Process for the preparation of 6-beta hydroxy morphinan compounds

1. A process for preparing a compound, the process comprising:

(a) contacting a 6-keto morphinan compound comprising Formula (I) with a reducing agent, a first proton acceptor and a solvent, wherein the concentration of the 6-keto morphinan of Formula (I) in the solvent is at least 25 grams per liter, to form a first homogeneous reaction mixture, wherein some of compound (I) is converted to a 6-hydroxy morphinan compound comprising Formula (II) to produce a substantially heterogeneous reaction mixture; and

(b) contacting the heterogeneous reaction mixture with a second proton acceptor to form a second homogeneous reaction mixture, wherein some of compound (I) that was not converted to compound (II) in step (a) is converted to compound (II), the process of steps (a) and (b) proceeding according to the reaction scheme:

wherein:

R is chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl and hydroxy protecting group;

R 1 is chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl;

R 2 and R 3 are independently chosen from hydrogen, OH, NH 2 , SH, hydrocarbyl, substituted hydrocarbyl, alkyl ketal, alkyl thiol ketal, and alkyl dithiol ketal, wherein when R 1 and R 2 are different they form an epimeric pair, and wherein R 1 and R 2 together may form a group chosen from cycloalkyl ketal, cycloalkyl thiol ketal, and cycloalkyl dithiol ketal;

R 4 , R 5 , R 6 , and R 7 are independently chosen from hydrogen, halogen, NH 2 , CN, SH, CF 3 , OR 9 , hydrocarbyl, and substituted hydrocarbyl;

R 8 is chosen from hydrogen and hydroxy; and

R 9 is chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, and hydroxy protecting group.

2. The process of claim 1 , wherein:

R is chosen from hydrogen, alkyl, and methyl;

R 1 is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, aryl, benzyl, and C(O) n R 10− ;

R 2 , R 3 , R 4 , R 5 , and R 7 are each hydrogen;

R 6 is chosen from H, Br, Cl, F, OH, O-methyl, and O-benzyl;

R 10 is chosen from alkyl, alkenyl, and aryl; and

n is an integer from 1 to 2.

3. The process of claim 1 , wherein the 6-hydroxy morphinan compound (II) is a mixture of 6-alpha-hydroxy and 6-beta-hydroxy morphinan epimers.

4. The process of claim 3 , wherein the epimeric ratio of 6-beta-hydroxy to 6-alpha-hydroxy morphinan epimers is chosen from at least 4:1, at least 50:1, and at least about 99:1.

5. The process of claim 1 , wherein the reducing agent is a sulfinic acid chosen from formamidine sulfinic acid and hydroxymethane sulfinic acid; and the first proton acceptor and the second proton acceptor are independently chosen from sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium bicarbonate.

6. The process of claim 1 , wherein the molar/molar ratio of compound (I) to reducing agent is from about 1:2 to about 1:8; the molar/molar ratio of compound (I) to the first proton acceptor is from about 1:3 to about 1:11; and the molar/molar ratio of compound (I) to the second proton acceptor is from about 1:0.5 to about 1:2.

7. The process of claim 1 , wherein the reaction is conducted in the presence of a protic solvent.

8. The process of claim 1 , wherein the reaction is conducted at a temperature ranging from about 20° C. to about 75° C.

9. The process of claim 1 , wherein at least about 40% of compound (I) is converted to compound (II) in step (a).

10. The process of claim 1 , wherein at least about 70% of compound (I) is converted to compound (II) in both steps (a) and (b).

11. The process of claim 2 , wherein the optical activity of compound (I) is (+) or (−), and the configuration of C-5, C-13, C-14, and C-9, respectively, is chosen from RRRR, RRSR, RRRS, RRSS, RSRR, RSSR, RSRS, RSSS, SRRR, SRSR, SRRS, SRSS, SSRR, SSSR, SSRS, and SSSS, provided that the C-15 and the C-16 carbons are both either on the alpha face of the molecule or the beta face of the molecule; and the optical activity of compound (II) is (+) or (−), and the configuration of C-6, C-5, C-13, C-14, and C-9, respectively, is chosen from RRRRR, RRRRS, RRSRR, RRSRS, RRRSR, RRRSS, RRSSR, RRSSS, RSRRR, RSRRS, RSSRR, RSSRS, RSRSR, RSRSS, RSSSR, RSSSS, SRRRR, SRRRS, SRSRR, SRSRS, SRRSR, SRRSS, SRSSR, SRSSS, SSRRR, SSRRS, SSSRR, SSSRS, SSRSR, SSRSS, SSSSR, and SSSSS, provided that the C-15 and the C-16 carbons are both either on the alpha face of the molecule or the beta face of the molecule, and the 6-hydroxy is on the beta face of the molecule.