Preparation of normorphinans
View Patent ↗The present invention provides processes for preparing normorphinans from N-substituted morphinans. In particular, the invention provides methods for removing the N-substituent from the N-substituted morphinan to from a normorphinan carbamate, and then removing the carbamate functionality from the normorphinan carbamate to form the normorphinan.
1. A process for preparing a compound of Formula (III), the process comprising:
(a) contacting a compound of Formula (I) with a hydrocarbyl haloformate, XC(O)OR 18 , and a hindered tertiary amine to form a compound of Formula (II); and
(b) contacting the compound of Formula (II) with a quaternary ammonium salt to form the compound of Formula (III) according to the following reaction scheme:
wherein:
A is oxygen;
R is hydrocarbyl or substituted hydrocarbyl;
R 1 , R 2 , and R 3 are independently hydrogen, amino, halogen, {—}OH, {—}OR 1611 , {—}SH, {—}SR 1611 , {—}NHR 1611 , {—}NR 1611 R 1612 , hydrocarbyl, or substituted hydrocarbyl;
R 5 , R 6a , R 6b , R 7a , R 7b , R 8a R 8b , R 9 , R 10a , R 10b , R 14 , R 15a , R 15b , R 16a , and R 16b are independently hydrogen, amino, halogen, {—}OH, {—}OR 1611 , {—}SH, {—}SR 1611 , {—}NHR 1611 , {—}NR 1611 R 1612 , hydrocarbyl, or substituted hydrocarbyl; wherein any pair of R #a and R #b wherein # is any one of 6, 7, 8, 10, 15, 16, optionally together form a moiety chosen from {═}O, {═}S, {═}CH 2 , {═}NR 1612 , or {—}O(CH 2 ) n O{—}, wherein n is an integer of 1 or greater;
R 18 is hydrocarbyl or substituted hydrocarbyl
R 1611 and R 1612 are independently hydrocarbyl or substituted hydrocarbyl;
X is halogen ; and
the dashed lines between the carbon atoms at positions 6 and 7, 7 and 8, and 8 and 14 represent carbon to carbon bonds chosen from (a) single bonds between all carbon atoms, wherein optionally one of the R 6 pair and R 14 form an alkano bridge; (b) single bonds between the carbons at both positions 7 and 8 and 8 and 14, and a double bond between the carbons at positions 6 and 7, wherein only one of R 6 pair is present; (c) single bonds between the carbons at both positions 6 and 7 and 8 and 14, and a double bond between the carbons at positions 7 and 8, wherein only one of each R 7 and R 8 pair is present; or (d) double bonds between the carbons at both positions 6 and 7 and 8 and 14, and a single bond between the carbons at positions 7 and 8, wherein only one of each R 6 , R 7 , and R 8 pair is present and R 14 is not present.
2. The process of claim 1 , wherein R is methyl, cyclopropylmethyl, cyclobutylmethyl, or allyl; R 3 is {—}OH, {—}O-alkyl, or {—}OR 1611 ; R 1 , R 2 , R 5 , R 8a R 8b , R 9 , R 10a , R 10b , R 15a , R 15b , R 16a , and R 16b , if present, are hydrogen; R 14 is hydrogen, {—}OH, {—}O-alkyl, {—}OR 1611 , or forms an alkano bridge with one of the R 6 pair; and R 18 is alkyl, halo-substituted alkyl, alkoxyalkyl, alkenyl, aryl, or substituted aryl.
3. The process of claim 2 , wherein R 6a is {—}OH, {—}O-alkyl, {—}OR 1611 , or {—}NR 1611 R 1612 , and R 6b is hydrogen, or together R 6a and R 6b form {═}O, {═}CH 2 , or {—}O(CH 2 ) n O{—}, R 7a and R 7b are hydrogen, and R 14 is hydrogen, {—}OH, {—}O-alkyl, or {—}OR 1611 ; or R 6a is {—}OH, {—}O-alkyl, or {—}OR 1611 , R 6b and R 14 form an alkano bridge, R 7a is alkyl or substituted alkyl, and R 7b is hydrogen.
4. The process of claim 1 , wherein the hydrocarbyl haloformate is an alkyl haloformate, a halo-substituted alkyl haloformate, an alkenyl haloformate, an alkoxyalkyl haloformate, or an aryl haloformate.
5. The process of claim 1 , wherein the hindered tertiary amine is N,N-diisopropylethylamine, N,N-diisopropyl-2-ethylbutylamine; N,N-diisopropyl-3-pentylamine, triisopropylamine, triethylamine, N-ethylpiperidine, or a combination thereof.
6. The process of claim 1 , wherein the mole to mole ratio of the compound of Formula (I) to the hydrocarbyl haloformate to the hindered tertiary amine is from about 1:1:1 to about 1:3:3.
7. The process of claim 1 , wherein step (a) further comprises an inorganic proton acceptor, the inorganic proton acceptor is an inorganic salt, and the mole to mole ratio of the hindered tertiary amine to the inorganic salt is from about 1:7 to about 1:8.
8. The process of claim 1 , wherein step (a) is conducted in the presence of a solvent chosen from dichloromethane, dichloroethane, chloroform, acetonitrile, methyl ethylketone, methyl isobutylketone, toluene, or a combination thereof; the volume to mass ratio of the solvent to the compound of Formula (I) is from about 2:1 to about 20:1; and step (a) is conducted at a temperature from about 20° C. to about 60° C.
9. The process of claim 1 , the mole to mole ratio of the compound of Formula (II) to the quaternary ammonium salt is from about 1:20 to about 1:80.
10. The process of claim 9 , wherein step (b) is conducted in the presence of a solvent chosen from dimethyl sulfoxide, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, N,N-dimethylpropylamide, or a combination thereof; the volume to mass ratio of the solvent to the compound of Formula (II) is from about 5:1 to about 20:1; and step (b) is conducted at a temperature from about 70° C. to about 100° C.
11. The process of claim 1 , wherein steps (a) and (b) are conducted in a single reaction pot without isolation of the compound of Formula (II).
12. The process of claim 1 , wherein the compounds of Formulas (I), (II), and (III) independently have an optical activity of (−) or (+); and the configuration of C-5, C-13, C-14, and C-9, respectively, is RRRR, RRSR, RRRS, RRSS, RSRR, RSSR, RSRS, RSSS, SRRR, SRSR, SRRS, SRSS, SSRR, SSSR, SSRS, or SSSS, provided that the C-15 and the C-16 carbons are both either on the alpha face of the molecule or the beta face of the molecule.
13. The process of claim 1 , wherein step (a) is omitted.
14. The process of claim 13 , wherein the mole to mole ratio of the compound of Formula (II) to the quaternary ammonium salt is from about 1:20 to about 1:80; the process is conducted in the presence of a solvent chosen from dimethyl sulfoxide, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, N,N-dimethylpropylamide, or a combination thereof; the volume to mass ratio of the solvent to the compound of Formula (II) is from about 5:1 to about 20:1; and the process is conducted at a temperature from about 70° C. to about 100° C.
15. The process of claim 14 , wherein R 3 is {—}OH, {—}O-alkyl, or {—}OR 1611 ; R 1 , R 2 , R 5 , R 8a R 8b , R 9 , R 10a , R 10b , R 15a , R 15b , R 16a , and R 16b , if present, are hydrogen; R 14 is hydrogen, {—}OH, {—}O-alkyl, {—}OR 1611 , or forms an alkano bridge with one of the R 6 pair; and R 18 is alkyl, halo-substituted alkyl, alkoxyalkyl, alkenyl, aryl, or substituted aryl.
16. The process of claim 15 , wherein R 6a is {—}OH, {—}O-alkyl, {—}OR 1611 , or {—}NR 1611 R 1612 , and R 6b is hydrogen, or together R 6a and R 6b form {═}O, {═}CH 2 , or {—}O(CH 2 ) n O{—}, R 7a and R 7b are hydrogen, and R 14 is hydrogen, {—}OH, {—}O-alkyl, or {—}OR 1611 ; or R 6a is {—}OH, {—}O-alkyl, or {—}OR 1611 , R 6b and R 14 form an alkano bridge, R 7a is alkyl or substituted alkyl, and R 7b is hydrogen.
17. The process of claim 13 , wherein the compounds of Formulas (II) and (III) independently have an optical activity of (−) or (+); and the configuration of C-5, C-13, C-14, and C-9, respectively, is RRRR, RRSR, RRRS, RRSS, RSRR, RSSR, RSRS, RSSS, SRRR, SRSR, SRRS, SRSS, SSRR, SSSR, SSRS, or SSSS, provided that the C-15 and the C-16 carbons are both either on the alpha face of the molecule or the beta face of the molecule.