Preparation of N-alkylated opiates by reductive amination

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

the process comprising reducing an N-imine morphinan or hemiaminal morphinan in the presence of an asymmetric catalyst and a hydrogen source, wherein the asymmetric catalyst comprises a dichloro(arene)Ru(II) dimer and a N-tosyl-diphenylethylenediamine ligand, the N-imine morphinan or hemiaminal 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 6 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or —OR 611

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 611 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 >NCH(OH)(R 9 ) or >N + ═CH(R 9 );

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

R 9 is hydrogen, acyl, hydrocarbyl, substituted hydrocarbyl, or heterocyclo.

2. The process of claim 1 , wherein the hydrogen source is isopropanol, formic acid, organic or inorganic salts of formic acid, or a combination thereof.

3. The process of claim 1 , wherein the process occurs in a solvent selected from the group consisting of a nitrile, tetrahydrofuran (THF), an alcohol, a halocarbon, dimethylformamide (DMF), dimethylacetamide (DMAc), N-methylpyrrolidinone (NMP), an alkyl acetate, toluene or a combination thereof.

4. The process of claim 1 , wherein:

R 1 is hydrogen or —OR 111 ;

R 111 is hydrogen, alkyl, acyl, alkaryl, aryl, or a hydroxy protecting group;

R 2 is hydrogen or —OR 211 ;

R 211 is hydrogen, alkyl, acyl, alkaryl, aryl, or a hydroxy protecting group;

R 3 is hydrogen or —OR 311 ;

R 311 is hydrogen, alkyl, acyl, alkaryl, aryl, or a hydroxy protecting group;

R 6 is hydrogen, or substituted or unsubstituted C 1-8 alkyl, C 2-8 alkenyl, phenyl, or —OR 611 ; and

R 611 is C 1-8 alkyl, C 2-8 alkenyl, hydrogen or a hydroxy protecting group.

5. The process of 1 , wherein:

R 1 is hydrogen;

R 2 is hydrogen;

R 3 is —OR 311 ;

R 311 is hydrogen or C 1-8 alkyl;

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

R 9 is methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, t-butyl, cyclobutyl, pentyl or cyclopentyl.

6. The process of claim 1 , wherein the N-alkylated morphinan (II) is buprenorphine:

7. The process of claim 1 , wherein the process occurs within a temperature range of about 20° C. to about 40° C.

8. The process of claim 1 , wherein the hemiaminal morphinan (I) is prepared from a normorphinan (X) having the formula:

the process comprising reacting the nor-morphinan (X) with an aldehyde of the formula CH(O)R g in a solvent to form the hemiaminal morphinan (I) having the formula:

wherein

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

R 9 is hydrocarbyl, acyl, substituted hydrocarbyl, or heterocyclo.

9. The process of claim 8 , wherein the hemiaminal morphinan is in equilibrium with the corresponding N-imine morphinan, the hemiaminal having a >NCH(OH)(R 9 ) moiety for Z 1 and the N-imine morphinan having a >N + ═CH(R 9 ) moiety for Z 1 .

10. The process of claim 9 , wherein:

R 3 is —OR 311 ;

R 311 is hydrogen;

R 6 is —OR 611 ;

R 611 is methyl;

R 7 is substituted alkyl or 3,3-dimethylbutan-2-ol; and

R 9 is cyclopropyl.

11. The process of claim 9 , wherein the reaction occurs at about room temperature, and the solvent is acetonitrile.

12. The process of claim 9 , wherein the nor-morphinan (X) is Nor-buprenorphine.

13. The process of claim 1 , wherein the hemiaminal morphinan (I) is prepared by reacting a 6-keto nor-morphinan having the Formula (XI):

with ethylene glycol and an acid to form a 6-ketal nor-morphinan having the Formula (XII):

14. The process of claim 13 , wherein the acid is methanesulfonic acid.

15. The process of claim 13 , wherein the 6-keto nor-morphinan (XI) is noroxymorphone and the 6-ketal nor-morphinan (XII) is 6-ketalnoroxymorphone.

16. The process of claim 15 , wherein the 6-keto nor-morphinan (XII) is further reacted with an aldehyde of the formula CH(O)R 9 in a solvent to form the hemiaminal morphinan (I) having the formula:

wherein

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

R 9 is hydrocarbyl, acyl, substituted hydrocarbyl, or heterocycle.

17. The process of claim 16 , wherein the hemiaminal morphinan is in equilibrium with the corresponding N-imine morphinan, the hemiaminal morphinan having a >NCH(OH)(R 9 ) moiety for Z 1 and the N-imine morphinan having a >N + ═CH(R 9 ) moiety for Z 1 .

18. The process of claim 17 , wherein:

R 3 is —OR 311 :

R 311 is hydrogen;

R 9 is cyclopropyl;

the reaction occurs at about room temperature; and

the solvent is acetonitrile.