Process for preparing hydrocodone using a super acid
View Patent ↗The present disclosure generally relates to a process for converting a fused, tricyclic compound to a fused, tetracyclic compound that includes a furan ring therein. More particularly, the present disclosure related to a process for preparing a hydrocodone compound, or a compound structurally related thereto, and in particular (+)-hydrocodone, by subjecting a structurally corresponding sinomenine starting compound to a super acid-assisted furan ring closure reaction.
1. A process for carrying out a furan ring closure reaction to transform a compound of Formula (III) to a compound of Formula (IV):
wherein:
R 1 and R 2 are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, cyano, hydrocarbyl, substituted hydrocarbyl and NR c R d , where each of R c and R d are independently selected from the group consisting of hydrogen, hydroxy and hydrocarbyl;
R 3 and R 5 are independently selected from the group consisting of hydrogen, hydrocarbyl and substituted hydrocarbyl;
R 4 is selected from the group consisting of hydrogen, acyl, trialkylsilyl, tertiary-alkyl, aryl-substituted methyl, and alkoxy-carbonyl;
R 6 is a substituent at C5 or C7 and is selected from hydrogen, alkyl, and acyl; and, the dashed bond between carbon atoms C7 and C8 indicates the optional presence of a carbon-carbon double bond;
the process comprising contacting the compound of formula (III) with a super acid under process conditions suitable for forming a bond between the oxygen atom of the —OR 4 substituent and the C5 carbon atom to form a furan ring.
2. The process of claim 1 , wherein the super acid is selected from the group consisting of CF 3 SO 3 H (trifluoromethanesulfonic acid), HBF 4 (tetrafluoroboric acid), HPF 6 (fluorophosphoric acid), FSO 3 H (fluorosulfuric acid), HSbF 6 (fluoroantimonic acid), FP(O)(OH) 2 (fluorophosphoric acid), and combinations thereof.
3. The process of claim 1 , wherein the super acid and the compound of Formula (III) are contacted in a reaction mixture further comprising an aprotic solvent.
4. The process of claim 3 , wherein the aprotic solvent is selected from the group consisting of chloroform, dichloromethane, chlorobenzene, toluene, dichloroethane, tetrahydrofuran, diethyl ether, acetonitrile, and combinations thereof.
5. The process of claim 1 , wherein the super acid is formed in situ.
6. The process of claim 5 , wherein the super acid is formed in situ by reacting water or methanol with an anhydride of the super acid.
7. The process of claim 1 , wherein the process further comprises contacting the compound of Formula (III) with an acid that is not a super acid.
8. The process of claim 7 , wherein the acid that is not a super acid is selected from the group consisting of MeSO 3 H, CH 3 C 6 H 4 SO 3 H, H 3 PO 4 and CF 3 CO 2 H, and combinations thereof.
9. The process of claim 1 , wherein R 1 , R 2 and R 4 are hydrogen.
10. The process of claim 9 , wherein R 3 and R 5 are methyl.
11. The process of claim 1 , wherein R 3 and R 5 are hydrogen.
12. The process of claim 1 , wherein R 3 is methyl and R 5 is hydrogen.
13. The process of claim 1 , wherein R 1 and R 4 are hydrogen; R 2 is bromine; and R 3 , R 5 and R 6 are methyl.
14. The process of claim 1 , wherein R 1 , R 2 and R 4 are hydrogen; R 3 and R 6 are methyl; and R 5 is cyclopropylmethyl.
15. The process of claim 1 , wherein R 1 , R 2 , R 4 and R 5 are hydrogen and R 3 and R 6 are methyl.
16. The process of claim 1 , wherein R 1 , R 2 , R 3 , R 4 and R 6 are hydrogen; and R 5 is methyl.
17. The process of claim 1 , wherein R 1 , R 2 and R 4 are hydrogen and R 3 , R 5 and R 6 are methyl.
18. The process of claim 17 , wherein the compound of Formula (III) is (+)-hydrocodone.
19. The process of claim 1 , wherein the resulting mixture of the compound of Formula (III) and the super acid is agitated for between about 2 and about 8 hours, or between about 4 and about 6 hours.
20. The process of claim 1 , wherein the resulting mixture of the compound of Formula (III) and the super acid is maintained at a temperature between about −20° C. and about 100° C., or between about 0° C. and about 45° C.
21. The process of claim 1 , wherein the compound of Formula III and the compound of Formula IV have the following structures:
wherein R 6 is H or CH 3 .
22. The process of claim 1 , wherein the compound of Formula III and the compound of Formula IV have the following structures:
wherein R 6 is H or CH 3 .
23. A process for making a compound of Formula (VI):
wherein:
R 1 and R 2 are independently selected from the group consisting of hydrogen, halogen, alkoxy, cyano, hydrocarbyl, substituted hydrocarbyl and NR c R d , wherein each of R c and R d are independently selected from the group consisting of hydrogen hydroxy and hydrocarbyl;
R 3 and R 5 are independently selected from the group consisting of hydrogen, hydrocarbyl and substituted hydrocarbyl;
R 4 is selected from the group consisting of hydrogen, acyl, trialkylsilyl, tertiary-alkyl, aryl-substituted methyl and alkoxy carbonyl; and,
R 6 is a substituent at C5 or C7 and is selected from H or CH 3 ;
the process comprising contacting a compound of Formula (V) with a super acid under process conditions suitable for forming a bond between the oxygen atom of the —OR 4 substituent and the C5 carbon atom to form a furan ring.
24. The process of claim 23 , wherein R 1 , R 2 and R 4 are H, and R 3 and R 5 are CH 3 .