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. A method of producing a product comprising ingenol-3-angelate (I),
comprising the steps of:
esterifying ingenol protected with a dihydroxyl protecting group at the 5 and 20 positions, with angelic acid or a derivative thereof selected from the group consisting of angelic acid, methyl angelate, vinyl angelate, angeloyl chloride, angelic anhydride, angeloyl 2,4,6-trichlorobenzoyl anhydride, [(Z)-2-methylbut-2-enoyl]2,4,6-trichlorobenzoate, and angeloyl 4-nitrobenzoyl anhydride 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 the product comprising ingenol-3-angelate (I).
2. The method of claim 1 , wherein the base is selected from the group consisting of a disilazide salt and a carbonate salt.
3. The method of claim 2 , wherein the base is selected from the group consisting of lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, and cesium carbonate.
4. The method of claim 2 , wherein the base is a disilazide salt.
5. The method of claim 4 , wherein the disilazide salt is lithium hexamethyldisilazide, sodium hexamethyldisilazide, or potassium hexamethyldisilazide.
6. The method of claim 1 , wherein the dihydroxyl protecting group is selected from the group consisting of ketals and acetals.
7. The method of claim 1 , wherein the 5, 20-protected ingenol is ingenol-5, 20-acetonide (Compound 1):
8. A method of producing a product comprising ingenol-3-angelate (I),
comprising the steps of:
converting angelic acid to angelic anhydride;
esterifying ingenol protected with a dihydroxyl protecting group at the 5 and 20 positions, with angelic anhydride 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 the product comprising ingenol-3-angelate (I).
9. The method of claim 8 , wherein the converting step comprises mixing angelic acid with a coupling reagent.
10. The method of claim 9 , wherein the coupling reagent is N,N′-dicyclohexylcarbodiimide (DCC), 1-methyl-2-chloro-pyridinium iodide, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU), or N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI).
11. The method of claim 9 , wherein the coupling reagent is N,N′-dicyclohexylcarbodiimide (DCC).
12. The method of claim 8 , wherein the angelic anhydride is purified by chromatography.
13. The method of claim 8 , wherein the base is a non-nucleophilic base.
14. The method of claim 8 , wherein the base is selected from the group consisting of lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, and cesium carbonate.
15. The method of claim 8 , wherein the dihydroxyl protecting group is selected from the group consisting of ketals and acetals.
16. The method of claim 8 , wherein the 5, 20-protected ingenol is ingenol-5, 20-acetonide (Compound 1):
17. The method of claim 8 , wherein the esterifying step has a yield of at least 90%.
18. The method of claim 17 , wherein the product comprises ingenol-3-tiglate and ingenol-3-angelate (I) at a molar ratio of at most 5:95.
19. A method of producing a product comprising 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 angelic 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 the product comprising ingenol-3-angelate (I);
wherein the product comprises ingenol-3-tiglate and the ingenol-3-angelate (I) at a molar ratio of at most 5:95.
20. The method of claim 19 , wherein the product comprises ingenol-3-tiglate and the ingenol-3-angelate (I) at a molar ratio of at most 3:97.
21. The method of claim 19 , wherein the product comprises ingenol-3-tiglate and the ingenol-3-angelate (I) at a molar ratio of at most 2:98.
22. The method of claim 19 , wherein the base is non-nucleophilic.
23. The method of claim 19 , wherein the dihydroxyl protecting group is selected from the group consisting of ketals and acetals.
24. The method of claim 22 , wherein the base is selected from the group consisting of a disilazide salt and a carbonate salt.
25. The method of claim 24 , wherein the dihydroxyl protecting group is selected from the group consisting of ketals and acetals.