Method of producing ingenol-3-angelate

1. A method of producing ingenol-3-angelate (I) from ingenol (II):

the method comprising the steps of:

(a) reacting one or both hydroxyl groups in positions 5 and 20 of ingenol (II) with suitable hydroxyl protecting agents, which may be the same or different, to obtain a compound of the general formula (III) or (IV)

wherein R 1 represents hydrogen or a hydroxyl protective group and R 2 represents hydrogen or a hydroxyl protective group,

with the proviso that R 1 and R 2 are not both hydrogen,

and wherein D represents a dihydroxyl protective group;

(b) esterifying the hydroxyl group at the 3-position of the compound of formula (III) or (IV) to obtain a compound of the general formula (V) or (VI)

wherein R 1 , R 2 and D are as described above; and

(c) removing the hydroxyl protective groups R 1 or R 2 , or R 1 and R 2 , or D from the compound of formula (V) or (VI) to obtain ingenol-3-angelate (I).

2. A method of producing ingenol-3-angelate (I) from ingenol (II):

the method comprising the steps of:

(d) esterifying the 3- and the 20-hydroxyl group and optionally esterifying the 5-hydroxyl group of ingenol (II) to obtain a compound of the formula (VII)

wherein R 3 represents hydrogen or angeloyl; and

(e) cleaving the angelate ester(s) in position 20 or in position 5 and 20 of the compound of formula (VII) to obtain ingenol-3-angelate (I).

3. The method according to claim 1 , wherein R 1 represents hydrogen or an ether, acetal, ketal, silylether, ester, carbonate, or a sulfenate derived hydroxyl protective group, and R 2 represents hydrogen or an ether, acetal, ketal, silylether, ester, carbonate, or a sulfenate derived hydroxyl protective group.

4. The method according to claim 1 , wherein D represents an acetal, ketal, diacetal, diketal, ortho ester, silyl, boronate or a carbonate derived dihydroxyl protective group.

5. The method according to claim 1 , wherein R 1 is selected from the group consisting of hydrogen or [(3,4-dimethoxybenzyl)oxy]methyl, guaiacolmethyl, 2-methoxyethoxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, allyl, prenyl, p-methoxybenzyl, triphenylmethyl, 2-(trimethylsilyl)ethoxymethyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, tert-butyldiphenylsilyl, triphenylsilyl, acetyl, chloroacetyl, phenoxyacetyl or angeloyl.

6. The method according to claim 1 , wherein R 2 is selected from the group consisting of hydrogen or [(3,4-dimethoxybenzyl)oxy]methyl, guaiacolmethyl, 2-methoxyethoxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, allyl, prenyl, p-methoxybenzyl, triphenylmethyl, 2-(trimethylsilyl)ethoxymethyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, tert-butyldiphenylsilyl, triphenylsilyl, acetyl, chloroacetyl, phenoxyacetyl or angeloyl.

7. The method according to claim 1 , wherein D is selected from the group consisting of isopropylidene, cyclopentylidene, cyclohexylidene, p-methoxybenzylidene, methoxymethylene, 2-oxacyclopentylidene, 2,3-dimethoxybutane-2,3-di-yl, 1,2-dimethoxycyclohexan-1,2-di-yl, octahydro-[2,2′]-bipyran-2,2′-di-yl, di-tert-butylsilylene, 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene), phenyl boronate, 3-pentylidene, 2,4-dimethyl-3-pentylidene, 2,6-dimethyl-4-heptylidene, 3,3-dimethyl-2-butylidene, 1-phenyl-1-ethylidene, benzylidene, 2,4-dimethoxybenzylidene, 4-nitrobenzylidene, 2,4,6-trimethylbenzylidene, 2,2-dimethyl-1-propylidene, ethoxymethylene or isopropoxymethylene.

8. The method according to claim 1 , wherein R 1 represents a hydroxyl protective group and R 2 represents hydrogen.

9. The method according to claim 2 , wherein R 3 represents hydrogen.

10. The method according to claim 1 , wherein step (b) comprises reacting compound (III) or (IV) with angelic acid in the presence of a coupling reagent or an enzyme.

11. The method according to claim 1 , wherein step (b) comprises reacting the compound of formula (III) or (IV) with angelic acid in the presence of a coupling reagent.

12. The method according to claim 1 , wherein step (b) comprises reacting the compound of formula (III) or (IV) with angelic acid in the presence of N,N′-Dicyclohexylcarbodiimide, N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate, N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide or 2-chloro-1-methyl-pyridinium iodide.

13. The method according to claim 1 , wherein step (b) comprises reacting the compound of formula (III) or (IV) with an activated derivative of angelic acid.

14. The method according to claim 1 , wherein step (b) comprises reacting the compound of formula (III) or (IV) with methyl angelate, angeloyl chloride, angelic acid anhydride, [(Z)-2-methylbut-2-enoyl]2,4,6-trichlorobenzoate, or angeloyl 4-nitrobenzoyl anhydride.

15. The method according to claim 1 , wherein step (b) comprises reacting the compound of formula (III) or (IV) with an angelic acid halide or with angelic acid anhydride or with a mixed angelic acid anhydride.

16. The method according to claim 1 , wherein step (b) comprises reacting the compound of formula (III) or (IV) with angeloyl chloride, angelic acid anhydride, [(Z)-2-methylbut-2-enoyl]2,4,6-trichlorobenzoate, or angeloyl 4-nitrobenzoyl anhydride.

17. A compound of general formula (V):

wherein R 1 represents hydrogen or a hydroxyl protective group and R 2 represents hydrogen or a hydroxyl protective group;

with the proviso that not both R 1 and R 2 represent hydrogen:

and with the proviso that R 1 and R 2 do not represent acetyl;

and with the proviso that R 1 and R 2 do not represent 2-[(2-aminobenzoyl)amino]benzoyl;

and with the proviso that R 1 does not represent decanoyl;

and with the proviso that R 1 does not represent 3-phenyl-2-propenoyl.

18. The compound according to claim 17 , wherein R 1 represents hydrogen or an ether, acetal, ketal, silylether, ester, carbonate, or a sulfenate derived hydroxyl protective group, and R 2 represents hydrogen or an ether, acetal, ketal, silylether, ester, carbonate, or a sulfenate derived hydroxyl protective group.

19. The compound according to claim 17 , wherein R 1 and R 2 independently represents hydrogen or [(3,4-dimethoxybenzyl)oxy]methyl, guaiacolmethyl, 2-methoxyethoxymethyl, tetrahydropyranyl, tetrahydrofuranyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, allyl, prenyl, p-methoxybenzyl, triphenylmethyl, 2-(trimethylsilyl)ethoxymethyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, tert-butyldiphenylsilyl, triphenylsilyl, chloroacetyl or phenoxyacetyl.

20. The compound according to claim 17 , wherein R 1 represents a hydroxyl protective group and R 2 represents hydrogen.

21. The compound according to claim 17 , wherein the compound is Ingenol-20-(tert-butyldimethylsilyl)-ether-3-angelate.

22. A compound of general formula (VI):

wherein D represents a dihydroxyl protective group; with the proviso that D does not represent isopropylidene.

23. A compound according to claim 22 , wherein D represents cyclopentylidene, cyclohexylidene, p-methoxybenzylidene, methoxymethylene, 2-oxacyclopentylidene, 2,3-dimethoxybutane-2,3-di-yl, 1,2-dimethoxycyclohexan-1,2-di-yl, octahydro-[2,2′]-bipyran-2,2′-di-yl, di-tert-butylsilylene, 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene), phenyl boronate, 3-pentylidene, 2,4-dimethyl-3-pentylidene, 2,6-dimethyl-4-heptylidene, 3,3-dimethyl-2-butylidene, 1-phenyl-1-ethylidene,benzylidene, 2,4-dimethoxybenzylidene, 4-nitrobenzylidene, 2,4,6-trimethylbenzylidene, 2,2-dimethyl-1-propylidene, ethoxymethylene or isopropoxymethylene.

24. The compound according to claim 22 , wherein the compound is ingenol-5,20-(di(tert-butyl)silylene)-ether-3-angelate.

25. A compound of general formula (III):

wherein R 1 and R 2 independently represents hydrogen or an ether, acetal, ketal, silylether, or a sulfenate derived hydroxyl protective group;

with the proviso that not both R 1 and R 2 represent hydrogen;

and with the proviso that R 1 does not represent triphenylmethyl;

and with the proviso that R 1 does not represent t-butyldimethylsilyl.

26. A compound of general formula IV:

wherein D represents cyclopentylidene, cyclohexylidene, p-methoxybenzylidene, methoxymethylene, 2-oxacyclopentylidene, 2,3-dimethoxybutane-2,3-di-yl, 1,2-dimethoxycyclohexan-1,2-di-yl, octahydro-[2,2′]-bipyran-2,2′-di-yl, di-tert-butylsilylene, 1,3-(1,1,3,3-tetraisopropyldisiloxanylidene), phenyl boronate, 3-pentylidene, 2,4-dimethyl-3-pentylidene, 2,6-dimethyl-4-heptylidene, 3,3-dimethyl-2-butylidene, 1-phenyl-1-ethylidene,benzylidene, 2,4-dimethoxybenzylidene, 4-nitrobenzylidene, 2,4,6-trimethylbenzylidene, 2,2-dimethyl-1-propylidene, ethoxymethylene or isopropoxymethylene.

27. The compound according to claim 26 , wherein the compound is selected from the group consisting of

Ingenol-5,20-(3-pentylidene)-ketal,

Ingenol-5,20-(2,4-dimethyl-3-pentylidene)-ketal,

Ingenol-5,20-(2,6-dimethyl-4-heptylidene)-ketal,

Ingenol-5,20-cyclopentylidene-ketal,

Ingenol-5,20-cyclohexylidene-ketal,

Ingenol-5,20-(3,3-dimethyl-2-butylidene)-ketal,

Ingenol-5,20-(1-phenyl-1-ethylidene)-ketal,

Ingenol-5,20-benzylidene-acetal,

Ingenol-5,20-(4-methoxybenzylidene)-acetal,

Ingenol-5,20-(2,4-dimethoxybenzylidene)-acetal,

Ingenol-5,20-(4-nitrobenzylidene)-acetal,

Ingenol-5,20-(2,4,6-trimethylbenzylidene)-acetal,

Ingenol-5,20-(2,2-dimethyl-1-propylidene)-acetal,

Ingenol-5,20-methyl-orthoformate,

Ingenol-5,20-ethyl-orthoformate,

Ingenol-5,20-(prop-2-yl)-orthoformate, and

Ingenol-5,20-(di(tert-butyl)silylene)-ether.

28. A compound of general structure (VII):

wherein R 3 represents hydrogen or angeloyl.