Method of isolating ingenol

Patent metadata

Field	Value
Publication number	US-2016039733-A1
Application number	US-201514922581-A
Country	US
Kind code	A1
Filing date	Oct 26, 2015
Priority date	Oct 4, 2011
Publication date	Feb 11, 2016
Grant date	—

Abstract

The present invention relates to a new method for isolating ingenol (C 20 H 28 O 5 ) from mixtures of diterpenoid esters and ingenol esters in a single step. Ingenol isolated by means of this method can be used as a precursor for the synthesis of biologically active ingenol derivatives, such as ingenol-3-angelate and ingenol-3-tigliate.

First claim

1 . A method of isolating ingenol from plant material, said method comprising:
a) subjecting said plant material to mechanical stirring in a solution of sodium methylate in methanol to obtain a solution containing hydrolyzed ingenol; b) extracting from the preceding solution a fraction containing ingenol with an acidified water and an organic solvent solution to obtain a fraction contain ingenol; and c) optionally purifying the ingenol to provide an isolated ingenol.

2 . The method according to claim 1 , wherein the plant material are Euphorbia lathyris seeds.

3 . The method according to claim 1 , wherein the concentration of sodium methylate in methanol is 0.20 N and the time for which the seeds are subjected to mechanical stirring is 4 hours.

4 . The method according to claim 1 , further comprising filtering or suctioning on celite the solution obtained in step a).

5 . The method according to claim 1 , wherein the acidified water solution consists of a combination of 2N H 2 SO 4 and H 2 O plus NaCl at 35% weight/volume at a ratio of 1:1.

6 . The method according to claim 1 wherein the step of purifying ingenol is performed by means of gravity column chromatography.

7 . The method according to claim 6 , wherein a silica gel column is used as a stationary phase with a petroleum ether-ethyl acetate as a mobile phase.

8 . The method according to claim 1 , wherein the purified isolated ingenol is subjected to an additional process of partial chemical synthesis to produce a derivative at position 3 selected from: ingenol-3-tigliate, ingenol3-angelate or mixtures thereof.

9 . The method according to claim 8 , wherein the additional process of partial chemical synthesis for obtaining ingenol derivatives at position 3 to which the purified isolated ingenol is subjected has ingenol-5,20-acetonide as the common intermediate.

Assignees

• Indena Spa

Inventors

• Bellido Cabello De Alba Maria Luz
• Appendino Giovanni
• Pagani Alberto
• Munoz Blanco Eduardo

Classifications

• C07C45/78 Primary

  Separation; Purification; Stabilisation; Use of additives · CPC title

• C07C67/08

  by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds · CPC title

• C07C45/85 Primary

  by treatment giving rise to a chemical modification (by chemisorption C07C45/79) · CPC title

• B01D15/08

  Selective adsorption, e.g. chromatography · CPC title

• C07D319/08

  condensed with carbocyclic rings or ring systems · CPC title