Processes for increasing the yield of opiate alkaloid derivatives
The present invention provides processes for the production of opiate alkaloids. In particular, the present invention provides processes for recycling impurities into useful intermediates during the synthesis of opiate alkaloids.
1. A process for the preparation of a compound of Formula (II), the process comprising contacting a compound of Formula (I) with a hydrolysis agent to form the compound of Formula (II):
wherein:
R 1 , R 7 , R 8 , and R 9 are independently selected from the group consisting of hydrocarbyl and substituted hydrocarbyl;
R 2 , and R 3 are independently selected from the group consisting of hydrogen, hydrocarbyl and substituted hydrocarbyl;
R 4 and R 5 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, {—}OH, {—}NH 2 , {—}SH, {—}SR 7 , and {—}OR 7 ;
R 6 is independently selected from the group consisting of hydrogen, a protecting group, hydrocarbyl, and substituted hydrocarbyl; and
X is oxygen, and
wherein the molar ratio of the compound of Formula (I) to the hydrolysis agent is from about 1:5 to about 1:9 and wherein the molar yield of Formula (II) is at least 65%.
2. The process of claim 1 , wherein R 1 , R 6 , R 8 , and R 9 are alkyl or substituted alkyl; and R 2 , R 3 , R 4 , and R 5 are hydrogen.
3. The process of claim 1 , wherein the hydrolysis agent is a compound having a pKa of greater than about 12.0.
4. The process of claim 1 , wherein R 1 , R 6 , R 8 , and R 9 are alkyl or substituted alkyl; the hydrolysis agent is a hydroxide of a group 1 or group 2 metal; the reaction is conducted in the presence of an organic solvent; the reaction is conducted at a pH of at least about 12.0; and the reaction is conducted at a temperature from about 150° C. to about 200° C.
5. The process of claim 4 , wherein the hydrolysis agent is potassium hydroxide.
6. The process of claim 1 , wherein the optical activity of the compound of Formula (I) or (II) is selected from the group consisting of (+), (−), and combinations thereof; the configuration of each of C5 and C6 is R; and the configuration of C7, C9, C13, and C14, respectively, is selected from the group consisting of may be RRSS, RSRR, SRSS, and SSRR, provided that the C15 and the C16 carbons are both either on the alpha face or the beta face of the molecule.
7. A process for the preparation of a compound of Formula (IIa), the process comprising contacting a compound of Formula (Ia) with a hydrolysis agent to form the compound of Formula (IIa):
wherein the molar ratio of the compound of Formula (Ia) to the hydrolysis agent is from about 1:5 to about 1:9 and wherein the molar yield of Formula (IIa) is at least 65%.
8. The process of claim 7 , wherein the hydrolysis agent is a compound having a pKa of greater than about 12.0.
9. The process of claim 7 , wherein the hydrolysis agent is a hydroxide of a group 1 or group 2 metal; the reaction is conducted in the presence of an organic solvent; the reaction is conducted at a pH of at least about 12.0; and the reaction is conducted at a temperature from about 150° C. to about 200° C.
10. The process of claim 9 , wherein the hydroxide is potassium hydroxide.
11. The process of claim 7 , wherein the optical activity of the compound of Formulas (Ia) or (IIa) is selected from the group consisting of (+), (−), and combinations thereof; the configuration of each of C5 and C6 is R; and the configuration of C7, C9, C13, and C14, respectively, is selected from the group consisting of may be RRSS, RSRR, SRSS, and SSRR, provided that the C15 and the C16 carbons are both either on the alpha face or the beta face of the molecule.
12. A process for the preparation of a compound of Formula (II), the process comprising:
a) contacting a compound of Formula (Ib) with a first hydrolysis agent to form the compound of Formula (II) and a compound of Formula (I):
wherein:
R 1 , R 7 , R 8 , and R 9 are independently selected from the group consisting of hydrocarbyl and substituted hydrocarbyl;
R 2 and R 3 are independently selected from the group consisting of hydrogen, hydrocarbyl, and substituted hydrocarbyl;
R 4 and R 5 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, {—}OH, {—}NH 2 , {—}SH, {—}SR 7 , and {—}R 7 ;
R 6 is independently selected from the group consisting of hydrogen, a protecting group, hydrocarbyl, and substituted hydrocarbyl; and X is oxygen; and
b) isolating the compound of Formula (I); and
c) contacting the isolated compound of Formula (I) with a second hydrolysis agent to form additional amounts of the compound of Formula (II), wherein the molar ratio of the compound of Formula (Ib) to the first hydrolysis agent is from about 1:9 to about 1:15 and the molar ratio of the compound of Formula (I) to the second hydrolysis agent is from about 1:5 to about 1:9.
13. The process of claim 12 , wherein R 1 , R 6 , R 8 , and R 9 are alkyl or substituted alkyl; and R 2 , R 3 , R 4 , and R 5 are hydrogen.
14. The process of claim 12 , wherein the first and second hydrolysis agents are each a compound having a pKa of greater than about 12.0.
15. The process of claim 12 wherein R 1 , R 6 , R 8 , and R 9 are alkyl or substituted alkyl; the first and second hydrolysis agents are each a hydroxide of a group 1 or group 2 metal; the reactions in steps (a), (b) and (c) are conducted in the presence of an organic solvent; the reaction in step (b) further comprises an addition of water; the reactions in steps (a), (b) and (c) are conducted at a pH of at least about 12.0; and the reactions in steps (a) and (b) are conducted at a temperature from about 150° C. to about 200° C.
16. The process of claim 12 , wherein the amount of the compound of Formula (I) formed is from about 1% to about 10% by weight of the total amount of the compound of Formula (II) and the compound of Formula (I) formed in step (a); and the molar yield of the compound of Formula (II) in step (a) is greater than about 70%; and the molar yield of the compound of Formula (II) in step (c) is greater than about 70%.
17. The process of claim 12 , wherein the optical activity of the compound of Formulas (I), (Ib), or (II) is selected from the group consisting of (+), (−), and combinations thereof; the configuration of each of C5 and C6 is R; and the configuration of C7, C9, C13, and C14, respectively, is selected from the group consisting of may be RRSS, RSRR, SRSS, and SSRR, provided that the C15 and the C16 carbons are both either on the alpha face or the beta face of the molecule.
18. A process for the preparation of a compound of Formula (IIa), the process comprising:
a) contacting a compound of Formula (Ic) with a first hydrolysis agent to form the compound of Formula (IIa) and a compound of Formula (Ia):
b) isolating the compound of Formula (Ia); and
c) contacting the isolated compound of Formula (Ia) with a second hydrolysis agent to form additional amounts of the compound of Formula (IIa), wherein the molar ratio of the compound of Formula (Ic) to the first hydrolysis agent is from about 1:9 to about 1:15 and the molar ratio of the compound of Formula (Ia) to the second hydrolysis agent is from about 1:5 to about 1:9.
19. The process of claim 18 , wherein the first and second hydrolysis agents are each a compound having a pKa of greater than about 12.0.
20. The process of claim 18 , wherein the first and second hydrolysis agents are each a hydroxide of a group 1 or group 2 metal; the reactions in steps (a), (b) and (c) are conducted in the presence of an organic solvent; the reaction of step (b) further comprises an addition of water; the reactions in steps (a), (b) and (c) are conducted at a pH of at least about 12.0; and the reactions in steps (a) and (c) are conducted at a temperature from about 150° C. to about 200° C.
21. The process of claim 20 , wherein the first and second hydrolysis agents are each potassium hydroxide.
22. The process of claim 18 , wherein the amount of the compound of Formula (Ia) formed is from about 1% to about 10% by weight of the total amount of the compound of Formula (IIa) and the compound comprising Formula (Ia) formed in step (a); and the molar yield of the compound of Formula (IIa) in step (a) is greater than about 70% and the molar yield of compound of Formula (IIa) in step (c) is greater than 70%.
23. The process of claim 18 , wherein the optical activity of the compound of Formulas (Ia), (Ic), or (IIa) is selected from the group consisting of (+), (−), and combinations thereof; the configuration of each of C5 and C6 is R; and the configuration of C7, C9, C13, and C14, respectively, is selected from the group consisting of may be RRSS, RSRR, SRSS, and SSRR, provided that the C15 and the C16 carbons are both either on the alpha face or the beta face of the molecule.