Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-04-25
2002-09-17
Trinh, Ba K. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S511000
Reexamination Certificate
active
06452025
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to the production of the anti-neoplastic compound paclitaxel. More particularly, the present invention is directed to the production of paclitaxel from a protected coupled ester intermediate, which may be formed by esterifying a protected baccatin III backbone with a suitably protected side chain acid. In particular, the present invention relates to the production of paclitaxel by esterifying 7-CBZ baccatin III with a 3-N-CBZ-2-O-protected-(2R,3S)-3-phenylisoserine to produce a protected coupled ester intermediate that may thereafter be deprotected and N-benzoylated to produce paclitaxel.
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 has the formula:
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 exhibit 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 from precursor compounds. In order to successfully synthesize paclitaxel, convenient access to a chiral, non-racemic side chain acid and an abundant natural source of a usable baccatin III backbone as well as an effective means of joining the two are necessary. However, the esterification of the side chain acid to the protected baccatin III backbone is difficult because of the steric hindrance of the 13-hydroxyl which is located in the baccatin III backbone within the concave region of the hemispherically shaped baccatin III skeleton.
Some early synthetic routes in the semi-synthesis of paclitaxel are described, for example, in U.S. Pat. No. 5,770,745 to Swindell et al. 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.
One technique for the semi-synthesis of paclitaxel is found in U.S. Pat. No. 5,750,737 to Sisti et al. As discussed therein, paclitaxel can be synthesized by joining 7-CBZ baccatin III of the formula:
(where CBZ is the “benzyloxycarbonyl” group, —CO
2
CH
2
Ph), with 3-N-CBZ-2-O-protected (2R,3S)-3-phenylisoserine of the formula:
where the 2-hydroxyl is protected by a hydrogenatable benzyl-type group P
1
such as benzyloxymethyl (BOM) or benzyl. 7-CBZ baccatin III may be formed through the synthesis and use of 7-metal alkoxide intermediates and analogs of baccatin III, as described, for example, in U.S. Pat. Nos. 5,750,737 and 5,973,170 to Sisti et al. The production of the 3-N-CBZ-2-O-protected (2R,3S)-3-phenylisoserine is taught, for example, in U.S. Pat. No. 5,684,175 to Sisti et al.
Following the esterification of the protected baccatin III with the protected side chain to form a protected coupled ester of the formula:
the compound may be suitably deprotected, acylated, and further deprotected to yield paclitaxel. Specifically, the CBZ protecting groups at the 7-O and 3′-N positions are removed, a benzoyl group is added at the 3′-N position and the 2′-O-protecting group is removed. U.S. Pat. No. 5,750,737 describes a deprotection and acylation sequence involving various steps to arrive at the final desired product. In particular, that patent teaches the use of work-ups involving recovery and purification steps (such as filtration, reduction to residue under vacuum, organic phase separation, and the like) in between the various steps. Furthermore, the hydrogenolysis of the coupled ester with Pearlman's catalyst as described therein could take about one day to proceed to completion of the deprotection at the 7-O and the 3′-N positions by removal of the two CBZ groups. Additionally, after benzoylation of the 3′-amino group, the hydrogenolysis of the 2′-O-BOM paclitaxel took several days to complete, and included catalyst replacement as well as isolation and purification of the 2′-O-BOM paclitaxel intermediate. Additionally, factors such as preliminary purification of the 2′-O-BOM-paclitaxel intermediate as well as change of the catalyst and reaction medium contribute to high cost of the hydrogenation process.
While the existing techniques for synthesizing paclitaxel certainly have merit, there is still a need for improved chemical processes that can produce this anti-cancer compound and intermediates useful in the synthesis and semi-synthesis thereof. In particular, it is desirable to provide efficient processes requiring shorter times and fewer steps while still providing acceptable yields in the semi-synthesis of paclitaxel. Accordingly, the present invention is directed to an improved synthesis of paclitaxel or other taxanes from a protected coupled ester intermediate. The present invention teaches a new, useful and more efficient method for the conversion of the protected coupled ester to paclitaxel that may be performed in a single reaction vessel.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a new and useful method for synthesizing paclitaxel.
It is another object of the present invention to provide new intermediate compounds useful in the production of paclitaxel.
It is a further object of the present invention to produce a protected coupled ester of the formula:
wherein P
1
is a hydrogenatable protecting group, such as a benzyl, substituted benzyl, benzyloxymethyl or benzoyl group, which may then be deprotected, and N-acylated and further deprotected to yield paclitaxel.
It is yet another object of the present invention to provide methods for producing paclitaxel which are simplified and which may be suitable for large scale production of paclitaxel for anti-neoplastic applications.
It is yet another object of the present invention to improve the efficiency of the hydrogenolytic conversion of a protected coupled ester to paclitaxel.
It is yet another object of the present invention to convert a protected coupled ester to paclitaxel in a single vessel without isolation or purification of a 2′-O-protected paclitaxel intermediate.
According to the present invention, then, a method is provided of producing paclitaxel from a protected coupled ester compound having a formula:
wherein P
1
is a hydrogenatable protecting group, such as a benzyl, substituted benzyl, benzyloxymethyl, or benzoyl group. The method comprises the steps of deprotecting 7-O-position and 3′-N-position of the protected coupled ester compound to form a first intermediate compound having a formula:
benzoylating said first intermediate compound at the 3′-nitrogen position thereby to form a second intermediate compound having the formula:
and deprotecting said second intermediate compound by replacing
McChesney James D.
Zygmunt Jan
Henson Michael R.
Martin Timothy J.
NaPro BioTherapeutics, Inc.
Trinh Ba K.
Weygandt Mark H.
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