Method of isolating ingenol

Patent metadata

Field	Value
Publication number	US-9416083-B2
Application number	US-201514922581-A
Country	US
Kind code	B2
Filing date	Oct 26, 2015
Priority date	Oct 4, 2011
Publication date	Aug 16, 2016
Grant date	Aug 16, 2016

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

The invention claimed is:

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 consisting of a glacial acetic acid or perchloric acid at a concentration of 0.03 M and an organic solvent solution to obtain a fraction containing ingenol; and
c) optionally purifying the ingenol to provide an isolated ingenol, wherein said plant material are Euphorbia lathyris seeds.

2. 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.

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

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

5. The method according to claim 4 , wherein a silica gel column is used as a stationary phase with a petroleum ether-ethyl acetate as a mobile phase.

6. 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, ingenol-3-angelate or mixtures thereof.

7. The method according to claim 6 , 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

• C07C67/60

  by treatment giving rise to chemical modification (by chemisorption C07C67/56) · CPC title

• C07C45/65 Primary

  by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups · CPC title

• C07C49/727

  a keto group being part of a condensed ring system · CPC title

• C07D319/08

  condensed with carbocyclic rings or ring systems · CPC title

• C07C45/80

  by liquid-liquid treatment · CPC title