Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-07-05
2002-12-17
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
06495705
ABSTRACT:
FIELD OF THE INVENTION
The present invention generally relates to the purification of a biomass extract to form useful materials. More particularly, the present invention is directed to the conversion of unwanted taxanes in a biomass extract to taxanes that can be used in the synthesis of paclitaxel. Specifically, the present invention relates to the conversion of unwanted taxanes into 10-deacetyl baccatin III, a useful precursor in the formation of 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, including refractory ovarian and metastatic breast cancers. Clinical trials, including those for the treatment of lung, head, neck and other cancers, indicate that paclitaxel promises a broad range of potent anti-leukemic and tumor-inhibiting activity. Further development of this pharmaceutical lead and identification of its superior analogs is crucial to continued advancement of cancer chemotherapy.
Paclitaxel has the formula and numbering as follows:
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 is very low. The species of evergreen yew 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.
Accordingly, numerous efforts have been directed to the partial synthesis of paclitaxel from closely related precursor compounds. 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, cephalommanine, 10-deacetyl baccatin III, etc., which are also able to be extracted from the yew. Some of these other taxane compounds are more readily extracted in higher yields.
In order to successfully synthesize paclitaxel, convenient access to a chiral, non-racemic side chain 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 to the protected baccatin III backbone is difficult because of the sterically hindered C-13 hydroxyl in the baccatin III backbone which is located within the concave region of the hemispherical protected baccatin III skeleton. Techniques have been developed for the partial synthesis of paclitaxel from the naturally occurring diterpenoid substances baccatin III and closely related 10-deacetyl baccatin III (“10-DAB III”), which accordingly have become important precursors for use in synthetic routes to paclitaxel. Baccatin III and 10-DAB III have the formulas as follows:
10-DAB III is more abundant in nature than is baccatin III. Indeed, a relatively high concentration of 10-DAB III can be extracted from the leaves of the yew as a renewable resource. Co-occurring with paclitaxel, baccatin III and 10-DAB III in biomass are several closely related taxanes containing the same diterpenoid structure element of baccatin III or 10-DAB III. They are removed as side stream products during usual purification procedures for paclitaxel or 10-DAB III. These side stream products include cephalomannine, nitine, taxol C, 7-xylosyl taxols, 10-deacetyl taxol, and several other taxanes and non-taxanes. As shown in Table 1, many of these taxanes have the same general backbone structure as follows:
TABLE 1
Product
R
1
R
2
CEPHALOMANNINE
tigloyl
Ac
NITINE
phenyl acetyl
Ac
TAXOL C
hexanoyl
Ac
10-DEACETYL TAXOL
benzoyl
H
Although these side stream products have general structures similar to the structures of paclitaxel, baccatin III and 10-DAB III, they are currently left over as unusable waste products of the purification processes for paclitaxel or 10-DAB III. Accordingly, it would be desirable to convert such leftover side stream products into usable materials for paclitaxel synthesis, thereby to increase the availability of this important anti-cancer agent.
Only a few methods have been reported for the selective hydrolysis of the various ester groups present in paclitaxel. Magri et al have reported on the selective reductive cleavage of the C-13 side chain of paclitaxel, using tetrabutyl ammonium borohydride (Journal of Organic Chemistry, 1986, 51, 3239-3242). U.S. Pat. Nos. 5,202,448 and 5,256,801 to Carver et al. teach the conversion of partially purified taxane mixtures into baccatin III and 10-DAB III using a borohydride reducing salt in the presence of a Lewis acid.
The selective hydrolysis of the benzoate group at C-2 has been achieved by three research groups. In one method by Chen et al, a 7,13-diprotected baccatin III with Red-AI afforded the corresponding 2-debenzoylated derivative in 78% yield (Bioorg. Med. Chem. Lett. 1994, 4, 479-482). In another method, reported by Chaudhary et al, hydrolysis of 2′,7-diprotected paclitaxel with NaOH under phase transfer conditions formed the corresponding 2-debenzoylpaclitaxel derivative in moderate yield (J. Am. Chem. Soc., 1994,116, 4097). In a third method, reported by Datta et al, selective deesterification of baccatin III derivatives at C-2 and C-4 was achieved in 69% and 58% yields respectively with potassium tert-butoxide as base (J. Org. Chem., 1994, 59, 4689-4690).
Appurba Datta, Michael Hepperle, and Gunda I. Georg have also reported, in J. Org. Chem, 1995, 60, 761-63, selective deesterification processes to remove the C-10 and C-13 ester functionalities of pure cephalomannine and paclitaxel by hydrazinolysis. That work was encouraged by a recognition that both ammonia and hydrazine are used for the removal of ester groups under mild conditions wherein acetates are preferentially cleaved over benzoate groups. Datta, Hepperle and Georg reported that a solution of paclitaxel in 95% ethanol that was treated with hydrazine monohydrate at room temperature for two hours yielded 10-DAB III as the only product obtained. The 10-DAB III product was formed by cleavage of the ester linkages of paclitaxel at C-10 and C-13. Datta, Hepperle and Georg extended this reaction to a National Cancer Institute mixture of mainly paclitaxel and cephalomannine with some other minor impurities, which cleanly yielded 10-DAB III when reacted with hydrazine monohydrate. The reactions reported by Datta, Hepperle and Georg utilizing a hydrazine monohydrate solution in 95% ethanol were at a pH of about 10, such that the hydrazine monohydrate, a strong base, is reactive to cleave ester groups similarly to other basic nucleophiles.
However, there remains a need to provide simple and efficient methods to convert sidestream products from extraction processes, which generally result in highly acidic biomass extracts, into usable products such as 10-DAB III. In particular, there remains a need for a process to convert a complex mixture of taxanes, such as one containing cephalomannine, 10-deacetyl taxol, baccatin III and several other taxanes in a relatively unpurified or partially purified form, to 10-DAB III which can be purified and utilized for semi-synthesis purposes to synthesize paclitaxel and its analogs. The present invention is directed to meeting these needs.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a new and useful process for the conversion of sidestream products from taxane extraction processes into usable products for paclitaxel synthesis.
It is another object to provide a simple and efficient method to convert a complex mixture of taxanes into paclitaxel precursor products.
It is yet another object to produce useful synthetic precursors from
Chander Madhavi C.
McChesney James D.
Gegick Rebecca A.
Henson Michael R.
Martin Timothy J.
NaPro BioTherapeutics, Inc.
Trinh Ba K.
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