PROCESS FOR THE PREPARATION OF MORPHINANE COMPOUNDS

Abstract

The invention describes the process of catalytic O-demethylation of 3-methoxymorphinane compounds using boron tribromide. Addition of catalysts reduces the reaction time, improves reacting the substrate to give the product in very good purity and yield. The process can be used, for example, for the preparation of oxycodone, oxymorphone, naltrexone, naloxone and nalbuphine from their respective O-methyl derivatives.

Claims

1. A process for the preparation of a morphinane compound (2) from a morphinane compound (1) or salts thereof, the process comprising: (i) mixing the morphinane compound (1) with a catalyst in an aprotic organic solvent; and (ii) adding boron tribromide to the mixture of (i), wherein substituent R in the morphinane compound (1) and the morphinane compound (2) is selected from hydrogen, hydrocarbyl or substituted hydrocarbyl, according to a scheme: ##STR00004##

2. The process according to claim 1, wherein substituent R in the morphinane compound (1) and the morphinane compound (2) is hydrogen, methyl, ethyl, propyl, allyl, cyclopropylmethyl or cyclobutylmethyl, and the aprotic organic solvent is selected from the group consisting of benzene, toluene, o-xylene, m-xylene, p-xylene, chlorobenzene, dichloromethane, chloroform, and mixtures thereof.

3. The process according to claim 1, wherein the morphinane compound (1) is 4,5α-epoxy-14-hydroxy-3-methoxymorphinan-6-one (noroxycodone), 4,5α-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one (oxycodone), 4,5α-epoxy-14-hydroxy-3-methoxy-17-ethylmorphinan-6-one, or 4,5α-epoxy-14-hydroxy-3-methoxy-17-propyl-morphinan-6-one, 4,5α-epoxy-14-hydroxy-3-methoxy-17-allylmorphinan-6-one (3-methoxynaloxone), 4,5α-epoxy-14-hydroxy-3-methoxy-17-cyclopropylmethyl-morphinan-6-one (3-methoxynaltrexone) or 4,5α-epoxy-14-hydroxy-3-methoxy-17-cyclobutylmethyl-morphinan-6-one (3-methoxynalbuphone); and the morphinane compound (2) is 4,5α-epoxy-3,14-dihydroxymorphinan-6-one (noroxymorphone), 4,5α-epoxy-3,14-dihydroxy-17-methyl-morphinan-6-one (oxymorphone), 4,5α-epoxy-3,14-dihydroxy-17-ethylmorphinan-6-one, 4,5α-epoxy-3,14-dihydroxy-n-propyl-morphinan-O-one, 4,5α-epoxy-3,14-dihydroxy-17-allylmorphinan-6-one (naloxone), 4,5α-epoxy-3,14-dihydroxy-17-cyclopropylmethyl-morphinan-6-one (naltrexone) or 4,5α-epoxy-3,14-dihydroxy-17-cyclobutylmethyl-morphinan-6-one (nalbuphone).

4. The process according to claim 1, wherein the boron tribromide is added in excess in relation to the morphinane compound (1).

5. The process according to claim 4, wherein the excess of the boron tribromide is more than 1 molar equivalent.

6. The process according to claim 1, wherein the catalyst is (i) an inorganic iodide; or (ii) a quaternary iminium or phosphonium compound of formula: ##STR00005## wherein Y is N or P; R.sub.1 is hydrogen, hydrocarbyl or substituted hydrocarbyl, aryl or cycloalkyl; R.sub.2 is hydrogen, hydrocarbyl or substituted hydrocarbyl, aryl or cycloalkyl; R.sub.3 is hydrogen, hydrocarbyl or substituted hydrocarbyl, aryl or cycloalkyl; R.sub.4 is hydrogen, hydrocarbyl or substituted hydrocarbyl, aryl or cycloalkyl; and X is F, Cl, Br, I, sulphate, sulphite, hydrogensulphate, hydrogensulphite, nitrate, nitrite, phosphate, hydrogenphosphate or dihydrogenphosphate.

7. The process according to claim 6, wherein the inorganic iodide catalyst is lithium iodide, sodium iodide, or potassium iodide.

8. The process according to claim 6, wherein the catalyst is in an amount of 0.1 to 1 molar equivalent in relation to the morphinane compound (1).

9. The process according to claim 6, wherein the catalyst is tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, benzyltriethylammonium chloride, benzyltriethylammonium bromide, benzyltriethylammonium iodide, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide, benzyltrimethylammonium iodide, cetyltriethylammonium chloride, cetyltriethylammonium bromide or cetyltriethylammonium iodide.

10. A process for catalytic O-demethylation of a morphinane compound having a structure of formula 1 (morphinane compound (1)), wherein substituent R is selected from hydrogen, hydrocarbyl or substituted hydrocarbyl ##STR00006## the process comprising: (i) mixing the morphinane compound (1) with a catalyst in an aprotic organic solvent; and (ii) adding boron tribromide to the mixture of (i).

11. The process according to claim 10, wherein R in the morphinane compound (1) is hydrogen, methyl, ethyl, propyl, allyl, cyclopropylmethyl, or cyclobutylmethyl, and the aprotic organic solvent is selected from the group consisting of benzene, toluene, o-xylene, m-xylene, p-xylene, chlorobenzene, dichloromethane, chloroform, and mixtures thereof.

12. The process according to claim 10, wherein the morphinane compound (1) is 4,5α-epoxy-14-hydroxy-3-methoxymorphinan-6-one (noroxycodone), 4,5α-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one (oxycodone), or 4,5α-epoxy-14-hydroxy-3-methoxy-17-ethylmorphinan-6-one, 4,5α-epoxy-14-hydroxy-3-methoxy-17-propyl-morphinan-6-one, 4,5α-epoxy-14-hydroxy-3-methoxy-17-allylmorphinan-6-one (3-methoxynaloxone), 4,5α-epoxy-14-hydroxy-3-methoxy-17-cyclopropylmethylmorphinan-6-one (3-methoxynaltrexone) or 4,5α-epoxy-14-hydroxy-3-methoxy-17-cyclobutylmethyl-morphinan-6-one (3-methoxynalbuphone).

13. The process according to claim 10, wherein the boron tribromide is added in excess in relation to the morphinane compound (1).

14. The process according to claim 13, wherein the excess of the boron tribromide is more than 1 molar equivalent.

15. The process according to claim 10, wherein the catalyst is (i) an inorganic iodide or (ii) a quaternary iminium or phosphonium compound of formula: ##STR00007## wherein Y is N or P; R.sub.1 is hydrogen, hydrocarbyl or substituted hydrocarbyl, aryl or cycloalkyl; R.sub.2 is hydrogen, hydrocarbyl or substituted hydrocarbyl, aryl or cycloalkyl; R.sub.3 is hydrogen, hydrocarbyl or substituted hydrocarbyl, aryl or cycloalkyl; R.sub.4 is hydrogen, hydrocarbyl or substituted hydrocarbyl, aryl or cycloalkyl; and X is F, Cl, Br, I, sulphate, sulphite, hydrogensulphate, hydrogensulphite, nitrate, nitrite, phosphate, hydrogenphosphate or dihydrogenphosphate.

16. The process according to claim 15, wherein the inorganic iodide catalyst is lithium iodide, sodium iodide, or potassium iodide.

17. The process according to claim 15, wherein the catalyst is in an amount of 0.1 to 1 molar equivalent in relation to the morphinane compound (1).

18. The process according to claim 15, wherein the catalyst is tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, benzyltriethylammonium chloride, benzyltriethylammonium bromide, benzyltriethylammonium iodide, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide, benzyltrimethylammonium iodide, cetyltriethylammonium chloride, cetyltriethylammonium bromide or cetyltriethylammonium iodide.

19. The process according to claim 10, wherein the catalytic O-demethylation of the morphinane compound (1) prepares a morphinane compound having a structure of formula 2 (morphinane compound (2)), wherein substituent R is selected from hydrogen, hydrocarbyl or substituted hydrocarbyl: ##STR00008##

20. The process according to claim 19, wherein substituent R in the morphinane compound (2) is hydrogen, methyl, ethyl, propyl, allyl, cyclopropylmethyl or cyclobutylmethyl, and the aprotic organic solvent is selected from the group consisting of benzene, toluene, o-xylene, m-xylene, p-xylene, chlorobenzene, dichloromethane, chloroform, and mixtures thereof.

21. The process according to claim 19, wherein the morphinane compound (2) is 4,5α-epoxy-3,14-dihydroxymorphinan-6-one (noroxymorphone), 4,5α-epoxy-3,14-dihydroxy-17-methylmorphinan-6-one (oxy morph one), 4,5α-epoxy-3,14-dihydroxy-17-ethylmorphinan-6-one, or 4,5α-epoxy-3,14-dihydroxy-17-propyl morphinan-6-one, or 4,5α-epoxy-3,14-dihydroxy-17-allylmorphinan-6-one (naloxone), 4,5α-epoxy-3,14-dihydroxy-17-cyclopropylmethylmorphinan-6-one (naltrexone) or 4,5α-epoxy-3,14-dihydroxy-17-cyclobutylmethylmorphinan-6-one (nalbuphone).

22-27. (canceled)

28. The process according to claim 4, wherein the excess of the boron tribromide is 3 to 4 molar equivalents.

29. The process according to claim 6, wherein the catalyst is in an amount of 0.3 to 0.5 molar equivalent in relation to the morphinane compound (1).

30. The process according to claim 13, wherein the excess of the boron tribromide is 3 to 4 molar equivalents.

31. The process according to claim 15, wherein the catalyst is in an amount of 0.3 to 0.5 molar equivalent in relation to the morphinane compound (1).

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0024] FIG. 1 shows the effect of the catalyst on the O-demethylation rate of oxycodone on oxymorphone through the action of BBr.sub.3.

EXAMPLES

[0025] The examples provided are intended to illustrate the invention.

Example 1: Preparation of Oxymorphone by O-Demethylation of Oxycodone in the Presence of NaI

[0026] The oxycodone base (5.0 g) is weighed together with sodium iodide (0.5 eq.) and toluene (75 mL) is added. The suspended mixture is cooled to 0° C. BBr.sub.3 (3.3 eq.) is added dropwise over 15 minutes by means of a dropping funnel with continuous stirring. During the addition, the temperature is maintained between 5 and 15° C. The reaction mixture is allowed to warm to room temperature after the addition, and the stirring continues. After 23 hours, 2.0 area % of the starting material remains in the reaction mixture. The reaction mixture is hydrolyzed with water and the oxymorphone is isolated by precipitation or extraction into an organic solvent after pH adjustment to >7.

Example 2: Preparation of Oxymorphone by O-Demethylation of Oxycodone in the Presence of KI

[0027] The oxycodone base (5.0 g) is weighed together with potassium iodide (0.5 eq.) and toluene (75 mL) is added. The suspended mixture is cooled to 0° C. BBr.sub.3 (3.3 eq.) is added dropwise over 15 minutes by means of a dropping funnel with continuous stirring. During the addition, the temperature is maintained between 5 and 15° C. The reaction mixture is allowed to warm to room temperature after the addition, and the stirring continues. After 23 hours, 4.1 area % of the starting material remains in the reaction mixture. The reaction mixture is hydrolyzed with water and the oxymorphone is isolated by precipitation or extraction into an organic solvent after pH adjustment to >7.

Example 3: Preparation of Oxymorphone by O-Demethylation of Oxycodone in the Presence of TBAI

[0028] The oxycodone base (5.0 g) is weighed together with TBAI (0.5 eq.) and toluene (75 mL) is added. The suspended mixture is cooled to 0° C. BBr.sub.3 (3.3 eq.) is added dropwise over 15 minutes by means of a dropping funnel with continuous stirring. During the addition, the temperature is maintained between 5 and 15° C. The reaction mixture is allowed to warm to room temperature after the addition, and the stirring continues. After 8 hours, 3.8 area % of the starting material remains in the reaction mixture. The reaction mixture is hydrolyzed with water and the oxymorphone is isolated by precipitation or extraction into an organic solvent after pH adjustment to >7.

Example 4: Preparation of Oxymorphone by O-Demethylation of Oxycodone in the Presence of TBAB

[0029] The oxycodone base (5.0 g) is weighed together with TBAB (0.5 eq.) and toluene (75 mL) is added. The suspended mixture is cooled to 0° C. BBr.sub.3 (3.6 eq.) is added dropwise over 15 minutes by means of a dropping funnel with continuous stirring. During the addition, the temperature is maintained between 5 and 15° C. The reaction mixture is allowed to warm to room temperature after the addition, and the stirring continues. After 5 hours, <1 area % of the starting material remains in the reaction mixture. The reaction mixture is hydrolyzed with water and the oxymorphone is isolated by precipitation or extraction into an organic solvent after pH adjustment to >7.

Example 5: Preparation of Oxymorphone by O-Demethylation in the Presence of CTAB

[0030] The oxycodone base (5.0 g) is weighed together with CTAB (0.1 eq.) and toluene (75 mL) is added. The suspended mixture is cooled to 0° C. BBr.sub.3 (3.3 eq.) is added dropwise over 15 minutes by means of a dropping funnel with continuous stirring. During the addition, the temperature is maintained between 5 and 15° C. The reaction mixture is allowed to warm to room temperature after the addition, and the stirring continues. After 23 hours, 5.9 area % of the starting material remains in the reaction mixture. The reaction mixture is hydrolyzed with water and the oxymorphone is isolated by precipitation or extraction into an organic solvent after pH adjustment to >7.

Example 6: Preparation of Oxymorphone by O-Demethylation in the Presence of TEBA

[0031] The oxycodone base (5.0 g) is weighed together with TEBA (0.3 eq.) and toluene (75 mL) is added. The suspended mixture is cooled to 0° C. BBr.sub.3 (3.6 eq.) is added dropwise over 15 minutes by means of a dropping funnel with continuous stirring. During the addition, the temperature is maintained between 5 and 15° C. The reaction mixture is allowed to warm to room temperature after the addition, and the stirring continues. After 8 hours, less than 5 area % of the starting material remains in the reaction mixture. The reaction mixture is hydrolyzed with water and the oxymorphone is isolated by precipitation or extraction into an organic solvent after pH adjustment to >7.

Example 7: Preparation of Oxymorphone by O-Demethylation of Oxycodone in the Presence of Tributylhexadecylphosphonium Bromide (THPB)

[0032] The oxycodone base (5.0 g) is weighed together with THPB (0.1 eq.) and toluene (75 mL) is added. The suspended mixture is cooled to 0° C. BBr.sub.3 (4.0 eq.) is added dropwise over 15 minutes by means of a dropping funnel with continuous stirring. During the addition, the temperature is maintained between 5 and 15° C. The reaction mixture is allowed to warm to room temperature after the addition, and the stirring continues. After 5 hours, <1 area % of the starting material remains in the reaction mixture. The reaction mixture is hydrolyzed with water and the oxymorphone is isolated by precipitation or extraction into an organic solvent after pH adjustment to >7.

Example 8: Preparation of Noroxymorphone by O-Demethylation of Noroxycodone in the Presence of Tetrabutylphosphonium Bromide (TPB-Br)

[0033] The noroxycodone (5.0 g) is weighed together with TPB-Br (0.8 eq.) and chlorobenzene (75 mL) is added. The suspended mixture is cooled to 0° C. BBr.sub.3 (3.8 eq.) is added dropwise over 15 minutes by means of a dropping funnel with continuous stirring. During the addition, the temperature is maintained between 5 and 15° C. The reaction mixture is allowed to warm to room temperature after the addition, and the stirring continues. After 6 hours, less than 2 area % of the starting material remains in the reaction mixture. The reaction mixture is hydrolyzed with water and the noroxymorphone is isolated by precipitation or extraction into an organic solvent after pH adjustment to >7.

Example 9: Preparation of Naltrexone by O-Demethylation of 3-Methoxynaltrexone in the Presence of TBAB

[0034] 3-methoxznaltrexone (5.0 g) is weighed together with TBAB (0.1 eq.) and toluene (75 mL) is added. The suspended mixture is cooled to 0° C. BBr.sub.3 (3.1 eq.) is added dropwise over 15 minutes by means of a dropping funnel with continuous stirring. During the addition, the temperature is maintained between 5 and 15° C. The reaction mixture is allowed to warm to room temperature after the addition, and the stirring continues. After 3 hours, less than 1 area % of the starting material remains in the reaction mixture. The reaction mixture is hydrolyzed with water and the naltrexone is isolated by precipitation or extraction into an organic solvent after pH adjustment to >7.

Example 10: Preparation of Naloxone by O-Demethylation of 3-Methoxynaloxone in the Presence of TBAB

[0035] 3-methoxynaloxone (5.0 g) is weighed together with TBAB (0.2 eq.) and toluene (75 mL) is added. The suspended mixture is cooled to 0° C. BBr.sub.3 (3.2 eq.) is added dropwise over 15 minutes by means of a dropping funnel with continuous stirring. During the addition, the temperature is maintained between 5 and 15° C. The reaction mixture is allowed to warm to room temperature after the addition, and the stirring continues. After 3 hours, less than 1 area % of the starting material remains in the reaction mixture. The reaction mixture is hydrolyzed with water and the naloxone is isolated by precipitation or extraction into an organic solvent after pH adjustment to >7.