Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2001-06-27
2003-11-25
Richter, Johann (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C562S401000
Reexamination Certificate
active
06653501
ABSTRACT:
FIELD OF THE INVENTION
The present invention generally relates to the preparation of compounds useful in the semi-synthesis of taxanes. More particularly, the present invention is directed to the chiral resolution of mixtures of optical isomers to provide a target chiral compound that can be used as a C-13 side chain precursor to produce paclitaxel and other taxanes. The present invention specifically provides a chromatographic process for separating a target chiral compound from its enantiomer in a racemic mixture thereof.
BACKGROUND OF THE INVENTION
Various taxane compounds are known to exhibit anti-tumor activity. As a result of this activity, taxanes have received increasing attention in the scientific and medical community. Primary among these is a compound known as “paclitaxel” which is also referred to in the literature as “taxol”. Paclitaxel has been approved for the chemotherapeutic treatment of several different varieties of tumors, and the clinical trials indicate that paclitaxel promises a broad range of potent anti-leukemic and tumor-inhibiting activity.
Paclitaxel is a naturally occurring taxane diterpenoid which is found in several species of the yew (genus Taxus, family Taxaceae). Unfortunately, the concentration of this compound in the yew is very low, and the species of evergreen are also slow growing. Even though the bark of the yew trees typically exhibits the highest concentration of paclitaxel, the production of one kilogram of paclitaxel requires approximately 16,000 pounds of bark. Thus, the long-term prospects for the availability of paclitaxel through isolation are discouraging.
While the presence of paclitaxel in the yew tree is in extremely low concentrations, there are a variety of other taxane compounds, such as baccatin III, cephalomanine, 10-deacetylbaccatin III, etc., which are also able to be extracted from the yew bark and leaves. Some of these other taxane compounds are more readily extracted in higher yields. Indeed, a relatively high concentration of 10-deacetylbaccatin III can be extracted from the leaves of the yew as a renewable resource.
Accordingly, attention has turned to the semi-synthesis of paclitaxel, which has the formula:
as well as other related taxanes, such as docetaxel, which has the formula:
from precursor compounds. In order to successfully synthesize paclitaxel and other taxanes, convenient access to a chiral, non-racemic side chain acid is desired, as well as an abundant natural source of a usable baccatin III backbone. Various approaches have been developed for esterifying such a side chain acid at the 13-hydroxyl of baccatin III or 10-deacetyl baccatin III, or derivatives thereof, which respectively have the formulas:
The coupled ester product may then be converted to paclitaxel, docetaxel or other taxanes. For example, U.S. Pat. No. 4,924,011 to Denis et al. describes a process for preparing paclitaxel using a (2R,3S) side chain acid of the general formula:
where R
2
is a hydroxy-protecting group. Additionally, U.S. Pat. No. 4,924,012 to Colin et al. describes a process for preparing taxanes, such as docetaxel, that uses an acid of formula:
where R
1
is a hydroxy-protecting group. In the syntheses described by Denis et al. and Colin et al., the side chain acid is esterified with a baccatin III or 10-deacetyl baccatin III derivative, and the coupled product is thereafter deprotected, such as by replacing any protecting groups, including R
2
or R
1
in the above formulas, respectively, with hydrogen. It should be noted that the C
6
H
5
CONH— group of Denis et al. and the (CH
3
)
3
COCONH— group of Colin et al. are the final desired groups for the resulting paclitaxel and docetaxel products, respectively, such that no further chemical transformation at the nitrogen position is performed in the chemical syntheses disclosed therein.
U.S. Pat. No. 5,770,745 to Swindell et al. describes another early synthetic route in the semi-synthesis of paclitaxel, wherein the use of protecting groups to protect various positions of the taxane backbone and the side chain acid was investigated as a means of improving the chemical process to form paclitaxel, and of improving the esterification step in particular. Specifically, a side chain acid of the general formula:
is described, wherein R
1
can be an alkyl, olefinic or aromatic group (such as PhCH
2
), R
3
can be hydrogen or Ph, and P
1
can be a hydroxyl protecting group.
More recently, attention has been focused on the use of a 3-N-CBZ-2-O-protected (2R,3S)-3-phenylisoserine acid of the formula:
wherein P
1
is a hydrogenatable protecting group, such as benzyloxymethyl (BOM) or benzyl. Synthetic routes to produce taxanes such as paclitaxel or docetaxel using such a side chain are described, for example, in U.S. Pat. Nos. 5,675,025; 5,684,175; 5,688,977; 5,750,737; 5,939,566; 5,948,919; 5,973,170; 6,048,990; 6,066,749; 6,072,060; 6,107,497; 6,133,462; 6,136,999; and 6,143,902, and the teachings thereof are incorporated herein by reference.
As taught, for example, in U.S. Pat. No. 5,684,175 to Sisti et al., the 3-N-CBZ-2-O-protected (2R,3S)-3-phenylisoserine may be produced from a (2R,3S)-3-phenylisoserine ethyl ester starting compound of the formula:
which may be protected at the 3′-N and 2′-O positions and saponified to the corresponding acid for use in the esterification step.
The formation of a 3-phenylisoserine alkyl ester is known in the art and is described, for example, in U.S. Pat. No. 4,924,012 to Colin et al. In particular, Colin et al. describes an epoxide of the formula:
where R
4
denotes alkyl containing 1 to 4 carbon atoms, and preferably ethyl, which may be obtained under the conditions described by F. W. Bachelor and R. K. Bansal, J. Org. Chem., 34, 3600-04 (1969). This epoxide is converted to an azide of general formula:
according to known methods for opening an epoxide by means of sodium azide in ethanol in the heated state. The azide is thereafter reduced to a 3-phenylisoserine alkyl ester of the formula:
However, because this compound has two chiral centers (C-2 and C-3, respectively), processes to produce this compound may produce both the cis (2R,3S) and (2S,3R) enantiomers respectively, such as of the formulas:
as well as their trans (2R,3R) and (2S,3S) diastereomers respectively of the formulas:
It should be appreciated that the above optical isomers are shown using an ethyl group for R
4
in the formulas above, although other alkyl esters as described in Colin et al. may be formed. Additionally, various other derivatives or analogs of these optical isomers may be formed in the processes to produce the paclitaxel side chain, in view of the teachings of the above-identified patents, as would be understood by the ordinarily skilled person.
While baccatin III and derivatives thereof may be used as a resolving agent to selectively recover products having the desired (2R,3S) configuration, such an approach is quite costly and results in a substantial yield reduction of the desired product. Accordingly, efficient and economical methods are needed for recovering a desired (2R,3S) isomer or a derivative thereof at one or more points in the chemical processes for synthesizing taxanes.
One procedure to prepare the chiral (2R,3S) C-13 side chain of paclitaxel is described by Srivastava and McChesney, “A Practical and Inexpensive Synthesis of the Taxol C-13 Side Chain; N-Benzoyl-(2R,3S)-3-Phenylisoserine”, Natural Products Letters, Vol. 6, p. 147 (1995). This procedure involves the classical resolution of cis-3-phenylglycidic acid using D-(+)-ephedrine as the resolving agent. In particular, an optically pure cis-(2R,3R)-3-phenylglycidic acid-(+)-ephedrine salt of the formula:
is recovered from a mixture of diastereomeric salts by fractional crystallization with acetone. The optically pure intermediate is then converted to a 3-phenylisoserine derivative. Additional classical resolutions of side chain derivatives useful in paclitaxel synthesis have been described in U.S. Pat. No. 6,025,516 to Ramaswamy et al. and in U.S. Pat. No. 5,
Baehr David
Brinkman Herbert R.
McChesney James D.
Zegar Siead
Gegick Rebecca A.
Henson Michael R.
Martin Timothy J.
NaPro BioTherapeutics, Inc.
Richter Johann
LandOfFree
Chiral resolution method for producing compounds useful in... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Chiral resolution method for producing compounds useful in..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Chiral resolution method for producing compounds useful in... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3155779