N-demethylation of 6-keto morphinans
View Patent ↗The present invention provides processes for the demethylation of an N-methyl morphinan comprising a ketone functional group. In particular, the invention provides methods for the protection of the ketone functional group such that impurities are not generated during the demethylation of the N-methyl morphinan.
1. A process for preparing a compound of Formula (III) from a compound of Formula (I), the process comprising:
a) contacting the compound of Formula (I) with an agent that forms a ketone protecting group such that a compound of Formula (II) is formed; and
b) contacting the compound of Formula (II) with an N-demethylating agent comprising LC(O)OZ and a proton acceptor to form the compound of Formula (III);
wherein:
R 1 and R 2 are independently chosen from hydrogen, halogen, hydroxy, amino, cyano, {—}OR 8 , hydrocarbyl, and substituted hydrocarbyl;
R 3 is chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl;
R 14 is chosen from hydrogen, halogen, hydroxy, {—}OR 8 , hydrocarbyl, and substituted hydrocarbyl;
R 8 and Z are independently chosen from hydrocarbyl and substituted hydrocarbyl;
L is halogen; and
Y is chosen from alkene acetal, dialkyl acetal, and enol ether, wherein each dashed line indicates an optional double bond.
2. The process of claim 1 , wherein:
R 1 , R 2 , and R 14 are independently chosen from hydrogen, halogen, hydroxy, alkyoxy, acyl, alkyl, alkenyl, aryl, substituted alkyl, substituted alkenyl, substituted aryl, alkoxycarbonyl, and aroxycarbonyl;
R 3 is chosen from hydrogen, alkyl, alkenyl, aryl, substituted alkyl, substituted alkenyl, substituted aryl, acyl, alkoxycarbonyl, aroxycarbonyl, acetal, ether, silyl ether, and alkylsulfonyl; and
Z is chosen from alkyl, alkenyl, alkylaryl, aralkyl, aryl, substituted alkyl, substituted alkenyl, substituted alkyiaryl, substituted aralkyl, and substituted aryl.
3. The process of claim 1 , wherein the compound of Formula (II) is chosen from:
(a) an alkene acetal of Formula (IIa) that is formed by contacting the compound of Formula (I) with an alkene diol and a proton donor, the compound of Formula (IIa) having the structure:
wherein:
R 1 and R 2 are independently chosen from hydrogen, halogen, hydroxy, amino, cyano, {—}OR 8 , hydrocarbyl, and substituted hydrocarbyl;
R 3 is chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl;
R 14 is chosen from hydrogen, halogen, hydroxy, {—}OR 8 , hydrocarbyl, and substituted hydrocarbyl; and
R 8 is chosen from hydrocarbyl and substituted hydrocarbyl;
(b) a dialkyl acetal of Formula (IIb) that is formed by contacting the compound of Formula (I) with at least one alcohol and a proton donor, the compound of Formula (IIb) having the structure:
wherein:
R 1 and R 2 are independently chosen from hydrogen, halogen, hydroxy, amino, cyano, {—}OR 8 , hydrocarbyl, and substituted hydrocarbyl;
R 3 is chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl;
R 14 is chosen from hydrogen, halogen, hydroxy, {—}OR 8 , hydrocarbyl, and substituted hydrocarbyl; and
R 5 , R 6 , and R 8 are independently chosen from hydrocarbyl and substituted hydrocarbyl; and
(c) an enol ether of Formula (IIc) that is formed either a) by contacting the compound of Formula (I) with an alcohol and a proton donor followed by distillation of the alcohol, or b) by contacting the compound of Formula (I) with a proton acceptor and a dialkyl sulfate, the compound of Formula (IIc) having the structure:
wherein:
R 1 and R 2 are independently chosen from hydrogen, halogen, hydroxy, amino, cyano, {—}OR 8 , hydrocarbyl, and substituted hydrocarbyl;
R 3 is chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl;
R 14 is chosen from hydrogen, halogen, hydroxy, {—}OR 8 , hydrocarbyl, and substituted hydrocarbyl; and
R 7 and R 8 are independently chosen from hydrocarbyl and substituted hydrocarbyl.
4. The process of claim 1 , wherein the reaction of step (a) is conducted in the presence of an aprotic solvent, a nonpolar solvent, or combinations thereof; the weight ratio of the solvent to the compound of Formula (I) is from about 0.5:1 to about 20:1; the reaction of step (a) is conducted at a temperature from about 0° C. to about 60° C.; the N-demethylating agent is chosen from alkyl haloformate, alkoxyalkyl haloformate, phenyl haloformate, benzyl haloformate, vinyl haloformate, and 2-chloroalkyl haloformate; the proton acceptor has a pKa greater than about 7; the molar ratio of the compound of Formula (II) to LC(O)OZ to the proton acceptor is from about 1:1:1 to about 1:3:6; the reaction of step (b) is conducted in the presence of a solvent chosen from acetonitrile, chlorobenzene, chloroform, 1,2-dichloroethane, ethyl acetate, n-propyl acetate, isopropyl acetate, tetrahydrofuran, toluene, and combinations thereof; the weight ratio of the solvent to the compound of Formula (II) is from about 0.5:1 to about 20:1; and the reaction of step (b) is conducted at a temperature from about 0° C. to about 120° C.
5. The process of claim 1 , wherein the compound of Formula (III) comprises less than about 0.05% by weight of an aldol dimer impurity.
6. The process of claim 1 , wherein the compound of Formula (III) has a yield of at least about 40% by weight.
7. The process of claim 1 , further comprising contacting the compound of Formula (III) with a nucleophile to form a compound of Formula (IV):
wherein:
R 1 and R 2 are independently chosen from hydrogen, halogen, hydroxy, amino, cyano, {—}OR 8 , hydrocarbyl, and substituted hydrocarbyl;
R 3 is chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl;
R 14 is chosen from hydrogen, halogen, hydroxy, {—}OR 8 ,hydrocarbyl, and substituted hydrocarbyl;
R 8 is hydrocarbyl or substituted hydrocarbyl; and
Y is chosen from cyclic alkene acetal, dialkenol acetal, and enol ether, wherein each dashed line indicates an optional double bond.
8. The process of claim 7 , wherein the nucleophile is chosen from an amide, an alkoxide, a hydride, and a hydroxide; and the molar ratio of the compound of Formula (III) to the nucleophile is from about 1:1 to about 1:8.
9. The process of claim 7 , further comprising contacting the compound of Formula (IV) with a proton donor to form a compound of Formula (V):
wherein:
R 1 and R 2 are independently chosen from hydrogen, halogen, hydroxy, amino, cyano, {—}OR 8 , hydrocarbyl, and substituted hydrocarbyl;
R 3 is chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl;
R 14 is chosen from hydrogen, halogen, hydroxy, {—}OR 8 ,hydrocarbyl, and substituted hydrocarbyl; and
R 8 is hydrocarbyl or substituted hydrocarbyl.
10. The process of claim 9 , wherein the proton donor has a pKa of less than about −2; and the molar ratio of the compound of Formula (IV) to the proton donor is about 1:2 to about 1:10.
11. The process of claim 1 , wherein the optical activity of the compounds of Formulas (I), (II), or (III) is chosen from (−) enantiomer, (+) enantiomer, and combinations thereof; and 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.
12. The process of claim 3 , wherein the alkene diol is ethylene glycol;
the proton donor is methanesulfonic acid; the molar ratio of the compound of Formula (I) to ethylene glycol to methanesulfonic acid is about 1:4-30:3; and the reaction of step (a) is conducted at a temperature of less than about 40° C.
13. The process of claim 3 , wherein the proton acceptor is sodium hydride; the dialkyl sulfate is dimethyl sulfate; the molar ratio of the compound of Formula (I) to the proton acceptor to the dialkyl sulfate is about 1:1.5:1.4; and the reaction of step (a) is conducted at a temperature of less than about 40° C.
14. The process of 12 , wherein the N-demethylating agent is ethyl chloroformate or phenyl chloroformate; the proton acceptor is a carbonate or bicarbonate salt; the molar ratio of the compound of Formula (II) to the demethylating agent to the proton acceptor is from about 1:1.2:2-3; the reaction of step (b) is conducted at a temperature from about 40° C. to about 80° C.; the compound of Formula (Ill) comprises less than about 0.05% by weight of an aldol dimer impurity; and the optical activity of the compounds of Formulas (I), (II), or (III) is chosen from (−) enantiomer, (+) enantiomer, and combinations thereof; and 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.
15. The process of 13 , wherein the N-demethylating agent is ethyl chloroformate or phenyl chloroformate; the proton acceptor is a carbonate or bicarbonate salt; the molar ratio of the compound of Formula (II) to the demethylating agent to the proton acceptor is from about 1:1.2:2-3; the reaction of step (b) is conducted at a temperature from about 40° C. to about 80° C.; the compound of Formula (III) comprises less than about 0.05% by weight of an aldol dimer impurity; and the optical activity of the compounds of Formulas (I), (II), or (III) is chosen from (−) enantiomer, (+) enantiomer, and combinations thereof; and 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.