Semi-synthetic conversion of paclitaxel to docetaxel

Abstract

A process is provided for the semi-synthesis of taxane derivatives useful in the preparation of docetaxel, in particular, the semi-synthesis of protected taxane derivatives in a one pot reaction of protecting the C-2′, C-7 and C-10 and introducing a t-Boc group at the nitrogen of the amide group at the C-3′ position in paclitaxel and subsequently conversion to docetaxel, and derivatives used therein.

Description

CROSS-REFERENCE TO RELATED APPLICATION [0001] This application is a continuation of U.S. patent application Ser. No. 10 / 881,711 filed Jun. 29, 2004, now pending, which application is incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] The present invention relates to a semi-synthesis of taxane derivatives useful in the preparation of docetaxel, from pure or crude paclitaxel or related taxane starting material, in particular, the semi-synthesis of protected taxane derivatives in a one pot reaction and its conversion to docetaxel. [0004] 2. Description of the Related Art [0005] The taxane family of terpenes has received much attention in the scientific and medical community because the members of this family have demonstrated broad spectrum anti-leukemic and tumor-inhibitory activity. Docetaxel (1, Taxotere), a semi-synthetic analog, and paclitaxel (2, Taxol), a complex diterpene isolated from the bark of the Pacific yew...

AI Technical Summary

Benefits of technology

[0012] The present invention provides a simple process for conversion of paclitaxel or a paclitaxel-containing material to its synthetic analog—docetaxel. Accordingly, one embodiment of the present invention provides a process for producing a taxane intermediate under mild conditions using a pure or partially purified paclitaxel or a paclitaxel analog as a starting material, the taxane intermediate can later be used as a precursor to docetaxel. The process comprises protecting a compound of Formula (I): wherein, R1 is alkyl, alkenyl or aryl; and X, Y and Z are the same or different and independently hydroxy or protected hydroxy. In particular, the process comprises: protecting one or more hydroxy groups at the C-2′, C-7 and C-10 positions of the taxane; and introducing a t-Boc group at the nitrogen of the amide group at the C-3′ position of the taxane to provide a C-2′, C-7, C-10 and N-t-Boc protected paclitaxel derivative, wherein the steps of protecting one or more hydroxy groups and introducing the t-Boc group comprises combining, in a one pot reaction, the taxane with a hydroxy protecting group and a t-Boc agent.

[0020] In addition, the present invention provides a simplified and efficient process for preparing docetaxel from an initial mixture of taxanes, wherein the initial mixture comprises paclitaxel and at least one additional taxane selected from the group of 10-deacetylbaccatin III, 9-dihydro-13-acetylbaccatin III, baccatin III, cephalomannine, 10-deacetyl taxol, 7-xylosyl taxol and 10-deacetyl-7-xylosyl taxol, the process comprising the steps of: protecting the hydroxy groups at the C-2′ and C-7 positions of paclitaxel; introducing a t-Boc group at the nitrogen of the amide group at the C-3′ position of paclitaxel to provide a protected paclitaxel derivative having an urea linkage at the C-3′ position; selectively removing the benzoyl group from the urea linkage to provide a protected docetaxel; and converting the protected docetaxel to docetaxel by removing the hydroxy-protecting groups at the C-7, C-2′ and C-10 positions, wherein the step of protecting the hydroxy groups at C-2′ and C-7 positions, and introducing a t-Boc group at the nitrogen site of the amide group of paclitaxel are carried out in a one pot reaction wherein the mixture containing paclitaxel is combined with a hydroxy protecting agent and a t-Boc agent; and wherein the step of selectively removing the benzoyl group comprises subjecting the protected paclitaxel derivative having the urea linkage to a first base.

Problems solved by technology

However, the above methods thus far developed involve subjects such as reaction under the conditions of extremely low temperatures, generation of diastereomers, use of asymmetry controlling agents, and the reaction under strongly alkaline conditions, which cause problems upon the industrialization thereof.

Images