Method for the catalytic production of hydrocodone and hydromorphone
View Patent ↗A method for the catalytic conversion of codeine, morphine or analogs thereof into hydrocodone, hydromorphone or analogs thereof utilizing a transition metal catalyst of the formula [M(PR 3 R 4 R 5 ) n X m ] p ; wherein R 1 is H, alkyl, aryl or acyl; M is a Group VIII transition metal; R 3 , R 4 and R 5 are selected from the group consisting of alkyl, aryl, alkoxyl, phenoxyl and combinations thereof; X is a halide or an anion; n is 1, 2, 3 or 4; m is 1 or 2; and p is at least 1.
1. A method comprising catalytically converting a compound of Formula I into a compound of Formula II utilizing at least one transition metal complex of the formula [M(PR 3 R 4 R 5 ) n X m ] p ; wherein R 1 is H, alkyl, aryl or acyl; M is a Group VIII transition metal; R 3 , R 4 and R 5 are selected from the group consisting of alkyl, aryl, alkoxyl, phenoxyl and combinations thereof; X is H, a halide or an anion; n is 1, 2, 3 or 4; m is 1 or 2; and p is at least 1.
2. The method of claim 1 wherein R 1 is H or CH3.
3. The method of claim 1 wherein (PR 3 R 4 R 5 ) n is supported by a solid.
4. The method of claim 1 wherein (PR 3 R 4 R 5 ) n is selected from the group consisting of polymer supported (PR 3 R 4 R 5 ) n , silical supported (PR 3 R 4 R 5 ) n , resin-bound (PR 3 R 4 R 5 ) n and mixtures thereof.
5. The method of claim 1 wherein the metal complex is bound to a tertiary copolymer selected from the group consisting of styrene, divinylbenzene, and diphenyl(p-vinylphenyl)phosphine.
6. The method of claim 5 wherein the copolymer is substituted with a monomer selected from the group consisting of ethylene dimethacrylate, p-bromostyrene, divinylbenzene, butadiene, diallyl maleate, diallyl phthalate, glycol dimethacrylate, diolefins and triolefins.
7. The method of claim 1 wherein the metal complex is of the formula [Rh(PR 3 R 4 R 5 ) n X m ] p ; R 3 , R 4 and R 5 are selected from the group consisting of alkyl, aryl, alkoxyl, phenoxyl , and combinations thereof; X is a halide or an anion; n is 1, 2, 3 or 4; m is 1 or 2; and p is at least 1.
8. The method of claim 7 wherein n is 1, 2 or 3; p is at least 1; and X is selected from the group consisting of BF 4 , PF 6 , CIO 4 , CHO 2 , CF 3 CO 2 , CF 3 SO 3 , CH 3 CO 2 , ArCO 2 , CH 3 SO 3 , p-tolylSO 3 , HSO4 and H 2 PO 4 .
9. The method of claim 1 wherein in the metal complex is of the formula [RuXY(PR 3 R 4 R 5 ) n ] p ; R 3 , R 4 and R 5 are selected from the group consisting of alkyl, aryl, alkoxyl, phenoxyl and combinations thereof; X is an H, halide or an anion; Y is an H, halide or an anion; n is 1, 2, 3 or 4; m is 1 or 2; and p is at least 1.
10. The method of claim 9 wherein n=3, p is at least 1, Y=H and X=Cl; or n=3, p is at least 1, Y=H and X=H; or n=4, p is at least 1, X=H, Y=H; or n=2, 3 or 4 and X=Y is selected from the group consisting of CIO 4 , PF 6 , BF 4 , CHO 2 , CF 3 CO 2 , CF 3 SO 3 , CH 3 CO 2 , ArCO 2 , CH 3 SO 3 , p-tolylSO 3 , HSO4 and H 2 PO 4 .
11. A method comprising catalytically converting a compound of Formula I into a compound of Formula II utilizing at least one transition metal complex of a tertiary phosphine halide, wherein R 1 is H, alkyl, aryl or acyl; the metal complex is of the formula [M(PR 2 3 ) n X m ] p wherein M is a Group VIII transition metal; R 2 is an alkyl or aryl; X is H, a halide or an anion; n is 1, 2, 3 or 4; p is at least 1; and m is 1 or 2
12. The method of claim 11 wherein R 1 is H or CH 3 .
13. The method of claim 11 wherein the metal complex is of the formula [Rh(PR 2 3 ) n X] p , wherein R 2 is an alkyl or aryl; X is a halide or an anion; n is 1, 2 or 3; and p is at least 1.
14. The method of claim 13 wherein the metal complex is of the formula [Rh(PR 2 3 ) n Y] p , wherein n is 1, 2 or 3; p is at least 1; and Y is selected from the group consisting of BF 4 , PF 6 , CIO 4 , CHO 2 , CF 3 CO 2 , CF 3 SO 3 , CH3CO 2 , ArCO 2 , CH 3 SO 3 , p-tolylSO 3 , HSO4 and H 2 PO 4 .
15. The method of claim 11 wherein in the metal complex is of the formula [RuX 2 (PR 2 3 ) n ] p wherein R 2 is an alkyl or aryl; X is a halide; n is 1, 2, 3 or 4; and p is at least 1.
16. The method of claim 11 wherein the metal complex is of the formula [RuYX(PR 2 3 ) n ] p wherein R 2 is an alkyl or aryl and wherein n=3, p is at least 1, Y=H and X=Cl; or n=3, p is at least 1, Y=H and X=H; or n=4, p is at least 1, X=H, Y=H; or n=2, 3 or 4 and X=Y is selected from the group consisting of CIO 4 , CHO 2 , PF 6 , BF 4 . CHO 2 , CF 3 CO 2 , CF 3 SO 3 , CH 3 CO 2 , ArCO 2 , CH 3 SO 3 , p-tolylSO 3 , HSO 4 and H 2 PO 4 .
17. A method for producing hydrocodone comprising converting codeine into hydrocodone in the presence of at least one transition metal complex of the formula [M(PR 3 R 4 R 5 ) n X m ] p ; wherein M is a Group VIII transition metal; R 3 , R 4 and R 5 are selected from the group consisting of alkyl, aryl, alkoxyl, phenoxyl and combinations thereof; X is H, a halide or an anion; n is 1, 2, 3 or 4; m is 1 or 2; and p is at least 1.
18. The method of claim 17 wherein (PR 3 R 4 R 5 ) n is supported by a solid.
19. The method of claim 17 wherein (PR 3 R 4 R 5 ) n is selected from the group consisting of polymer supported (PR 3 R 4 R 5 ) n , silical supported (PR 3 R 4 R 5 ) n , resin-bound (PR 3 R 4 R 5 ) n and mixtures thereof.
20. The method of claim 17 wherein the metal complex is of the formula [Rh(PR 2 3 ) n X] p , wherein R 2 is an alkyl or aryl; X is a halide or an anion; n is 1, 2 or 3; and p is at least 1.
21. The method of claim 17 wherein the metal complex is of the formula [Rh(PR 2 3 ) n Y] p , wherein R 2 is an alkyl or aryl; n is 1, 2 or 3; p is at least 1; and Y is selected from the group consisting of BF 4 , PF 6 , CIO 4 , CHO 2 , CF 3 CO 2 , CF 3 SO 3 , CH 3 CO 2 , ArCO 2 , CH 3 SO 3 , p-tolylSO 3 , HSO4 and H 2 PO 4 .
22. The method of claim 17 wherein in the metal complex is of the formula [RuX 2 (PR 2 3 ) n ] p wherein R 2 is an alkyl or aryl; X is a halide; n is 1, 2, 3 or 4; and p is at least 1.
23. The method of claim 17 wherein the metal complex is of the formula [RuYX(PR 2 3 ) n ] p wherein R 2 is an alkyl or aryl and wherein n=3, p is at least 1, Y=H and X=Cl; or n=3, p is at least 1, Y=H and X=H; or n4, X=H, Y=H; or n=2, 3 or 4, p is at least 1 and X=Y is selected from the group consisting of CIO 4 , CHO 2 , PF 6 , BF 4 , CHO 2 , CF 3 CO 2 , CF 3 SO 3 CH 3 CO 2 , ArCO 2 , CH 3 SO 3 , p-tolylSO 3 , HSO4 and H 2 PO 4 .
24. A method for producing hydromorphone comprising converting morphine into hydromorphone in the presence of at least one transition metal complex of a tertiary phosphine wherein the metal complex is of the formula [M(PR 2 3 ) n X m ] p wherein M is a Group VIII -transition metal, R 2 is an alkyl or aryl; X is H, a halide or an anion; n is 1, 2, 3 or 4; p is at least 1; and m is 1 or 2.
25. The method of claim 24 wherein the metal complex is of the formula [Rh(PR 2 3 ) n X] p , wherein R 2 is an alkyl or aryl; X is a halide or an anion; n is 1, 2 or 3; and p is at least 1.
26. The method of claim 24 wherein the metal complex is of the formula [Rh(PR 2 3 ) n Y] p , wherein R 2 is an alkyl or aryl; n is 1, 2 or 3; p is at least 1; and Y is selected from the group consisting of BF 4 , PF 6 , CIO 4 CF 3 CO 2 , CF 3 SO 3 , CH 3 CO 2 , ArCO 2 , CH 3 SO 3 , p-tolylSO 3 , HSO4 and H 2 PO 4 .
27. The method of claim 24 wherein in the metal complex is of the formula [RuX 2 (PR 2 3 ) n ] p wherein R 2 is an alkyl or aryl; X is a halide; n is 1, 2, 3 or 4; and p is at least 1.
28. The method of claim 24 wherein the metal complex is of the formula [RuYX(PR 2 3 ) n ] p wherein R 2 is an alkyl or aryl and wherein n=3, Y=H and X=Cl; or n=3, Y=H, p is at least 1 and X=H; or n=4, p is at least 1, X=H, Y=H; or n=2, 3 or 4, p is at least 1 and X=Y is selected from the group consisting of CIO 4 , PF 6 , BF 4 , CF 3 CO 2 , CF 3 SO 3 , CH 3 CO 2 , ArCO 2 , CH 3 SO 3 , p-tolylSO 3 , HSO4 and H 2 PO 4 .
29. An improved metal catalyst recovery method comprising:
a) catalytically converting a compound of Formula I into a compound of Formula II utilizing at least one transition metal complex of a tertiary phosphine of the formula [M(PR 3 R 4 R 5 ) n X m ] p ; wherein R 1 is H, alkyl, aryl or acyl;
M is a Group VIII transition metal; R 3 , R 4 and R 5 are selected from the group consisting of alkyl, aryl, alkoxyl, phenoxyl and combinations thereof; X is a halide or an anion; n is 1, 2, 3 or 4; m is 1 or 2; and p is at least 1; and
b) recovering the metal containing solid catalyst.
30. The method of claim 29 wherein R 1 is H or CH 3 .
31. The method of claim 29 wherein (PR 3 R 4 R 5 ) n is supported by a solid.
32. The method of claim 29 wherein (PR 3 R 4 R 5 ) n is selected from the group consisting of polymer supported (PR 3 R 4 R 5 ) n , silical supported (PR 3 R 4 R 5 ) n , resin-bound (PR 3 R 4 R 5 ) n and mixtures thereof.