Demethylation of 14-hydroxy substituted alkaloid derivatives
The present invention is directed to a method for demethylating 14-hydroxy substituted alkaloid derivatives, in particular of 14-hydroxy-17-methyl-4,5-epoxymorphinane-6-on-derivatives. This is achieved by reacting a starting compound with a compound of general formula R 1 OOC—N═N—COOR 2 in a suitable solvent.
1. A method of producing a compound of formula (I)
or a salt thereof, comprising:
reacting a compound of formula (II)
with an azodicarboxylic acid dialkyl ester of general formula R 1 OOC—N═N—COOR 2 in a suitable solvent wherein
X is selected from H, alkyl, silyl or acetyl;
R 1 and R 2 are independently selected from linear or branched substituted or unsubstituted alkyl; and
wherein the bond between atoms 7 and 8 is single or a double bond.
2. The method according to claim 1 , wherein R 1 and/or R 2 independently are selected from isopropyl and ethyl.
3. The method of claim 2 , wherein R 1 and R 2 are identical.
4. The method of claim 1 , wherein the solvent is an aprotic dipolar solvent.
5. The method of claim 4 , wherein the solvent is selected from methanol, ethanol, acetone, toluene, dimethylformamide, N,N-dimethylacetamide, acetonitrile, acetic acid ethylester and methyl-tert-butylether.
6. The method of claim 5 , wherein the solvent is dimethylformamide.
7. The method of claim 1 , wherein the reaction is performed at a temperature in the range of room temperature (20° C.) to 100° C.
8. The method of claim 1 , wherein the reaction is performed at a temperature in the range of from 30-90° C.
9. The method of claim 1 , wherein the reaction is performed at a temperature in the range of from 40-80° C.
10. The method of claim 1 , wherein the reaction is performed at a temperature in the range of 50-70° C.
11. The method of claim 7 , wherein the temperature is maintained for at least one hour.
12. The method of claim 7 , wherein the temperature is maintained for at least two hours.
13. The method of claim 7 , wherein the temperature is maintained for at least three hours.
14. The method of claim 7 , wherein the temperature is maintained for at least four hours.
15. The method of claim 1 , wherein after reacting the compound of formula (II) with an azodicarboxylic acid dialkyl ester, the reaction solution is supplemented with 5,5-dimethylcyclohexane-1,3-dione (dimedone) and methanol or hydrazines and methanol.
16. The method of claim 15 , wherein the reaction solution is maintained at a temperature in the range of room temperature (20° C.) to 100° C.
17. The method of claim 15 , wherein the reaction solution is maintained at a temperature in the range of 30-80° C. over a time of 1-10 hours after adding dimedone and methanol.
18. The method of claim 15 , wherein the reaction solution is maintained at a temperature in the range of 30-80° C. over a time of 2-5 hours after adding dimedone and methanol.
19. The method of claim 15 , wherein the reaction solution is maintained at a temperature in the range of 40-70° C. over a time of 1-10 hours after adding dimedone and methanol.
20. The method of claim 15 , wherein the reaction solution is maintained at a temperature in the range of 40-70° C. over a time of 2-5 hours after adding dimedone and methanol.
21. The method of claim 1 , wherein following reacting the compound of formula (II) and optionally reacting with dimedone/hydrazines and methanol, an acid is added to the reaction solution.
22. The method of claim 21 , wherein the acid is a hydrochloric acid.
23. The method of claim 22 , wherein the hydrochloric acid has a concentration of about 5% V/V.
24. The method according to claim 1 , wherein linear or branched substituted or unsubstituted alkyl is C 1 -C 6 -alkyl.
25. The method according to claim 24 , wherein C 1 -C 6 -alkyl is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, and hexyl.