Processes for the synthesis of opiates alkaloids with reduced impurity formation
View Patent ↗The invention provides processes for the production of opiate alkaloids. In particular, the present invention provides processes for the formation of opiate alkaloids that minimizes the formation of impurities.
1. A process for the preparation of a compound of Formula (II):
the process comprising:
(a) forming a reaction mixture by combining a compound of Formula (I), with a dienophile and a solvent comprising an alcohol and at least 10% water, wherein the compound of Formula (I) is:
and
(b) heating the reaction mixture to form a compound of Formula (II), wherein:
R 1 and R 8 are independently selected from the group consisting of hydrocarbyl and substituted hydrocarbyl;
R 2 and R 3 are independently selected from the group 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 8 , and {—}OR 8 ;
R 6 and R 7 are independently selected from the group consisting of hydrogen, a protecting group, hydrocarbyl, and substituted hydrocarbyl; and
X is oxygen.
2. The process of claim 1 , wherein the solvent comprises from about 10% to 35% (v/v) of water.
3. The process of claim 1 , wherein the dienophile is methyl vinyl ketone; the molar ratio of the compound of Formula (I) to dienophile is from about 1:1.5 to about 1:5.5; and the reaction mixture is heated to a temperature of about 50° C. to about 100° C. for a period time that is sufficient for the conversion of a substantial portion of the compound of Formula (I) to the compound of Formula (II).
4. The process of claim 1 , wherein:
R 2 , R 3 , R 4 , and R 5 are hydrogen;
R 6 is selected from the group consisting of {—}CH 3 , and hydrogen;
R 7 is {—}CH 3 ; and
X is oxygen.
5. The process of claim 1 , wherein a seed material comprising a crystalline form of the compound of Formula (II) is added to the reaction mixture as the reaction mixture is cooled to a temperature of about 5° C.
6. The process of claim 1 , wherein the amount of α-epimer formed at C(7) is greater than about 99.5% by weight of the amount of compound of Formula (II); and the amount of β-epimer formed at C(7) is less than about 0.50% by weight of the amount of compound of Formula (II).
7. The process of claim 1 , wherein the dienophile is methyl vinyl ketone and wherein:
R 2 , R 3 , R 4 , and R 5 are hydrogen;
R 6 is selected from the group consisting of {—}CH 3 , and hydrogen;
R 7 is {—}CH 3 ; and
X is oxygen.
8. The process claim 1 , further comprising subjecting the compound of Formula (II) to hydrogenation to form a compound of Formula (III):
wherein:
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and X are as defined in claim 1 .
9. A process for the preparation of a compound of Formula (IIa):
the process comprising:
(a) forming a reaction mixture by combining a compound of Formula (Ia), with a dienophile and a solvent comprising an alcohol and at least 10% water, wherein the compound of Formula (Ia) is:
and
(b) heating the reaction mixture to form a compound of Formula (IIa), wherein:
R 1 and R 8 are independently selected from the group consisting of hydrocarbyl and substituted hydrocarbyl;
R 2 and R 3 are independently selected from the group hydrogen, hydrocarbyl and substituted hydrocarbyl; and
R 4 and R 5 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, {—}OH, {—}NH 2 , {—}SH, {—}SR 8 , and {—}OR 8 .
10. The process of claim 9 , wherein the molar ratio of the compound of Formula (Ia) to dienophile is from about 1:1.75 to about 1:3: the reaction mixture is heated to a temperature of about 50° C. to about 100° C. for a period time that is sufficient for the conversion of a substantial portion of the compound of Formula (Ia) to the compound of Formula (IIa) and then the reaction mixture is cooled: and the solvent comprises from about 10% to 35% (v/v) of water.
11. The process of claim 10 , wherein the dienophile is methyl vinyl ketone and R 2 , R 3 , R 4 , and R 5 are hydrogen.
12. The process of claim 11 , further comprising adding seed material comprising a crystalline form of the compound having Formula (IIa) as the reaction mixture cools.
13. The process of claim 9 , wherein the amount of β-epimer formed at C(7) is less than about 0.50% by weight of the amount of compound of Formula (IIa); and the amount of α-epimer formed at C(7) is greater than about 99.5% by weight of the amount of compound of Formula (IIa).
14. The process claim 9 , further comprising subjecting the compound of Formula (IIa) to hydrogenation to form a compound of Formula (IIIa):
wherein:
R 1 , R 2 , R 3 , R 4 , and R 5 are as defined in claim 9 .
15. A process for the preparation of a compound of Formula (IIb):
the process comprising:
(a) forming a reaction mixture by combining a compound of Formula (Ib), with a dienophile and a solvent comprising an alcohol and at least 10% water, wherein the compound of Formula (Ib) is:
and
(b) heating the reaction mixture to form a compound of Formula (IIb), wherein:
R 1 and R 8 are independently selected from the group consisting of hydrocarbyl and substituted hydrocarbyl;
R 2 and R 3 are independently selected from the group hydrogen, hydrocarbyl and substituted hydrocarbyl; and
R 4 and R 5 are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, {—}OH, {—}NH 2 , {—}SH, {—}SR 8 , and {—}OR 8 .
16. The process of claim 15 , wherein the molar ratio of the compound of Formula (Ib) to dienophile is from about 1:1.75 to about 1:3 the reaction mixture is heated to a temperature of about 50° C. to about 100° C. for a period time that is sufficient for the conversion of a substantial portion of the compound of Formula (Ib) to the compound of Formula (IIb) and then the reaction mixture is cooled; and the solvent comprises from about 10% to 35% (v/v) of water.
17. The process of claim 16 , wherein the dienophile is methyl vinyl ketone and R 2 , R 3 , R 4 , and R 5 are hydrogen.
18. The process of claim 16 , further comprising adding seed material comprising a crystalline form of the compound having Formula (IIb) as the reaction mixture cools.
19. The process of claim 15 , wherein the amount of β-epimer formed at C(7) is less than about 0.50% by weight of the amount of compound of Formula (IIb); and the amount of α-epimer formed at C(7) is greater than about 99.5% by weight of the amount of compound of Formula (IIb).
20. The process claim 15 , further comprising subjecting the compound of Formula (IIb) to hydrogenation to form a compound of Formula (IIIb):
wherein:
R 1 , R 2 , R 3 , R 4 , and R 5 are as defined in claim 15 .