Process for the preparation of 6-alpha-hydroxy-N-alkylated opiates
View Patent ↗The present invention is directed to the preparation of 6-keto morphinans.
1. A process for the preparation of a 6-keto morphinan having formula (I) prepared from a 6-keto nor-morphinan (X) having the formula:
the process comprising reacting the 6-keto nor-morphinan (X) with an aldehyde of the formula CH(O)R 9 in a solvent to form 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 9 is hydrogen, acyl, hydrocarbyl, substituted hydrocarbyl, or heterocyclo;
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; and
Z 1 is >N + ═CH(R 9 ).
2. The process of claim 1 , wherein the solvent is an organic solvent.
3. The process of claim 2 , wherein the solvent is acetonitrile, methanol, toluene, ethyl acetate, or a combination thereof.
4. The process of claim 1 , wherein R 3 is hydrogen or —OR 311 and R 311 is hydrogen, alkyl, acyl, alkaryl, aryl, or a hydroxy protecting group.
5. The process of claim 4 , wherein R 311 is hydrogen or alkyl.
6. The process of claim 1 , wherein the 6-keto nor-morphinan (X) is noroxymorphone.
7. The process of claim 1 , wherein R 9 is hydrogen, acyl, substituted or unsubstituted C 1-8 alkyl, C 2-8 alkenyl, aryl, or heterocyclo.
8. The process of claim 1 , wherein R 9 is hydrogen, methyl, cyclopropyl, cyclobutyl, or allyl.
9. The process of claim 1 , wherein R 9 is cyclobutyl.
10. The process of claim 1 , further comprising a process for the preparation of a 6-hydroxy morphinan (II) having the formula
the process comprising reducing the 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 9 is hydrogen, acyl, hydrocarbyl, substituted hydrocarbyl, or heterocyclo;
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, ora hydroxy protecting group;
R 311 is hydrogen, hydrocarbyl, substituted hydrocarbyl, ora 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 + ═CH(R 9 ); and
Z 2 is >NCH 2 (R 9 ).