Method for the catalytic production of hydrocodone, hydromorphone, and derivatives thereof
View Patent ↗A method for the catalytic production of hydrocodone derivatives and hydromorphone derivatives, respectively, utilizing a transition metal catalyst of the formula [M(PR 4 R 5 R 6 ) n X m ] p ; wherein M is a Group VIII transition metal; R 4 , R 5 and R 6 are selected from the group consisting of alkyl, aryl, alkoxyl, phenoxy 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 process for the conversion of a compound according to Formula VI to a compound according to Formula VII, the process comprising catalytically converting the compound according to Formula VI into the compound of Formula VII in the presence of at least one catalyst, wherein the catalyst is at least one transition metal complex of the formula [M(PR 4 R 5 R 6 ) n X m ] p ; wherein M is a Group VIII transition metal; R 4 , R 5 and R 6 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;
wherein R 2 is selected from the group consisting of H, a benzyl, a substituted benzyl, an alkyl, an aryl, an acyl, an aryl sulfonyl, an alkyl sulfonyl, a carboxyester, a carboxyamide, trialkylsilyl, tetrahydropyranyl and tetrahydrofuranyl group; and
R 3 is selected from the group consisting of H, an alkyl, an allyl, a cycloalkylalkyl, a benzyl, an aryl sulfonyl, an alkyl sulfonyl, an aryl, an acyl group, a formyl, a hydroxyl, a carboxyester and a carboxyamide.
2. The method of claim 1 wherein (PR 4 R 5 R 6 ) n is supported by a solid.
3. The method of claim 1 wherein (PR 4 R 5 R 6 ) n is selected from the group consisting of polymer supported (PR 4 R 5 R 6 ) n , silical supported (PR 4 R 5 R 6 ) n , resin-bound (PR 4 R 5 R 6 ) n and mixtures thereof.
4. 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.
5. The method of claim 4 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.
6. The method of claim 1 wherein the metal complex is of the formula [Rh(PR 4 R 5 R 6 ) n X m ] p ; wherein R 4 , R 5 and R 6 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.
7. The method of claim 6 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 , ClO 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 .
8. The method of claim 1 wherein in the metal complex is of the formula [RuXY(PR 4 R 5 R 6 ) n ] p ; wherein R 4 , R 5 and R 6 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.
9. The method of claim 8 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 ClO 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 , HOS 4 and H 2 PO 4 .
10. A process for the conversion of a compound according to Formula VIII to a compound according to Formula IX, the process comprising catalytically converting the compound according to Formula VIII into the compound of Formula IX in the presence of at least one catalyst, wherein the catalyst is at least one transition metal complex of the formula [M(PR 4 R 5 R 6 ) n X m ] p ; wherein M is a Group VIII transition metal; R 4 , R 5 and R 6 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;
wherein R 2 is selected from the group consisting of H, a benzyl, a substituted benzyl , an alkyl, an aryl, an acyl, an aryl sulfonyl, an alkyl sulfonyl, a carboxyester, a carboxyamide, trialkylsilyl, tetrahydropyranyl and tetrahydrofuranyl group;
R 8 and R 9 are independently selected from the group consisting of H, an alkyl group, an allyl group, a benzyl group, an aryl group and an alkytenecycloalkane, or R 8 and R 9 taken together form an oxide; and
X 1 , and X 2 are anions.
11. The method of claim 10 wherein X 1 , and X 2 are Br or Cl.
12. The method of claim 10 wherein X 1 and X 2 are anions selected from the group consisting of BF 4 , PF 6 , ClO 4 , CHO 2 , C 2 O 4 , 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 .
13. The method of claim 10 wherein (PR 4 R 5 R 6 ) n is supported by a solid.
14. The method of claim 10 wherein (PR 4 R 5 R 6 ) n is selected from the group consisting of polymer supported (PR 4 R 5 R 6 ) n , silical supported (PR 4 R 5 R 6 ) n , resin-bound (PR 4 R 5 R 6 ) n and mixtures thereof.
15. The method of claim 10 wherein the metal complex is bound to a tertiary copolymer selected from the group consisting of styrene, divinylbenzene, and diphenyl(p-vinylphenyl)phosphine.
16. The method of claim 13 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.
17. The method of claim 10 wherein the metal complex is of the formula [Rh(PR 4 R 5 R 6 ) n X m ] p ; wherein R 4 , R 5 and R 6 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.
18. The method of claim 15 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 , ClO 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 .
19. The method of claim 10 wherein in the metal complex is of the formula [RuXY(PR 4 R 5 R 6 ) n ] p ; wherein R 4 , R 5 and R 6 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.
20. The method of claim 17 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 ClO 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 , HSO 4 and H 2 PO 4 .