Reductive amination of 6-keto normorphinans by catalytic hydrogen transfer
View Patent ↗The present invention provides processes for the stereoselective synthesis of 6-alpha-amino morphinans. In particular, the invention provides processes for the reductive amination of 6-keto normorphinans by catalytic transfer hydrogenation.
1. A process for preparing a 6-alpha-amino-N17-formyl morphinan, the process comprising contacting a 6-keto normorphinan with an amine source, a hydrogen donor comprising a formate ion, a transition metal catalyst, and a proton acceptor to form the 6-alpha-amino-N17-formyl morphinan.
2. The process of claim 1 , wherein the 6-keto normorphinan is selected from a group consisting of norhydrocodone, norhydromorphone, noroxycodone, and noroxymorphone; the amine source is chosen selected from a group consisting of a primary amine and an ammonium salt; the hydrogen donor comprising a formate ion is selected from a group consisting of formic acid, a salt of formic acid, and a mixture of formic acid and an organic base; the transition metal catalyst comprises ruthenium, rhodium, or iridium; and the proton acceptor has a pKa of great than about 9.
3. The process of claim 1 , wherein at least one intermediate compound comprising a 6-imine moiety is produced during the process.
4. The process of claim 1 , wherein the 6-alpha-amino-N17-formyl morphinan comprises no more than about 2% of a 6-beta-amino epimer.
5. A process for preparing a compound of Formula (IV):
the process comprising:
reducing a compound of Formula (I) in the presence of an amine source (R 6 NH 2 ), a hydrogen donor comprising a formate ion, a transition metal catalyst, and a proton acceptor to form the compound of Formula (IV), the compound of Formula (I) having the structure:
wherein:
R 1 and R 2 are independently selected from a group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, and {—}OR 15 ;
R 3 , R 7 , and R 8 are independently selected from a group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and {—}OR 15 ;
R 6 is selected from a group consisting of hydrogen, hydrocarbyl and substituted hydrocarbyl;
R 14 is selected from a group consisting of hydrogen and {—}OR 15 ; and
R 15 is selected from a group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and a hydroxy protecting group.
6. The process of claim 5 , wherein R 1 , R 2 , R 7 , and R 8 are hydrogen; R 3 is selected from a group consisting of alkoxy, hydroxy, and protected hydroxy; R 14 is hydrogen or hydroxyl; R 6 is selected from a group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, and aryl; the hydrogen donor comprising a formate ion is selected from a group consisting of formic acid, a salt of formic acid, and a mixture of formic acid and an organic base; R 6 is selected from a group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, and aryl, and the amine source is a primary amine; the molar ratio of the compound of Formula (I) to the primary amine to the hydrogen donor is from about 1:1:1 to about 1:5:20; the transition metal catalyst comprises ruthenium, rhodium, or iridium; the molar ratio of the compound of Formula (I) to the transition metal catalyst is about 1:0.0001 to about 1:0.01; the reaction of the compound of Formula (I), the amine source, the transition metal catalyst, and the hydrogen donor occurs in the presence of a solvent selected from a group consisting of an aprotic solvent, a protic solvent, a non-polar solvent, and combinations thereof and occurs at a temperature from about 20° C. to about 100° C.; the proton acceptor has a pKa of greater than about 9 and the proton acceptor is selected from a group consisting of ammonia, ammonium hydroxide, potassium hydroxide, and sodium hydroxide.
7. The process of claim 5 , wherein R 6 is hydrogen and the amine source is an ammonium salt.
8. The process of claim 7 , wherein the molar ratio of the compound of Formula (I) to the ammonium salt to the hydrogen donor is from about 1:2:1 to about 1:20:20.
9. The process of claim 5 , wherein the hydrogen donor comprises formic acid and triethylamine.
10. The process of claim 9 , wherein the molar ratio of the compound of Formula (I) to triethylamine is from about 1:1 to about 1:10.
11. The process of claim 5 , wherein the transition metal catalyst is selected from a group consisting of dichloro(arene)Ru(II) dimer, dichloro(pentamethylcyclopentadienyl)Rh(II) dimer, BINAP-Ru(II) diacetate, BINAP-Ru(II) dichloride, BINAP-Ru(II) dibromide, BINAP-Ru(II) diiodide, [RuCl((R or S)BINAP)(C 6 H 6 )]Cl, dichloro(pentamethylcyclopentadieny)iridium(III) dimer, Ru(III) chloride, RuCl 3 hydrate, Ru(III) acetylacetonate, tetraalkylammonium RuCl 4 , and pyridinium RuCl 4 .
12. The process of claim 5 , wherein the transition metal catalyst is a Noyori catalyst.
13. The process of claim 5 , wherein two first intermediates of Formula (IIa) and Formula (IIb) are formed after the compound of Formula (I) is contacted with the amine source, the hydrogen source, and the transition metal catalyst; and the first intermediates are converted in situ to a second intermediate of Formula (III):
wherein:
R 1 and R 2 are independently selected from a group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, and {—}OR 15 ;
R 3 , R 7 , and R 8 are independently selected from a group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and {—}OR 15 ;
R 6 is selected from a group consisting of hydrogen, hydrocarbyl and substituted hydrocarbyl;
R 14 is selected from a group consisting of hydrogen and {—}OR 15 ; and
R 15 is selected from a group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and a hydroxy protecting group.
14. The process of claim 5 , wherein the compound of Formula (IV) has the structure of Formula (V):
wherein:
R 1 and R 2 are independently selected from a group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, and {—}OR 15 ;
R 3 , R 7 , and R 8 are independently selected from a group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and {—}OR 15 ;
R 14 is selected from a group consisting of hydrogen and {—}OR 15 ; and
R 15 is selected from a group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, and a hydroxy protecting group.
15. The process of claim 5 , wherein the amine source is a primary amine; the molar ratio of the compound of Formula (I) to the primary amine is about 1:2; the hydrogen donor comprises formic acid and triethylamine; the molar ratio of the compound of Formula (I) to formic acid to triethylamine is about 1:12:3; the transition metal catalyst is dichloro(p-cymene)Ru(II) dimer; the molar ratio of the compound of Formula (I) to the Ru(II) dimer is from about 1:0.001 to 1:0.01; reaction with the primary amine, Ru(II) dimer, and formic acid/triethylamine occurs in the presence of acetonitrile and at a temperature from about 20° C. to about 70° C.; the proton acceptor is ammonia; and reaction with the proton acceptor occurs in a protic solvent system comprising water, at a pH of about 9.5, and at room temperature.
16. The process of claim 5 , wherein the amine source is ammonium acetate; the molar ratio of the compound of Formula (I) to ammonium acetate is about 1:12; the hydrogen donor comprises formic acid and triethylamine; the molar ratio of the compound of Formula (I) to formic acid to triethylamine is about 1:12:5; the transition metal catalyst is dichloro(p-cymene)Ru(II) dimer; the molar ratio of the compound of Formula (I) to the Ru(II) dimer is from about 1:0.001 to 1:0.01; reaction of the ammonium acetate, the Ru(II) dimer, and the formic acid/triethylamine occurs in the presence of ethanol and at a temperature from about 20° C. to about 70° C.; the proton acceptor is ammonia; and reaction with the proton acceptor occurs in a protic solvent system comprising water, at a pH of about 9.5, and at room temperature.
17. The process of claim 5 , wherein the optical activity of the compounds of Formulas (I) or (IV) is (−) or (+), the configuration of C-5, C-13, C-14, and C 9, respectively, is chosen from RRRR, RRRS, RRSR, RSRR, SRRR, RRSS, RSSR, SSRR, SRRS, SRSR, RSRS, RSSS, SRSS, SSRS, SSSR, and SSSS, provided that C-15 and C-16 are both either on the alpha face or the beta face of the molecule; and the compound of Formula (IV) comprises less than 2% of a 6-beta-amino epimer.