Method of producing ingenol-3-angelate

• US 9,676,698 B2
• Filed: 06/09/2016
• Issued: 06/13/2017
• Est. Priority Date: 07/20/2010
• Status: Active Grant

• Current Assignee: LEO Laboratories Limited (Leo Fondet)
• Original Assignee: LEO Laboratories Limited (Leo Fondet)
• Inventors: Hogberg, Thomas, Petersen, Anders Klarskov, Liang, Xifu, Horneman, Anne Marie, Grue-Sorensen, Gunnar
• Primary Examiner(s): WITHERSPOON, SIKARL A
• Application Number:
  US15/178,112
• Publication Number:
  US 20160280627A1
• Time in Patent Office: 369 Days
• CPC Class Codes: C07C 2603/86 containing four rings
• CPC Class Codes: C07C 2603/98 containing at least one ring with more than six ring members
• CPC Class Codes: C07C 49/753 containing ether groups, groups, groups, or groups
• CPC Class Codes: C07C 59/90 containing singly bound oxygen-containing groups
• CPC Class Codes: C07C 67/08 by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
• CPC Class Codes: C07C 67/14 from carboxylic acid halides
• CPC Class Codes: C07C 67/297 by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
• CPC Class Codes: C07C 69/533 Monocarboxylic acid esters having only one carbon-to-carbon double bond
• CPC Class Codes: C07D 317/70 condensed with ring systems containing two or more relevant rings
• CPC Class Codes: C07D 319/08 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 493/08 Bridged systems
• CPC Class Codes: C07F 7/1804 Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

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.

Claims

1. A method of producing a 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),

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),

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.