Method of producing ingenol-3-angelate
The present invention relates to methods of producing ingenol-3-angelate (I) from ingenol (II). Furthermore, the invention relates to intermediates useful for the synthesis of ingenol-3-angelate (I) from ingenol (II) and to methods of producing said intermediates.
1. Method of producing ingenol-3-angelate (I), comprising the steps of:
esterifying ingenol protected with a dihydroxyl protecting group at the 5 and 20 positions, with angelic anhydride or angeloyl chloride in the presence of a base to produce 5,20 hydroxyl-protected ingenol-3-angelate (VI), wherein D represents a dihydroxyl protecting group; and
removing the dihydroxyl protecting group at the 5 and 20 positions to produce ingenol-3-angelate (I).
2. The method of claim 1 , wherein the dihydroxyl protecting group is selected from the group consisting of ketals and acetals.
3. The method of claim 1 , wherein the 5,20-protected ingenol is ingenol-5,20-acetonide (Compound 1):
4. The method of claim 1 , wherein the base is a non-nucleophilic base.
5. The method of claim 4 , wherein the non-nucleophilic base is selected from the group consisting of lithium hexamethyldisilazide; sodium hexamethyldisilazide; and potassium hexamethyldisilazide.
6. The method of claim 1 , wherein the base is cesium carbonate.
7. The method of claim 1 , wherein the dihydroxyl protecting group is removed with acid.
8. The method of claim 7 , wherein the acid is selected from the group consisting of hydrochloric acid, phosphoric acid and methanesulfonic acid.
9. The method of claim 1 , wherein the 5,20-protected ingenol is dissolved in tetrahydrofuran, methyl tert-butyl ether or acetonitrile prior to reaction with the angelic anhydride or angeloyl chloride.
10. The method of claim 1 , wherein the reaction takes place at ambient temperature.
11. The method of claim 1 , wherein the reaction takes place at between 10 and 15° C.
12. The method of claim 1 , wherein the reaction yields at least 90% ingenol-3-angelate.
13. The method of claim 12 , wherein the reaction yields at least 95% ingenol-3-angelate.
14. The method of claim 6 , wherein the 5,20-protected ingenol is mixed with angelic anhydride or angeloyl chloride and cesium carbonate in acetonitrile.
15. The method of claim 2 , wherein said ketals and acetals are selected from the group consisting of isopropylidene ketal (acetonide), cyclopentylidene ketal, cyclohexylidene ketal, cycloheptylidene ketal, benzophenone ketal, 1-tert-butylethylidene ketal, 1-phenylethylidene ketal, 3-pentylidene ketal, 2,4-dimethyl-3-pentylidene ketal, 2,6-dimethyl-4-heptylidene ketal, 3,3-dimethyl-2-butylidene ketal, benzylidene acetal, 2,4-dimethoxybenzylidene acetal, 4-nitrobenzylidene acetal, 2,4,6-trimethylbenzylidene acetal, 2,2-dimethyl-1-propylidene acetal, methylene acetal, ethylidene acetal, p-methoxybenzylidene acetal, tert-butylmethylidene acetal, 3-(benzyloxy)propylidene acetal, acrolein acetal, 2-nitrobenzylidene acetal, mesitylene acetal and 2-naphthaidehyde acetal.
16. The method of claim 1 , wherein said dihydroxyl protecting group is selected from the group consisting of cyclic ortho esters or ortho esters.
17. The method of claim 16 , wherein said cyclic ortho esters or ortho esters are selected from the group consisting of methoxymethylene acetal, ethoxymethylene acetal, 2-oxacyclopentylidene ortho ester and isopropoxymethylene acetal.
18. The method of claim 1 , wherein said dihydroxyl protecting group is a bisacetal derivative.
19. The method of claim 18 , wherein said bisacetal derivative is selected from the group consisting of butane 2,3-bisacetal, cyclohexane-1,2-diacetal and octahydro-[2,2′]-bipyranyl ketal.
20. The method of claim 1 wherein said dihydroxyl protecting group is selected from the group consisting of di-tert-butylsilylene, dialkylsilylene, 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene), 1,1,3,3-tetra-tert-butoxydisiloxanylidene, methylene-bis-(diisopropylsilanoxanylidene, 1,1,4,4-tetraphenyl-1,4-disilanylidene, cyclic carbonates, phenyl boronate, methyl boronate and ethyl boronate.