Process for the preparation of 6-alpha-hydroxy-N-alkylated opiates

1. A process for the preparation of a 6-hydroxy morphinan (II) having the formula

the process comprising reducing a 6-keto morphinan (I) in the presence of a ruthenium, rhodium, or iridium asymmetric catalyst and a hydrogen source, the 6-keto morphinan (I) having the formula:

wherein

R 1 is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR 111 ;

R 2 is hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, or —OR 211 ;

R 3 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or —OR 311 ;

R 7 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or —OR 711 ;

R 8 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or —OR 811 ;

R 14 is hydrogen or hydroxy;

R 111 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or a hydroxy protecting group;

R 211 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or a hydroxy protecting group;

R 311 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or a hydroxy protecting group;

R 711 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or a hydroxy protecting group;

R 811 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or a hydroxy protecting group;

Z 1 is >N(R 9 ), >N + (R 9 )(R 10 ), >NCH(OH)(R 9 ), or >N + ═CH(R 9 );

Z 2 is

(i) Z 1 when Z 1 is >N(R 9 ) or >N + (R 9 )(R 10 ); or

(ii) >NCH 2 (R 9 ) when Z 1 is >NCH(OH)R 9 or >N + ═CH(R 9 ); and

R 9 and R 10 are independently hydrogen, acyl, hydrocarbyl, substituted hydrocarbyl, or heterocyclo.

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

3. The process of claim 2 , wherein the epimeric ratio of 6-alpha-hydroxy to 6-beta-hydroxy morphinan epimers is chosen from greater than 9:1, greater than 19:1, and greater than 99:1.

4. The process of claim 1 , wherein the catalyst comprises a ruthenium complex or a rhodium complex.

5. The process of claim 1 , wherein the catalyst is chosen from:

dichloro(arene)Ru(II) dimer, dichloro(pentamethylcyclopentadienyl)Rh(II) dimer, BINAP-Ru (II) diacetate, BINAP-Ru (II) dichloride, BINAP-Ru (II) dibromide, BI NAP-Ru (II) diiodide, [RuCl((R or S)BINAP)(C 6 H 6 )]Cl, or dichloro(pentamethylcyclopentadienyl)iridium (III) dimer;

bidentate, chiral ligand complexed with the ruthenium, rhodium, or iridium complex via nitrogen, oxygen, or phosphorous donor atoms; and

a chiral ligand having the Formula (670), Formula (680), Formula (690), or Formula (700):

wherein

R 671 , R 672 , R 673 , R 681 , R 691 , R 692 , R 701 , and R 702 are independently alkyl or aryl and wherein R 691 and R 692 , and the carbon atoms to which they are attached, may optionally form a cyclic or bicyclic compound.

6. The process of claim 5 , wherein the ligand is chosen from:

the Formula (670) and R 672 and R 673 are phenyl; R 671 is aryl; and R 671 is tolyl, mesityl, or naphthyl;

the Formula (680) and R 681 is tolyl, mesityl, 2,4,6-triisopropylphenyl, or naphthyl; and

the Formula (700) and R 701 and R 702 are hydrogen.

7. The process of claim 5 , wherein the ligand is (1S,2S)-(+)-N-4-toluenesulfonyl-1,2-diphenylethylene-1,2-diamine, (1R,2R)-(−)-N-4-toluenesulfonyl-1,2-diphenylethylene-1,2-diamine, dl-N-tosyl-1,2-diphenylethylenediamine, N-tosyl-1,2-diphenylethylenediamine, N-tosyl-1,2-ethylenediamine, or N-tosyl-1,2-diaminocyclohexane.

8. The process of claim 1 , wherein the catalyst is selected from the group consisting of

wherein

Ar is aryl.

9. The process of claim 1 , wherein the catalyst is a Noyori catalyst.

10. The process of claim 1 , wherein the hydrogen source comprises protic compounds; the process occurs in an aprotic, polar solvent; and the process occurs within a temperature range of about 20° C. to about 40° C.

11. The process of claim 10 , wherein the hydrogen source is a mixture of formic acid and triethylamine; and the ratio of formic acid to triethylamine is about 5:2.

12. The process of claim 1 , wherein R 1 is hydrogen or —OR 111 and R 111 is hydrogen, alkyl, acyl, alkaryl, aryl, or a hydroxy protecting group; R 2 is hydrogen or —OR 211 and R 211 is hydrogen, alkyl, acyl, alkaryl, aryl, or a hydroxy protecting group; R 3 is hydrogen or —OR 311 and R 311 is hydrogen, alkyl, acyl, alkaryl, aryl, or a hydroxy protecting group; and R 311 is hydrogen or alkyl.

13. The process of claim 1 ,

wherein

R 1 is hydrogen;

R 2 is hydrogen;

R 3 is —OR 311 ; and

R 311 is hydrogen or C 1-8 alkyl.

14. The process of claim 13 , wherein R 7 is hydrogen, C 1-8 alkyl, or C 1-8 substituted alkyl; R 8 is hydrogen; R 14 is hydroxyl; Z 1 and Z 2 are >N(R 9 ) and R 9 is hydrogen, or substituted or unsubstituted C 1-8 alkyl, C 2-8 alkenyl, aryl or heterocyclo.

15. The process of claim 1 ,

wherein

Z 1 and Z 2 are >N + (R 9 )(R 10 ); and

R 9 and R 10 are independently hydrogen, acyl, or substituted or unsubstituted C 1-8 alkyl, C 2-8 alkenyl, aryl or heterocyclo.

16. The process of claim 15 wherein R 9 and R 10 are independently hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclopropylmethyl, butyl, isobutyl, t-butyl, cyclobutyl, cyclobutylmethyl, or allyl.

17. The process of claim 15 , wherein R 9 is cyclopropylmethyl and R 10 is methyl.

18. The process of claim 1 ,

wherein

Z 1 is >NCH(OH)(R 9 );

Z 2 is >NCH 2 (R 9 ); and

R 9 is hydrogen, acyl, or substituted or unsubstituted C 1-8 alkyl, C 2-8 alkenyl, aryl or heterocyclo.

19. The process of claim 1 ,

wherein

Z 1 is >N + ═CH(R 9 );

Z 2 is >NCH 2 (R 9 ); and

R 9 is hydrogen, acyl, or substituted or unsubstituted C 1-8 alkyl, C 2-8 alkenyl, aryl or heterocyclo.

20. The process of claim 1 ,

wherein

R 1 is hydrogen;

R 2 is hydrogen;

R 3 is —OR 311 ;

R 7 is hydrogen;

R 8 is hydrogen;

R 14 is hydroxy;

R 311 is hydrogen;

Z 1 is >N(R 9 ); and

R 9 is cyclobutylmethyl.

21. The process of claim 1 ,

wherein

R 1 is hydrogen;

R 2 is hydrogen;

R 3 is —OR 311 ;

R 7 is hydrogen;

R 8 is hydrogen;

R 14 is hydroxy;

R 311 is hydrogen;

Z 1 is >N + ═CH(R 9 );

Z 2 is >NCH 2 (R 9 ); and

R 9 is cyclobutyl.