbonyl)-nalorphine, and treating said O, O-di(vinyloxycarbonyl)-nalorphine under basic conditions with aqueous or alcoholic base or under strong acidic conditions with aqueous or alcoholic acid to obtain nalorphine.

Claim 20

A process for the synthesis of nalorphine from morphine which comprises the stepps of reacting morphine with vinyl chloroformate in the presence of a proton scavenger which is more basic than said morphine and less reactive than said morphine toward said vinyl chloroformate so as to effect removal of any acid liberated during said reaction and to obtain N,O,O-tri(vinyloxycarbonyl)-normorphine, treating said N,O,O-tri(vinyloxycarbonyl)-normorphine under mild acidic conditions with a hydrobolic acid and a hydroxylic reagent selected from the group consisting of water, a lower carboxylic acid and a lower alkanol to split off the vinyloxycarbonyl group froom the amino N atom and obtain the hydrohalide salt of O,O-di(vinyloxycarbonyl)-normorphine, neutralizing said hydrohalide salt and N-allylating the neutralized product by reaction with an allyl halide to obtain O,O-di(vinyloxycarbonyl)-nalorphine, and treating said O, O-di(vinyloxycarbonyl)-nalorphine under basic conditions with aqueous or alcoholic base or under strong acidic conditions with aqueous or alcoholic acid to obtain nalorphine.

Claim 21

A process for the synthesis of naloxone from oxymorphone which comprises the steps of reacting oxymorphone with vinyl chloroformate in the presence of a proton scavenger which is more basic than said oxymorphone and less reactive than said oxymorphone toward said vinyl chloroformate so as to effect removal of any acid liberated during said reaction and to obtain N-vinyloxycarbonyl-O3-vinyloxycarbonyl-14-hydroxydihydronormorphinone, treating said N-vinyloxycarbonyl-O3-vinyloxycarbonyl-14-hydroxydihydronormorphinone under mild acidic conditions with a hydrohalic acid and a hydroxylic reagent selected from the group consisting of water, A lower carboxylic acid and a lower alkanol to split off the vinyloxycarbonyl group from the amino N atom and obtain the hydrohalide salt of O3-vinyloxycarbonyl-14-hydroxydihydronormorphinone, neutralizing said hydrohalide salt and N-allylating the neutralized product by reaction with an allyl halide to obtain O3-vinyloxycarbonyl-naloxone, and treating said O3-vinyloxycarbonyl-naloxone with aqueous or alcoholic base to obtain naloxone.

Claim 22

A process for the synthesis of naloxone from oxymorphone which comprises the steps of reacting oxymorphone with vinyl chloroformate in the presence of a proton scavenger which is more basic than said oxymorphone and less reactive than said oxymorphone toward said vinyl chloroformate so as to effect removal of any acid liberated during said reaction and to obtain N-vinyloxycarbonyl-O3-vinyloxycarbonyl-14-hydroxydihydronormorphinone, treating said N-vinyloxycarbonyl-O3-vinyloxycarbonyl-14-hydroxydihydronormorphinone under mild acidic conditions with a hydrohalic acid and a hydroxylic reagent selected from the group consisting of water, A lower carboxylic acid and a lower alkanol to split off the vinyloxycarbonyl group from the amino N atom and obtain the hydrohalide salt of O3-vinyloxycarbonyl-14-hydroxydihydronormorphinone, neutralizing said hydrohalide salt and N-allylating the neutralized product by reaction with an allyl halide to obtain O3-vinyloxycarbonyl-naloxone, and treating said O3-vinyloxycarbonyl-naloxone with aqueous or alcoholic base to obtain naloxone.