Production of opioid analgesics

1. A process for the preparation of a 4,5-epoxymorphinan compound of formula (I)

wherein

R 1 is methyl, substituted methyl or alcohol protecting group;

R 2 is hydrogen, methyl, substituted methyl or amine protecting group,

R 3 is methyl, substituted methyl or alcohol protecting group;

comprising the steps of

(i) reacting an alcohol of formula (II)

wherein R 1 and R 2 are as hereinbefore defined, with benzophenone and potassium tert-alkylate in hydrocarbon solvent to generate a reaction mixture containing the enolate of formula (III)

wherein R 1 and R 2 are as hereinbefore defined; and

(ii) adding reaction mixture containing the enolate of formula (III) to the electrophilic agent of formula (IV)

R 3 X  IV

wherein R 3 is as hereinbefore defined and X is a leaving group, to yield a compound of formula (I), and

(iii) isolating the compound of formula (I).

2. The process of claim 1 , wherein the hydrocarbon solvent is selected from the group consisting of cyclohexane, toluene, heptane and combinations thereof.

3. The process of claim 1 , wherein the potassium tert-alkylate is selected from the group consisting of potassium tert-amylate, potassium tert-butoxide, and combinations thereof.

4. The process of claim 1 , wherein X is a leaving group selected from the group consisting of halide, sulfonate, sulfate, phosphate, phosphite, carboxylate, alkoxyl, and hydroxyl.

5. The process of claim 1 , wherein said compound of formula (I) is a compound of formula IA

wherein R 1 , R 2 , and R 3 are as defined hereinbefore.

6. The process of claim 1 , wherein the molar ratio of said alcohol of formula (II) to said benzophenone is in the range of about 1:3 to about 1:20.

7. The process of claim 6 , wherein the molar ratio of said alcohol of formula (II) to said benzophenone is in the range of about 1:6 to about 1:9.

8. The process of claim 1 , wherein step (i) is performed at a temperature in the range from about 5° C. to about 110° C.

9. The process of claim 8 , which is performed at a temperature in the range from about 15° C. to about 60° C.

10. The process of claim 8 , which is performed at a temperature in the range from about 20° C. to about 50° C.

11. The process of claim 1 , wherein said potassium tert-alkylate is present in an amount from about 1 to about 5 equivalents relative to the amount of said alcohol of formula (II).

12. The process of claim 11 , wherein said potassium tert-alkylate is present in an amount from about 1.4 to about 4 equivalents.

13. The process of claim 1 , wherein said electrophilic agent of formula (IV) is used in step ii in an amount of at least one equivalent relative to the amount of potassium tert-alkylate.

14. The process of claim 1 , wherein said alcohol of formula (II) is dihydrocodeine.

15. The process of claim 14 , wherein said electrophilic agent of formula (IV) in step ii is selected from the group consisting of dimethyl sulfate and acetic anhydride.

16. The process of claim 5 , wherein said compound of formula (IA) is selected from the group consisting of dihydrothebaine and dihydrocodeinone enol acetate.

17. A process for the preparation of a 4,5-epoxymorphinan compound of formula (I)

wherein

R 1 is methyl, substituted methyl or alcohol protecting group;

R 2 is hydrogen, methyl, substituted methyl or amine protecting group,

R 3 is methyl, substituted methyl or alcohol protecting group;

comprising the steps of

(i) reacting an alcohol of formula (II)

wherein R 1 and R 2 are as hereinbefore defined, with benzophenone and potassium tert-alkylate in hydrocarbon solvent to generate a reaction mixture containing the enolate of formula (III)

wherein R 1 and R 2 are as hereinbefore defined; and

(ii) adding the electrophilic agent of formula (IV)

R 3 X  IV

wherein R 3 is as hereinbefore defined and X is a leaving group, to the reaction mixture containing the enolate of formula (III) to yield a compound of formula (I); and

(iii) isolating the compound of formula (I).