Processes for preparing morphinan-6-one products with low levels of alpha beta-unsaturated compounds
View Patent ↗The present invention generally relates to processes for preparing highly pure morphinan-6-one products. The processes involve reducing the concentration of α,β-unsaturated ketone compounds present as impurities in morphinan 6 one products or reaction mixtures including morphinan 6 one compounds by treatment with a sulfur-containing compound.
1. A process for the preparation of a morphinan-6-one product, the process comprising:
forming a reaction mixture comprising a morphinan-6-one compound and an α,β-unsaturated ketone compound; treating the reaction mixture with a non-thiol sulfur-containing compound to reduce the concentration of the α,β-unsaturated ketone compound in the reaction mixture; and
recovering the morphinan-6-one compound to produce the morphinan-6-one product; wherein
the morphinan-6-one compound corresponds to Formula (2):
the α,β-unsaturated ketone compound corresponds to Formula (3):
X is —N(R 17 )— or —N + (R 17a R 17b )—;
R 1 and R 2 are independently selected from hydrogen, substituted and unsubstituted acyl, acyloxy, alkenyl, alkoxy, alkoxyaryl, alkyl, alkylamino, alkynyl, amino, aryl, arylalkoxy, carboalkoxy, carbonyl, carboxyalkenyl, carboxyalkyl, carboxyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylether, halo, haloalkoxy, haloalkyl, heteroaryl, heterocyclic, hydroxyalkyl, hydroxyl, or nitro;
R 3 is hydrogen, hydroxy, protected hydroxy, alkoxy, or acyloxy;
R 10 is hydrogen, hydroxy, protected hydroxy, halo, keto, tosyl, mesyl, or trifluoromesyl;
R 14 is hydrogen, hydroxy, or protected hydroxy;
R 17 is hydrogen, alkyl, cycloalkyl, alkylcarboxy, alkylenecycloalkyl, alkoxycarbonyl, allyl, alkenyl, acyl, aryl, formyl, formyl ester, formamide, benzyl, or an amino protecting group;
R 17a and R 17b are independently selected from hydrogen, alkyl, alkenyl, allyl, cycloalkyl, aryl, or benzylyl, and the morphinan-6-one product comprises less than about 0.1% (by weight morphinan-6-one product) of the α,β-unsaturated ketone compound.
2. The process as set forth in claim 1 wherein at least one of the following conditions are present:
(i) the molar ratio of non-thiol sulfur-containing compound to morphinan-6-one compound in the reaction mixture is from about 0.5:1 to about 3.0:1;
(ii) the reaction mixture is treated with the non-thiol sulfur-containing compound for at least about 1 hour;
(iii) the reaction mixture is treated with the non-thiol sulfur-containing compound at a temperature greater than room temperature; or
(iv) the morphinan-6-one compound is recovered from the reaction mixture without the use of an organic solvent.
3. A process for producing a morphinan-6-one product, the process comprising: forming a reaction mixture comprising an α,β-unsaturated ketone compound;
treating the reaction mixture with a non-thiol sulfur-containing compound to reduce the α,β-unsaturated ketone to form a morphinan-6-one compound; and
recovering the morphinan-6-one compound to form the morphinan-6-one product; wherein
the morphinan-6-one compound corresponds to Formula (2):
the α,β-unsaturated ketone compound corresponds to Formula (3):
X is —N(R 17 )— or —N + (R 17a R 17b )—;
R 1 and R 2 are independently selected from hydrogen, substituted and unsubstituted acyl, acyloxy, alkenyl, alkoxy, alkoxyaryl, alkyl, alkylamino, alkynyl, amino, aryl, arylalkoxy, carboalkoxy, carbonyl, carboxyalkenyl, carboxyalkyl, carboxyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylether, halo, haloalkoxy, haloalkyl, heteroaryl, heterocyclic, hydroxyalkyl, hydroxyl, or nitro;
R 3 is hydrogen, hydroxy, protected hydroxy, alkoxy, or acyloxy;
R 10 is hydrogen, hydroxy, protected hydroxy, halo, keto, tosyl, mesyl, or trifluoromesyl;
R 14 is hydrogen, hydroxy, or protected hydroxy;
R 17 is hydrogen, alkyl, cycloalkyl, alkylcarboxy, alkylenecycloalkyl, alkoxycarbonyl, allyl, alkenyl, acyl, aryl, formyl, formyl ester, formamide, benzyl, or an amino protecting group; and
R 17a and R 17b are independently selected from hydrogen, alkyl, alkenyl, allyl, cycloalkyl, aryl, or benzylyl.
4. The process as set forth in claim 1 wherein the non-thiol sulfur-containing compound is a sulfur-containing nucleophile.
5. The process as set forth in claim 1 wherein the non-thiol sulfur-containing compound is a sulfur-containing inorganic acid or salt thereof.
6. The process as set forth in claim 5 wherein the non-thiol sulfur-containing inorganic acid is selected from the group consisting of hydrosulfuric acid (H 2 S); sulfurous acid (H 2 SO 3 ); persulfuric acid (H 2 SO 5 ); thiosulfurous acid (H 2 S 2 O 2 ); dithionous acid (H 2 S 2 O 4 ); disulfurous acid (H 2 S 2 O 5 ); dithioic acid (H 2 S 2 O 6 ); pyrosulfuric acid (H 2 S 2 O 7 ); peroxydisulfuric acid (H 2 S 2 O 8 ); trithionic acid (H 2 S 3 O 6 ); tetrathionic acid (H 2 S 4 O 6 ); pentathionic acid (H 2 S 5 O 6 ); chlorosulfonic acid (HSO 3 Cl); furosulfonic acid (HSO 3 F); sulfamic acid (HSO 3 NH 2 ); salts thereof; and combinations thereof.
7. The process as set forth in claim 5 wherein the salt is selected from the group consisting of alkali metal salts, alkaline earth metal salts, ammonium salt (NH 4 + ), and quaternary ammonium salts.
8. The process as set forth in claim 1 wherein the reaction mixture further comprises a media material.
9. The process as set forth in claim 8 wherein the weight ratio of media material to morphinan-6-one compound in the reaction mixture is from about 1:1 to about 50:1.
10. The process as set forth in claim 8 wherein the media material is an aqueous media or an aqueous/organic solvent biphasic media.
11. The process as set forth in claim 10 wherein the aqueous media is water.
12. The process as set forth in claim 10 wherein the aqueous/organic solvent biphasic media further comprises a phase transfer catalyst.
13. The process as set forth in claim 12 wherein the phase transfer catalyst is a quaternary ammonium salt.
14. The process as set forth in claim 1 wherein the molar ratio of non-thiol sulfur-containing compound to morphinan-6-one compound in the reaction mixture of from about 0.5:1 to about 3.0:1.
15. The process as set forth in claim 1 wherein the treatment is carried out in an inert atmosphere.
16. The process as set forth in claim 1 wherein the treatment is carried out in ambient air.
17. The process as set forth in claim 1 wherein the treatment is carried out at a pressure of from about 0.5 atm to about 2.0 atm.
18. The process as set forth in claim 1 wherein the reaction mixture has a pH of from about 3 to about 9.
19. The process as set forth in claim 18 wherein the reaction mixture has a pH of from about 6 to about 9.
20. The process as set forth in claim 1 wherein the reaction mixture is treated with the non-thiol sulfur-containing compound for about 1 hour to about 18 hours.
21. The process as set forth in claim 1 wherein the reaction mixture is treated with the non-thiol sulfur-containing compound for about 1 hour to about 10 hours.
22. The process as set forth in claim 1 wherein the reaction mixture is treated with the non-thiol sulfur-containing compound for at least about 1 hour.
23. The process as set forth in claim 1 wherein the reaction mixture is treated with the non-thiol sulfur-containing compound for about 5 hours.
24. The process as set forth in claim 1 wherein the reaction mixture is treated with the non-thiol sulfur-containing compound at a temperature greater than room temperature.
25. The process as set forth in claim 1 wherein the reaction mixture is treated with the non-thiol sulfur-containing compound at a temperature of from about 30° C. to about 70° C.
26. The process as set forth in claim 1 wherein the morphinan-6-one product comprises less than about 0.01% (by weight morphinan-6-one product) of an α,β-unsaturated ketone compound.
27. The process as set forth in claim 1 wherein the morphinan-6-one product comprises less than about 0.001% (by weight morphinan-6-one product) of an α,β-unsaturated ketone compound.
28. The process as set forth in claim 1 wherein the morphinan-6-one product comprises no detectable amount of an α,β-unsaturated ketone compound.
29. The process as set forth in claim 1 wherein the morphinan-6-one compound is recovered from the reaction mixture without the use of an organic solvent.
30. The process as set forth in claim 1 wherein after treatment of the reaction mixture with the non-thiol sulfur-containing compound a residual sulfur-containing species is substantially removed from the reaction mixture.
31. The process as set forth in claim 7 wherein the non-thiol sulfur-containing compound is selected from the group consisting of sodium sulfite, sodium bisulfite, sodium hydrosulfite, ammonium bisulfite.