Process for the synthesis of morphinane compounds and intermediates thereof
View Patent ↗This invention relates to intermediates useful in the preparation of opiate alkaloids, particularly morphinane compounds. The invention also relates to processes for preparing such intermediates and to processes which utilise such intermediates in the synthesis of morphinane compounds.
1. A method for preparing a 6-oxo-14-hydroxy-Δ 7 -morphinane comprising oxidising a 6-methoxy-N-methyl-Δ 6 ,Δ 8 -morphinane for a time and under conditions sufficient to form a 6-oxo-14-hydroxy-N-methyl-Δ 7 -morphinane-N-oxide and converting the formed N-oxide to the 6-oxo-14-hydroxy-Δ 7 -morphinane.
2. A method according to claim 1 wherein the oxidation is carried out by treating the 6-methoxy-N-methyl-Δ 6 ,Δ 8 -morphinane with hydrogen peroxide in the presence of a carboxylic acid.
3. A method according to claim 2 wherein the carboxylic acid is formic acid or acetic acid.
4. A method according to claim 3 wherein the carboxylic acid is formic acid.
5. A method according to claim 4 wherein the concentration of formic acid is 45% by weight formic acid in water.
6. A method according to claim 2 wherein the 6-methoxy-N-methyl-Δ 6 ,Δ 8 -morphinane is treated with a molar excess of hydrogen peroxide at a concentration of 50% by weight in water.
7. A method according to claim 2 wherein the 6-methoxy-N-methyl-Δ 6 ,Δ 8 -morphinane is dissolved in a mixture of the carboxylic acid and a solvent prior to the addition of the hydrogen peroxide.
8. A method according to claim 7 wherein the solvent is ethanol.
9. A method according to claim 1 wherein the oxidation is conducted at a temperature below 50° C.
10. A method according to claim 9 wherein the temperature is about 20° C.
11. A method according to claim 1 further comprising the step of isolating the 6-oxo-14-hydroxy-N-methyl-Δ 7 -morphinane-N-oxide before the conversion to 6-oxo-14-hydroxy-Δ 7 -morphinane.
12. A method according to claim 11 wherein the isolation step comprises neutralising the oxidation reaction mixture to a pH of about 7 by adding a base and collecting the N -oxide as a solid.
13. A method according to claim 12 wherein the base is selected from sodium or potassium hydroxide or potassium carbonate.
14. A method according to claim 13 wherein the base is sodium hydroxide.
15. A method according to claim 14 wherein sodium hydroxide is added to the oxidation reaction mixture at a rate which ensures that the reaction temperature reaches 55° C.
16. A method according to claim 1 wherein the formed N-oxide is converted to the 6-oxo-14-hydroxy-Δ 7 -morphine by treating the N-oxide with a reducing agent.
17. A method for converting a 6-oxo-14-hydroxy-N-methyl-Δ 7 -morphinane -N-oxide to a 6-oxo-14-hydroxy-Δ 7 -morphinane comprising subjecting the N-oxide to reducing conditions to ring close the N-methyl group with the 14-hydroxy group forming an oxazolidine ring, and hydrolysing the ring closed oxazolidine product to form the 6-oxo-14-hydroxy-Δ 7 -morphinane.
18. A method according to claim 17 wherein the reducing conditions comprise treating the 6-oxo-14-hydroxy-N-methyl-Δ 7 -morphinane-N-oxide with a Fe(II) based reducing agent and formic acid.
19. A method according to claim 17 wherein the hydrolysing step is performed using a strong acid selected from hydrochloric acid, sulphuric acid, hydrobromic acid or phosphoric acid.
20. A method according to claim 19 wherein the strong acid is hydrochloric acid.
21. A method according to claim 18 wherein the 6-oxo-14-hydroxy-N-methyl-Δ 7 -morphinane-N-oxide is treated as a slurry in methanol with a Fe(II) based reducing agent, whereby formic acid is added.
22. A method for preparing N-alkyl or N-alkenyl 6-oxo-14-hydroxy-morphinanes comprising:
oxidising a 6-methoxy-N-methyl-Δ 6 ,Δ 8 -morphinane for a time and under conditions sufficient to form a 6-oxo-14-hydroxy-N-methyl-Δ 7 -morphinane-N-oxide,
converting the formed N-oxide to a 6-oxo-14-hydroxy-Δ 7 -morphinane,
reducing the Δ 7 double bond to form a 6-oxo-14-hydroxy morphinane, and
subjecting the 6-oxo-14-hydroxy-morphinane to N-alkylation to introduce the N-alkyl or N-alkenyl substituent.
23. A method according to claim 1 wherein the 6-methoxy-N-methyl-Δ 6 ,Δ 8 -morphinane is a compound of formula I:
where R is H, C 1 -C 6 alkyl, benzyl or acyl.
24. A method according to claim 23 wherein the 6-methoxy-N-methyl-Δ 6 ,Δ 8 -morphinane is a compound of formula I where R is H or CH 3 .
25. A method according to claim 23 wherein the 6-methoxy-N-methyl-Δ 6 ,Δ 8 -morphinane is a compound of formula I where R is H.
26. A method according to claim 1 wherein the 6-oxo-14-hydroxy-N-methyl-Δ 7 -morphinane-N-oxide is compound of formula II:
where R is independently selected from H, C 1 -C 6 alkyl, benzyl or acyl.
27. A method according to claim 26 wherein the 6-oxo-14-hydroxy-N-methyl-Δ 7 -morphinane N-oxide is compound of formula II where R is H or CH 3 .
28. A method according to claim 27 wherein the 6-oxo-14-hydroxy-N-methyl-Δ 7 -morphinane N-oxide is a compound of formula II where R is H.
29. A method according to claim 1 wherein the 6-oxo-14-hydroxy-Δ 7 -morphinane is a compound of formula III:
wherein R is H, C 1 -C 6 alkyl, benzyl or acyl.
30. A method according to claim 29 wherein the 6-oxo-14-hydroxy-Δ 7 -morphinane is a compound of formula III where R is H or CH 3 .
31. A method according to claim 30 wherein the 6-oxo-14-hydroxy-Δ 7 -morphinane is a compound of formula III where R is H.