Method of producing ingenol-3-angelate
AssigneeLEO Laboratories Limited
InventorsThomas Högberg, Gunnar Grue-Sørensen, Xifu Liang, Anne Marie Horneman, Anders Klarskov Petersen
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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.
Claims28
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 R1 represents hydrogen or a hydroxyl protective group and R2 represents hydrogen or a hydroxyl protective group,
- with the proviso that R1 and R2 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 R1, R2 and D are as described above;
- and
- (c) removing the hydroxyl protective groups R1 or R2, or R1 and R2, or D from the compound of formula (V) or (VI) to obtain ingenol-3-angelate (I).
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 R3 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).
A compound of general formula (V):
- wherein R1 represents hydrogen or a hydroxyl protective group and R2 represents hydrogen or a hydroxyl protective group;
- with the proviso that not both R1 and R2 represent hydrogen:
- and with the proviso that R1 and R2 do not represent acetyl;
- and with the proviso that R1 and R2 do not represent 2-[(2-aminobenzoyl)amino]benzoyl;
- and with the proviso that R1 does not represent decanoyl;
- and with the proviso that R1 does not represent 3-phenyl-2-propenoyl.
A compound of general formula (VI):
- wherein D represents a dihydroxyl protective group;
- with the proviso that D does not represent isopropylidene.
A compound of general formula (III):
- wherein R1 and R2 independently represents hydrogen or an ether, acetal, ketal, silylether, or a sulfenate derived hydroxyl protective group;
- with the proviso that not both R1 and R2 represent hydrogen;
- and with the proviso that R1 does not represent triphenylmethyl;
- and with the proviso that R1 does not represent t-butyldimethylsilyl.
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.
A compound of general structure (VII):
- wherein R3 represents hydrogen or angeloyl.
Dependencies are inferred from the claim text.