Numerous Ferula genus plants contain terpenes with estrogenic activity, known also as phytoestrogens, i.e. substances which regulate hormonal functions and are apparently a valid alternative to the use of synthetic hormones in the treatment of pre-menstrual syndrome and disorders related to menopause and aging. Extracts of some types of Ferula were used in ancient times as contraceptives and in the treatment of impotence and menopausal disorders. Recently, alcoholic extracts from Ferula asafoetida L. have been disclosed (WO 0230438) as anticancer drugs.
The most abundant compounds in Ferula genus plants are derivatives of jaeschkenadiol (II):
in particular daucane esters having the general formula (I)

Daucane esters are known compounds and are for example disclosed in Phytochemistry, vol. 37, n° 3, pages 597-623, 1994. In the formula (I) R is a straight or branched, saturated or unsaturated aliphatic acyl residue, or an optionally substituted aromatic acyl residue. Examples of R groups are iso-valeroyl, angeloyl, benzoyl, p-hydroxybenzyl, veratroyl or cinnammoyl.
Daucane esters from Ferula spp are estrogen modulators similar to SERMs (selective estrogen receptor modulators); among them, ferutinine (Ia) shows marked estrogenic activity, whereas the others have a rather mild activity.

In particular, ferutinine is an estrogen receptor alpha agonist (ERα) and an estrogen receptor beta agonist/antagonist (ERβ). It has also been shown that ferutinine has higher binding to estrogen receptors than tamoxifen.
There is therefore the need to obtain ferutinine-enriched extracts or optimise the extraction of ferutinine in the pure form from plant materials containing its precursors.
A process comprising the hydrolysis of a daucane esters whole extract to give crude jaeschkenadiol and the subsequent re-esterification of jaeschkenadiol with suitably protected p-hydroxybenzoic acid, for example with p-acetoxybenzoic acid, is known from the literature (J. Org. Chem. USSR (Engl. Transl.); EN; 28; 10; 1992; 1666-1673). Nevertheless, this process gives rather poor yields (about 45%), mainly due to competitive transesterification reactions.
USPTO Backgrounds
USPTO Backgrounds