Back to results
US 6,887,998 B2Granted
Process for 8-carboxamido-2,6-methano-3-benzazocines
AssigneeRensselaer Polytechnic Institute
InventorMark P. Wentland
Life of this patent
Estimating the term…
Abstract
8-Substituted-2,6-methano-3-benzazocines of general structure I in which A is —CH2—OH, —CH2NH2, —NHSO2CH3, and Y is O, S or NOH are useful as analgesics, anti-diarrheal agents, anticonvulsants, antitussives and anti-addiction medications. 8-Carboxamides, thiocarboxamides, hydroxyamidines and formamides are preferred.
Claims10
A process for converting a phenolic 3-hydroxyl on a morphinane of structure
- wherein
- R2 and R2a are both hydrogen or taken together R2 and R2a are ═O;
- R3 is chosen from hydrogen, lower alkyl, alkenyl, benzyl, aryl, heterocyclyl and hydroxyalkyl;
- R4 is chosen from hydrogen, hydroxy, amino, lower alkoxy, C1-C20 alkyl and C1-C20 alkyl substituted with hydroxy or carbonyl;
- R9 is hydrogen or lower alkyl;
- R10 is chosen from hydrogen, lower alkyl and hydroxy(lower alkyl);
- or
- together, R9 and R10 form a spiro-fused carbocycle of 5 to 10 carbons;
- R11 is hydrogen;
- R12 is chosen from hydroxy, lower alkoxy, —NH2, —N(CH2CH2Cl)2, and —NHC(O)CH═CHCOOCH3;
- or
- together, R11 and R12 form a carbonyl or a vinyl substituent;
- to a thiocarboxamide comprising:
- (a) reacting said phenolic hydroxyl with a reagent to convert said phenolic hydroxyl to a group displaceable by CN⊖;
- (b) reacting said group displaceable by CN⊖ with Zn(CN)2 in the presence of a Pd(0) catalyst to provide a nitrile;
- (c) hydrolyzing said nitrile to a carboxamide;
- and
- (d) reacting said carboxamide with a pentavalent phosphorus-sulfur reagent.
15 more elements
A process for converting a phenolic 3-hydroxyl on a morphinane of structure
- wherein
- R2 and R2a are both hydrogen or taken together R2 and R2a are ═O;
- R3 is chosen from hydrogen, lower alkyl, alkenyl, benzyl, aryl, heterocyclyl and hydroxyalkyl;
- R4 is chosen from hydrogen, hydroxy, amino, lower alkoxy, C1-C20 alkyl and C1-C20 alkyl substituted with hydroxy or carbonyl;
- R9 is hydrogen or lower alkyl;
- R10 is chosen from hydrogen, lower alkyl and hydroxy(lower alkyl);
- or
- together, R9 and R10 form a spiro-fused carbocycle of 5 to 10 carbons;
- R11 is hydrogen;
- R12 is chosen from hydroxy, lower alkoxy, —NH2, —N(CH2CH2Cl)2, and —NHC(O)CH═CHCOOCH3;
- or
- together, R11 and R12 form a carbonyl or a vinyl substituent;
- to a hydroxyamidine comprising:
- (a) reacting said phenolic hydroxyl with a reagent to convert said phenolic hydroxyl to a group displaceable by CN⊖;
- (b) reacting said group displaceable by CN⊖ with Zn(CN)2 in the presence of a Pd(0) catalyst to provide a nitrile;
- and
- (c) reacting said nitrile with hydroxylamine to produce a hydroxyamidine.
14 more elements
A process for converting a phenolic 3-hydroxyl on a morphinane of structure
- wherein
- R2 and R2a are both hydrogen or taken together R2 and R2a are ═O;
- R3 is chosen from hydrogen, lower alkyl, alkenyl benzyl, aryl, heterocyclyl and hydroxyalkyl;
- R4 is chosen from hydrogen, hydroxy, amino, lower alkoxy, C1-C20 alkyl and C1-C20 alkyl substituted with hydroxy or carbonyl;
- R9 is hydrogen or lower alkyl;
- R10 is chosen from hydrogen, lower alkyl and hydroxy(lower alkyl);
- or
- together, R9 and R10 form a spiro-fused carbocycle of 5 to 10 carbons;
- R11 is hydrogen;
- R12 is chosen from hydroxy, lower alkoxy, —NH2, —N(CH2CH2Cl)2, and —NHC(O)CH═CHCOOCH3;
- or
- together, R11 and R12 form a carbonyl or a vinyl substituent;
- to a carboxamide comprising:
- (a) reacting said phenolic hydroxyl with a reagent to convert said phenolic hydroxyl to a group displaceable by CN⊖;
- (b) reacting said group displaceable by CN⊖ with Zn(CN)2 in the presence of a Pd(0) catalyst to provide a nitrile;
- and
- (c) hydrolyzing said nitrile to a carboxamide.
14 more elements
A process for converting a phenolic 3-hydroxyl on a morphinane of structure
- wherein
- R2 and R2a are both hydrogen or taken together R2 and R2a are ═O;
- R3 is chosen from hydrogen, lower alkyl, alkenyl, benzyl, aryl, heterocyclyl and hydroxyalkyl;
- R4 is chosen from hydrogen, hydroxy, amino, lower alkoxy, C1-C20 alkyl and C1-C20 alkyl substituted with hydroxy or carbonyl;
- R9 is hydrogen or lower alkyl;
- R10 is chosen from hydrogen, lower alkyl and hydroxy(lower alkyl);
- or
- together, R9 and R10 form a spiro-fused carbocycle of 5 to 10 carbons;
- R11 is hydrogen;
- R12 is chosen from hydroxy, lower alkoxy, —NH2, —N(CH2CH2Cl)2, and —NHC(O)CH═CHCOOCH3;
- or
- together, R11 and R12 form a carbonyl or a vinyl substituent;
- to a carboxamide comprising:
- (a) reacting said phenolic hydroxyl with a reagent to convert said phenolic hydroxyl to a triflate;
- (b) reacting said triflate with carbon monoxide and ammonia in the presence of a Pd(0) catalyst to provide a morphinane carboxamide.
12 more elements
A process for converting a phenolic 3-hydroxyl on a morphinane of structure
- wherein
- R2 and R2a are both hydrogen or taken together R2 and R2a are ═O;
- R3 is chosen from hydrogen, lower alkyl, alkenyl, benzyl, aryl, heterocyclyl and hydroxyalkyl;
- R4 is chosen from hydrogen, hydroxy, amino, lower alkoxy, C1-C20 alkyl and C1-C20 alkyl substituted with hydroxy or carbonyl;
- R9 is hydrogen or lower alkyl;
- R10 is chosen from hydrogen, lower alkyl and hydroxy(lower alkyl);
- or
- together, R9 and R10 form a spiro-fused carbocycle of 5 to 10 carbons;
- R11 is hydrogen;
- R12 is chosen from hydroxy, lower alkoxy, —NH2, —N(CH2CH2Cl)2, and —NHC(O)CH═CHCOOCH3;
- or
- together, R11 and R12 form a carbonyl or a vinyl substituent;
- to a carboxamide comprising:
- (a) reacting said phenolic hydroxyl with a reagent to convert said phenolic hydroxyl to a triflate;
- (b) reacting said triflate with carbon monoxide and hexamethyldisilazane in the presence of a Pd(II) salt and a Pd(0) catalyst to provide a silylated carboxamide precursor;
- and
- (c) hydrolyzing said silylated carboxamide precursor to provide a carboxamide.
14 more elements
Dependencies are inferred from the claim text.