Paclitaxel is a known antitumor drug with taxane structure, whose industrial preparation is particularly complex.
Paclitaxel was first isolated by extraction from the trunk barks of Taxus brevifolia, and it is at present synthesized starting from 10-deacetylbaccatin III, an intermediate present in the leaves of different species of taxus, particularly in those of Taxus baccata L., thereby overcoming the environmental problems connected with the availability of bark of T. brevifolia.
A number of synthetic methods are reported in literature: U.S. Pat. No. Re. 34,277 (reissue of U.S. Pat. No. 4,924,011) discloses the. semi-synthesis of Paclitaxel starting from 10-deacetylbaccatin III protected at the C-7 hydroxyl group with a trialkylsilyl group, in particular triethylsilyl, and at the 10-position with an acetyl group. In WO 98/08832, the protection of the C-7 hydroxyl group is carried out using a trichloroacetyl group. The thus protected baccatin III derivative is reacted with acetyl bromide and, subsequently, with the suitable phenylisoserine derivative to obtain Paclitaxel, following deprotection of the hydroxyl groups at 7 and 2′ and benzoylation of the amine.
In WO 93/06094, Paclitaxel is prepared by reacting a beta-lactam-type compound with 7-triethylsilyl-baccatin III. The desired product is obtained by deprotection in acid medium.
In U.S. Pat. No. 5,476,954, the synthesis of Paclitaxel is carried out starting from 10-deacetylbaccatin III, protecting the C-7 hydroxyl with 2,2,2-trichloroethoxycarbonyl(Troc) and the C-10 hydroxyl with Troc or with an acetyl group.
It is therefore evident that the critical step for the synthesis of Paclitaxel is the selective esterification at C-7 with a group easily and selectively removable. Until now, 7-triethylsilyl-deacetylbaccatin III has been considered the key intermediate. The yield reported for the derivatization of 10-deacetylbaccatin III to 7-triethylsilyl-10-deacetylbaccatin III is about 85%, using 5 to 20 mols of silylating agent. The yield of the subsequent acetylation to give 7-triethylsilylbaccatin III is also about 85%.
U.S. Pat. No. 5,621,121 and U.S. Pat. No. 5,637,723 disclose the synthesis of taxanes, including Paclitaxel, by reacting suitably protected baccatin III or 10-deacetylbaccatin III with oxazolidine-5-carboxylic acids bearing at the 2-position a phenyl group substituted with alkoxy groups (U.S. Pat. No. 5,621,121) or with trihaloalkyl groups, in particular trichloromethyl (U.S. Pat. No. 5,637,723), followed by deprotection by opening of the oxazolidine ring.
The protective groups considered particularly suitable comprise silyl, 2,2,2-trichloroethoxycarbonyl or 2-(2 (trichloromethyl)propoxy)carbonyl groups.
Substantially the same methods can also be used for the preparation of Docetaxel, another known taxan derivative widely used in clinics.
It has now been found a process for the preparation of taxanes, in particular Paclitaxel and Docetaxel, which attains higher yields than the known methods.
USPTO Backgrounds
USPTO Backgrounds