Total synthesis of northebaine, normophine, noroxymorphone enantiomers and derivatives via N-Nor intermediates
AssigneeThe United States of America as represented by the Department of Health and Human Services
InventorsKenner C. Rice, Amy H. Newman
Life of this patent
Estimating the term…
Abstract
The invention involves a method of making key intermediates useful in the synthesis of many opiate narcotics and antagonists and agonists; and the non-opiate enantiomers thereof which have potent antitussive properties. The synthesis starts from either the natural or unnatural enantiomer of nordihydrocodeinone and produces 8, 14-dihydronorthebaine, the diketal of 7-bromonordihydrocodeinone, northebaine, norcodeinone diketal and 14-hydroxynorcodeinone intermediates without the necessity of leaving the N-nor structure. The syntheses have fewer steps than previous methods, and also have high yields.
Claims20
A method for producing 14-hydroxynorcodeinone of both the natural (-) and unnatural (+) series, wherein the method for producing the unnatural (+) series compound comprises the steps of:
- (a) reacting (+)-nordihydrocodeinone with a trialkylorthoformate CH(OR).sub.3, alcohol ROH and phenolic sulfonic acid to produce a first mixture containing compounds of formula (10) ##STR11## and its corresponding ketal;
- (b) converting all of said corresponding ketal to said compounds of formula (10) by removing said alcohol ROH from said first mixture to form a second mixture;
- (c) converting said second mixture to a two phase system by adding to said second mixture at least an aqueous base to form a two phase system having an aqueous phase and an immisible organic solvent phase, said compounds of formula (10) dissolving in the organic phase for removal therefrom;
- (d) reacting said compounds of formula (10) with a brominating agent to produce compounds of formula (11) ##STR12## (e) reacting said compounds of formula (11) with a strong base in a polar aprotic solvent to produce compounds of formula (12) ##STR13## ;
- and (f) reacting said compounds of formula (12) with an oxidizing agent to produce the compound of formula (13) ##STR14## wherein R is a C.sub.1 -C.sub.8 alkyl group.
A method for producing northebaine compound derivatives of both the natural (-) and unnatural (+) series, wherein the method for producing the unnatural (+) series compounds comprises the steps of:
- (a) reacting (+)-nordihydrocodeinone with trialkyl orthoformate CH(OR).sub.3, alcohol ROH and phenolic sulfonic acid to produce a first mixture containing compounds of formula (10) ##STR15## and its corresponding ketal;
- (b) converting all of said corresponding ketal to said compounds of formula (10) by removing said alcohol ROH from said first mixture to form a second mixture;
- (c) converting said second mixture to a two phase system by adding to said second mixture at least an aqueous base to form a two phase system having an aqueous phase and an immisible organic solvent phase, said compounds of formula (10) dissolving in the organic phase for removal therefrom;
- (d) reacting said compounds of formula (10) with brominating agent to produce compounds of formula (11) ##STR16## (e) reacting said compounds of formula (11) with a strong base in a polar aprotic solvent to produce compounds of formula (12) ##STR17## wherein R is a C.sub.1 -C.sub.8 alkyl group.
A method for producing 8,14-dihydronorthebaine compound derivatives of both the natural (-) and unnatural (+) series, wherein the method for producing unnatural (+) series compounds comprises the steps of:
- (a) reacting (+)-nordihydrocodeinone with trialkyl orthoformate CH(OR).sub.3, alcohol ROH and phenolic sulfonic acid to produce a first mixture containing compounds of formula (10) ##STR18## and its corresponding ketal, wherein R is a C.sub.1 -C.sub.8 alkyl group;
- (b) converting all of said corresponding ketal to said compounds of formula (10) by removing said alcohol ROH to form a second mixture;
- and
- (c) converting said second mixture to a two phase system by adding to said second mixture at least an aqueous base to form a two phase system having an aqueous phase and an immiscible organic solvent phase, wherein said compounds of formula (10) dissolve in the organic phase for removal therefrom;
- and wherein the method for producing natural (-) series compounds employs (-)-nordihydrocodeinone in step (a).
A method for producing 14-hydroxynorcodeinone of the natural (-) and unnatural (+) series, wherein the method for producing the unnatural (+) series compounds comprises the step of:
- reacting compounds of formula (12) ##STR19## with an oxidizing agent to produce a compound of formula (13) ##STR20## wherein R is a C.sub.1 -C.sub.8 alkyl group.
Dependencies are inferred from the claim text.