Process for making taxane derivatives

Details Process for making taxane derivatives Process for making taxane derivatives

2001-03-23

2003-03-11

Trinh, Ba K. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S510000, C549S511000

Reexamination Certificate

active

06531611

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a novel semi-synthetic method of producing the cancer drug, Paclitaxel. The method employs a unique method of obtaining unsaturated derivatives by the use of activated oxazoles which can subsequently be hydrolyzed to taxane derivatives useful in an oxidative-rearrangement procedure producing Paclitaxel. The method has the potential to be useful in the synthesis of a variety of novel taxane derivatives.
2. Description of the Related Art
The semi-synthesis of taxanes from 10-deacetyl baccatin III (“10-DAB III”) has been actively pursued for several years. The first synthesis was demonstrated by Greene et. al.
1
but was inefficient in that a large excess of the costly side-chain was used, low yields were obtained and epimerization of the 2′-position was a problem. Holton, et. al.
2
demonstrated a more efficient synthesis utilizing cyclic amide derivatives. This synthesis is being used commercially by Bristol-Myers Squibb. Rhone-Poulenc Rorer showed an efficient synthesis of taxotere and Paclitaxel employing specific cyclic acetal derivatives
3
. Finally, Bristol-Myers demonstrated an efficient synthesis using oxazoline derivatives
4
. A number of other syntheses have been described but are of lesser value. While a number of the above routes are quite efficient, they do not allow for the ready formation of other taxane derivatives from an advanced common intermediate as is the case in our synthesis. The specific side-chain amide must be formed at the start of the synthesis.
The present inventors sought a method that would produce a variety of useful taxane derivatives from a common intermediate. Our initial interest was sparked by a method published by Kingston et.al.
5
. It was thought that if we could discover a novel, efficient method of producing these intermediates, we would be able to develop a commercial synthesis capable of producing a number of valuable taxanes. This present invention accomplishes our goal. Likewise, we have found the Kingston conditions to be rather ineffective and we have had to considerably modify them to obtain the desired results.
SUMMARY OF THE INVENTION
An efficient method of production of Paclitaxel has been invented. The method involves the production of an unique phenylisoserine derivative which is then reacted with a suitably blocked Baccatin III derivative to produce a taxane substrate which may be elaborated into Paclitaxel and other potentially useful taxane derivatives. The invention is disclosed in greater detail as follows.
Other objects and features of the present invention will become apparent from the following detailed description considered in conjunction with the accompanying drawings. It is to be understood, however, that the drawings are designed solely for purposes of illustration and not as a definition of the limits of the invention, for which reference should be made to the appended claims. It should be further understood that the drawings are not necessarily drawn to scale and that, unless otherwise indicated, they are merely intended to conceptually illustrate the structures and procedures described herein.


REFERENCES:
patent: 5470866 (1995-11-01), Kingston et al.
patent: 5476954 (1995-12-01), Bourzat et al.

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