Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-09-21
1998-03-03
Trinh, Ba K.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
549511, C07D30514
Patent
active
057236356
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/FR 94/0030, dated Mar. 18, 1994.
The present invention relates to a process for the purification of taxoids by centrifugal partition chromatography.
More especially, the present invention relates to a process for the purification of Taxotere and of 10-deacetylbaccatin III.
10-Deacetylbaccatin III extracted from yew leaves is useful in the preparation of Taxotere under the conditions described, for example, in European Patents EP 0,253,738 or EP 0,336,841 or in International PCT WO 92/09,589.
10-Deacetylbaccatin III obtained by extraction of yew leaves contains, depending on the species from which it originates, impurities which are chiefly products belonging to the taxoid family, such as, for example, 2.alpha.-benzoyloxy-4-acetoxy-5.beta.,20-epoxy-1.beta.,7.beta.,10.beta.,13 .alpha.,19-pentahydroxy-9-oxo-11-taxene, 2.alpha.-benzoyloxy-4-acetoxy-5.beta.,20-epoxy-1.beta.,7.alpha.,10.beta.,1 3.alpha.-tetrahydroxy-11-taxene or taxins.
Taxotere which is obtained by partial synthesis from 10-deacetylbaccatin III contains as chief impurities the esterification products of the impurities contained in 10-deacetylbaccatin III, as well as other impurities originating, for example, from the epimerization of the carbon at position 2' of the side chain.
10-Deacetylbaccatin III and Taxotere itself may generally be purified by liquid chromatographic methods on a column, and more especially by high performance liquid chromatography (HPLC) on a silica column. However, while these methods are especially well suited to the purification of a few tens of grams, their industrial extrapolation comes up against constraints, such as the quantity of solvents consumed and the handling and destruction of the (silica) support contaminated by toxic residues, which become paramount.
In the case of taxoids which constitute products whose toxicity is often very high and whose lability is great, it is especially important to have the possibility of using purification methods which have good productivity, which do not require a solid support which is expensive to buy, use and destroy, which require the use of small quantities of solvents and which can be readily automated to permit continuous production.
It has now been found, and this forms the subject of the present invention, that the purification of taxoids, and more especially the purification of Taxotere and of 10-deacetylbaccatin III, may be achieved by carrying out centrifugal partition chromatography (CPC) or high speed countercurrent chromatography, the principle of which is described, for example, by A. Foucault and P. Rosset, Analusis, 16 (3), 157-167 (1988).
Centrifugal partition chromatography makes it possible to effect partition of the constituents of the mixture to be separated between two immiscible liquid phases, by establishing successive equilibria produced in a logical manner and automatically.
This method is characterized by a very efficient partition mechanism, a strong retention of the stationary phase and a high speed of the mobile phase, leading to excellent separations in a few hours.
Centrifugal partition chromatography requires the use of two or more solvents supplying 2 partially miscible phases. Although there is an unlimited number of solvents displaying this feature, it is especially important industrially to use non-chlorinated and non-toxic industrial solvents. Among solvents which may be used industrially incurring lower risks, alcohols such as methanol, ethers such as methyl t-butyl ether, esters such as ethyl acetate, ketones such as methyl isobutyl ketone and aliphatic hydrocarbons such as heptane or isooctane may be mentioned.
To carry out an efficient purification, it is necessary to choose a mixture of solvents whose rapid and complete separation yields two phases for which the partition coefficient is between 0.1 and 10, and preferably between 0.5 and 5, and still more especially in the vicinity of 1.
A product for which the partition coefficient (K) is, for example, equal to 10 is 10 times more soluble in the upper
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Durand Andre
Gerbaud Alain
Margraff Rodolphe
Rhone-Poulenc Rorer S.A.
Trinh Ba K.
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