Process and compounds for the production of (+)opiates
View Patent ↗The invention generally provides processes and intermediate compounds useful for the production of (+)-opiates. Non-limiting examples of (+) opiates that may be derived from one or more compounds of the invention include (+)-noroxymorphone, (+)-naltrexone, (+)-naloxone, (+)-N-cyclopropylmethylnorhydrocodone, (+)-N-cycloproylmethylnorhydromorphone, (+)-N-allylnorhydrocodone, (+)-N-allylnorhydromorphone, (+)-noroxycodone, (+)-naltrexol, (+)-naloxol, and (+)-3-O-methyl-naltrexone.
1. A compound having a formula (Ia):
wherein:
R 3 is selected from the group consisting of hydrogen, {−}C(O)R 6 , and {−}R 6 ;
R 5 is selected from the group consisting of alkyl having from 1 to 8 carbons, CH 3 CHCl—{−} and CH 2 ═CH—{−};
R 6 is selected from the group consisting of hydrocarbyl and hydrocarbyl substituted with at least one atom other than carbon;
R 8 and R 9 are independently selected from the group consisting of hydrogen, hydroxyl, hydrocarbyl, and hydrocarbyl substituted with at least one atom other than carbon, or R 8 and R 9 together form a carbonyl group;
R 12 and R 13 are independently selected from the group consisting of hydrogen, hydrocarbyl, and hydrocarbyl substituted with at least one atom other than carbon, or R 12 and R 13 together form a carbonyl group; and
R 10 , R 11 , and R 14 are independently selected from the group consisting of hydrogen, hydrocarbyl, hydrocarbyl substituted with at least one atom other than carbon, and a halogen.
2. A compound having a formula (Ib):
wherein:
R 1 is selected from the group consisting of hydrogen, and {−}C(O)R 5 ;
R 3 is selected from the group consisting of hydrogen, {−}C(O)R 6 , and {−}R 6 ;
R 5 and R 5 are independently selected from the group consisting of hydrocarbyl and hydrocarbyl substituted with at least one atom other than carbon;
R 8 and R 9 are independently selected from the group consisting of hydrogen, hydroxyl, hydrocarbyl, and hydrocarbyl substituted with at least one atom other than carbon, or R 8 and R 9 together form a carbonyl group;
R 12 and R 13 are independently selected from the group consisting of hydrogen, hydrocarbyl, and hydrocarbyl substituted with at least one atom other than carbon, or R 12 and R 13 together form a carbonyl group; and
R 10 , R 11 , R 14 and R 15 are independently selected from the group consisting of hydrogen, hydrocarbyl, hydrocarbyl substituted with at least one atom other than carbon, and a halogen, or R 14 and R 15 together form a carbonyl group.
3. A process for the preparation of compound (Ib) according to the following reaction scheme:
wherein:
R is selected from hydrocarbyl, and hydrocarbyl substituted with at least one atom other than carbon;
R 1 is selected from the group consisting of hydrogen and {−}C(O)R 5 ;
R 3 is selected from the group consisting of hydrogen, {−}C(O)R 6 , and {−}R 6 ;
R 5 and R 6 are independently selected from the group consisting of hydrocarbyl and hydrocarbyl substituted with at least one atom other than carbon;
R 8 and R 9 are independently selected from the group consisting of hydrogen, hydroxyl, hydrocarbyl, and hydrocarbyl substituted with at least one atom other than carbon, or R 8 and R 9 together form a carbonyl group;
R 12 , and R 13 are independently selected from the group consisting of hydrogen, hydrocarbyl, and hydrocarbyl substituted with at least one atom other than carbon, or R 12 and R 13 together form a carbonyl group;
R 10 , R 11 , and R 14 are independently selected from the group consisting of hydrogen, hydrocarbyl, hydrocarbyl substituted with at least one atom other than carbon, and a halogen;
R 15 is hydrogen; and
X is a halogen.
4. The process of claim 3 , wherein R, R 5 and R 6 are independently selected from the group consisting of an alkyl group having from 1 to 8 carbon atoms, an aryl group, CH 3 CHCl—{−}, and an {−}CH 2 -aryl group, and X is chlorine.
5. The process of claim 3 , the molar ratio of the compound comprising formula (II) to ROCOX to proton acceptor is from about 1:3:1 to about 1:12:12; the proton acceptor is a salt with a pH greater than 7; the reaction of Step A is conducted in the presence of an aprotic solvent; and at a temperature ranging from about 45° C. to about 120° C.; the molar ratio of compound (Ia) to transition metal catalyst is from about 1:0.0005 to about 1:0.005, the reaction of Step B is conducted under pressurized hydrogen having a pressure from about 0 to about 500 PSI, the reaction of Step B is conducted in the presence of a methanol-containing solvent, and at a temperature ranging from about 20° C. to about 120° C.
6. A process for the preparation of compound (Ib) according to the following reaction scheme:
wherein:
R is selected from hydrocarbyl, and hydrocarbyl substituted with at least one atom other than carbon;
R 1 is selected from the group consisting of hydrogen and {−}C(O)R 5 ;
R 3 is selected from the group consisting of hydrogen, {−}C(O)R 6 , and {−}R 6 ;
R 5 and R 6 are independently selected from the group consisting of hydrocarbyl and hydrocarbyl substituted with at least one atom other than carbon;
R 8 and R 9 are independently selected from the group consisting of hydrogen, hydroxyl, hydrocarbyl, and hydrocarbyl substituted with at least one atom other than carbon, or R 8 and R 9 together form a carbonyl group;
R 12 , and R 13 are independently selected from the group consisting of hydrogen, hydrocarbyl, and hydrocarbyl substituted with at least one atom other than carbon, or R 12 and R 13 together form a carbonyl group;
R 10 , R 11 , and R 14 are independently selected from the group consisting of hydrogen, hydrocarbyl, hydrocarbyl substituted with at least one atom other than carbon, and a halogen;
R 15 is hydrogen; and
X is a halogen.
7. The process of claim 6 , wherein R, R 5 and R 6 are independently selected from the group consisting of an alkyl group having from 1 to 8 carbon atoms, an aryl group, CH 3 CHCl—{−}, CH 2 ═CH—{−}, and an {−}CH 2 -aryl group, and X is chlorine.
8. The process of claim 6 , wherein the molar ratio of the compound comprising formula (II) to proton donor to transition metal catalyst is from about 1:0.5:0.0005 to about 1:10:0.05, the of reaction of Step A is conducted under pressurized hydrogen having a pressure from about 0 to about 500 PSI, the reaction of Step A is conducted in the presence of a methanol-containing solvent, and the at a temperature ranging from about 20° C. to about 120° C.; the molar ratio of the compound comprising formula (IIa) to ROCOX to proton acceptor is from about 1:2:1 to about 1:20:20, the reaction of Step B is conducted in the presence of an aprotic solvent, and at a temperature ranging from about 45° C. to about 120° C.
9. The process of claim 8 , wherein the proton donor is selected from the group consisting of HOAc, HCO 2 H, HCl, and H 2 SO 4 ; the transition metal catalyst is selected from the group consisting of Pd/C, Pt/C, Ru/C, and Rh/C; and the proton acceptor is selected from the group consisting of NaHCO 3 , KHCO 3 , LiHCO 3 , Na 2 CO 3 , K 2 CO 3 , Li 2 CO 3 , and combinations thereof.