Opiate reduction utilizing catalytic hydrogen transfer reaction

1. A method for converting a compound according to Formula II or a pharmaceutically acceptable salt thereof into a compound according to Formula III or a pharmaceutically acceptable salt thereof, the method comprising:

reducing the compound according to Formula II or a pharmaceutically acceptable salt thereof with a hydrogen transfer reagent in the presence of a metal catalyst to form the compound according to Formula III or a pharmaceutically acceptable salt thereof

wherein R 1 and R 3 are independently selected from H; benzyl; 1-8 carbon alkane sulfonyl; p-tosyl; an alkyl group of 1-20 carbons; a substituted alkyl group, wherein the alkyl group is substituted with phenyl, substituted phenyl, 1-8 carbon alkoxyl or phenoxyl groups; and RCO, wherein R is an alkyl group of 1-20 carbons or an aryl group, and

wherein:

(a) the hydrogen transfer reagent is selected from the group consisting of HCO 2 H/HCO 2 NH 4 , HCO 2 H/HCO 2 Na, HCO 2 H/NEt 3 , HCHO and HCHO/NR 3 , wherein each R group is independently selected from H, alkyl, aryl and mixtures thereof; or

(b) the reaction temperature is maintained at about 60° C. to about 110° C.

2. The method of claim 1 further comprising reducing the compound of Formula II or a pharmaceutically acceptable salt thereof in the presence of oxygen to form a compound according to Formula III or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 further comprising reducing the compound of Formula II or a pharmaceutically acceptable salt thereof under substantially atmospheric pressure to form a compound according to Formula III or a pharmaceutically acceptable salt thereof.

4. The method of claim 1 wherein the hydrogen transfer reagent is selected from the group consisting of HCO 2 H/HCO 2 NH 4 , HCO 2 H/HCO 2 Na, HCO 2 H/NEt 3 , HCHO and HCHO/NR 3 , wherein each R group is independently selected from H, alkyl, aryl and mixtures thereof and wherein the reaction temperature is maintained at about 60° C. to about 110° C.

5. The method of claim 1 wherein the metal catalyst is selected from the group consisting of transition metals on carbon, late transition metal oxides, phosphine ligand metal complexes, and mixtures thereof.

6. The method of claim 1 wherein the hydrogen transfer reagent is selected from the group consisting of HCO 2 H/HCO 2 NR 4 , HCO 2 H/HCO 2 Na, HCO 2 H/NEt 3 , HCHO and HCO 2 H/HCO 2 NH 4 , HCO 2 H/HCO 2 Na, HCO 2 H/NEt 3 , HCHO and HCHO/NR 3 , wherein each R group is independently selected from H, alkyl, aryl and mixtures thereof and the temperature is substantially maintained at about −5° C. to about 110° C.

7. A method for preparing an opiate compound according to Formula III or a pharmaceutically acceptable salt thereof, the method comprising:

substantially dissolving a compound according to Formula I or a pharmaceutically acceptable salt thereof in at least one solvent to form a reaction mixture;

adding at least one oxidant and at least one acid to the reaction mixture, wherein the at least one oxidant and the at least one acid react to form at least one peroxyacid;

allowing the peroxyacid to oxidize the compound according to Formula I or a pharmaceutically acceptable salt thereof to form a compound according to Formula II or a pharmaceutically acceptable salt thereof;

reducing the compound according to Formula II or a pharmaceutically acceptable salt thereof with at least one hydrogen transfer reagent in the presence of a metal catalyst to form a compound according to Formula III or a pharmaceutically acceptable salt thereof

wherein R 1 , R 2 and R 3 are independently selected from H; benzyl; 1-8 carbon alkane sulfonyl; p-tosyl; an alkyl group of 1-20 carbons; a substituted alkyl group, wherein the alkyl group is substituted with phenyl, substituted phenyl, 1-8 carbon alkoxyl or phenoxyl groups; and RCO, wherein R is an alkyl group of 1-20 carbons or an aryl group, and

wherein:

(a) the hydrogen transfer reagent is selected from the group consisting of HCO 2 H/HCO 2 NH 4 , HCO 2 H/HCO 2 Na, HCO 2 H/NEt 3 , HCHO and HCHO/NR 3 , wherein each R group is independently selected from H, alkyl, aryl and mixtures thereof; or

(b) Formula II or a pharmaceutically acceptable salt thereof is reduced at a temperature of from about 60° C. to about 110° C.

8. The method of claim 7 further including maintaining the reaction mixture at a temperature high enough to prevent oxidation of ketone or phenoxyl functional groups.

9. The method of claim 7 wherein Formula II or a pharmaceutically acceptable salt thereof is reduced at a temperature of from 60° C. to 110° C.

10. The method of claim 7 wherein the peroxyacid is formed in the reaction mixture by reacting an oxidant with an acid.

11. The method of claim 7 further including adding at least one strong acid selected from the group consisting of H 2 SO 4 , H 3 PO 4 , MeSO 3 H, HCl, p-toluenesulfonic acid and mixtures thereof.

12. The method of claim 7 further comprising reducing the compound of Formula II or a pharmaceutically acceptable salt thereof in the presence of oxygen to form a compound according to Formula III or a pharmaceutically acceptable salt thereof.

13. The method of claim 7 wherein the hydrogen transfer reagent is selected from the group consisting of HCO 2 H/HCO 2 NH 4 , HCO 2 H/HCO 2 Na, HCO 2 H/NEt 3 , HCHO and HCHO/NR 3 , wherein each R group is independently selected from H, alkyl, aryl and mixtures thereof and wherein Formula II or a pharmaceutically acceptable salt thereof is reduced at a temperature of from about 60° C. to about 110° C.

14. The method of claim 7 wherein the metal catalyst is selected from the group consisting of transition metals on carbon, late transition metal oxides, phosphine ligand metal complexes, and mixtures thereof.