Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-11-01
2001-03-06
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
06197981
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for converting 9-dihydro-13-acetylbaccatin III into taxane, and is particularly concerned with a process for converting 9-dihydro-13-acetylbaccatin III into taxol, baccatin III, 10-deacetylbaccatin III and their intermediates.
BACKGROUND OF THE INVENTION
Paclitaxel (taxol), represented by the following structural formula:
is a potent antitumor compound. Paclitaxel exhibits a unique mechanism for preventing the growth of cancer cells by affecting the microtubules, which play an important role in cell division and other cell functions. At the beginning of cell division, a large number of microtubules are produced, and as the division reaches an end, the microtubules are normally broken down. Taxol prevents microtubules from breaking down, which has the effect of clogging up cancer cells to an extent that the cells cease to grow and divide.
Taxol is clinically effective for the treatment of refractory human ovarian and breast cancer, and has exhibit promising activity against a number of other types of cancers such as liver, peritoneal, cervical, prostate, colon, and esophageal cancers.
Taxol was primarily extracted from the bark of the Pacific yew
Taxus brevifolia.
Unfortunately, the yew grows very slow, approximately eight inches per year, and therefore the tree is a limited source of taxol. This has lead researchers to seek alternative means for producing taxol and analogs thereof which may display superior antitumor activity.
SUMMARY OF THE INVENTION
In one aspect of the present invention, there is provided a process for preparing a taxane comprising the step of oxidizing the C-9 position of 9-dihydro-13-acetylbaccatin III with a suitable oxidizing reagent such as tetra-n-propylammonium perruthenate, Collin's reagent or activated methyl sulfoxide (DMSO).
In another aspect of the present invention, there is provided a process for preparing taxol and a derivative thereof comprising the steps of:
(a) protecting the C-7 hydroxy group of 9-dihydro-13-acetylbaccatin III with a suitable protecting group to obtain a protected product; and
(b) oxidizing the C-9 hydroxy group of the protected product. Preferably, the protecting group is selected from the group consisting of benzyl, substituted benzyl, benzylformate, substituted benzylformate, tosyl, substituted tosyl, dihydropyran, methoxymethyl, benzoyl and substituted benzoyl.
The process may further include the steps of deacetylating the C-13 position, and deprotection of the C-7 position to obtain baccatin III. Alternatively, following the C-13 deacetylation, the C-10 position can be deacetylated and the C-7 position can be deprotected to obtain 10-deacetylbaccatin III. Or alternatively, following the C-13 deacetylation, a suitable side chain can be added to the C-13 position and the resulting intermediate selectively deprotected to obtain a desired product such as taxol. To obtain taxol, the deprotection is done at the C-7 and 2′ positions. Suitable side chains are (2R, 2S)-N-benzoyl-O-(1-ethoxyethyl)-3-phenylisoserine and (3R, 4S)-3-(1-ethoxyethoxy)-4-(phenyl)-N-benzoyl-2-azetidinone.
In accordance with another aspect of the present invention, there is provided a compound having the following chemical structure:
wherein R is selected from the group consisting of benzyl, substituted benzyl, benzylformate, substituted benzylformate, tosyl, substituted tosyl, dihydropyran, methoxymethyl, benzoyl, substituted benzoyl, benzoylmethyl and substituted benzoylmethyl.
In accordance with another aspect of the present invention, there is provided a compound of the formula:
wherein R is selected from the group consisting of benzyl, substituted benzyl, benzylformate, substituted benzylformate, tosyl, substituted tosyl, dihydropyran, methoxymethyl, benzoyl, substituted benzoyl, benzoylmethyl and substituted benzoylmethyl.
DETAILED DESCRIPTION OF THE INVENTION
Table 1 lists definitions and chemical structures of compounds as used herein, and those definitions and chemical structures are to be applied throughout the present specification.
TABLE 1
Definitions And Chemical Structures
Name
Definition/chemical structure
Functional group
an atom or group of atoms having a
characteristic chemical reactivity
Benzyl
Substituted benzyl
a benzyl group as defined above substituted
with one or more functional group(s)
Dihydropyran
Benzylformate
Substituted benzylformate
a benzylformate as defined above substituted
with one or more functional group(s)
Methoxymethyl
—CH
2
—O—CH
3
Benzoylmethyl
Substituted benzoylmethyl
a benzoylmethyl as defined above substituted
with one or more functional group(s)
Tosyl
Substituted tosyl
a tosyl as defined above substituted with one
or more functional group(s)
The starting material, 9-dihydro-13-acetylbaccatin III, can be obtained by various means including by extraction of Taxus species as described in Applicant's Canadian Patent Application No. 2,203,844 filed on Apr. 28, 1997 and will be published at the end of October 1998. Briefly, the isolation process entails collecting plant material such as stems and needles, and grounding and extracting the material with methanol. The extraction is carried through for about 24 hours, and the resulting mixture is filtered and the extract collected. The extract is concentrated to about 10% of its original volume by evaporation, and further diluted with water. The aqueous solution is extracted several times with hexane to give an aqueous layer and a non-aqueous layer. The aqueous layer is extracted several times with chloroform or dichloromethane. The chloroform or dichloromethane extract is concentrated to dryness, and the residue is dissolved in a mixture of chloroform, methanol and acetone (10:1:0.5), and fractionated by dry column chromatography to obtain fractions of taxol and 9-dihydro-13-acetylbaccatin III. The fractions are combined, extracted and the 9-dihydro-13-acetylbaccatin III is crystallized out.
Taxol and derivatives thereof may be synthesized from 9-dihydro-13-acetylbaccatin III by a number of protection, oxidation, reaction and deprotection steps. For example, referring to the processes illustrated below in Schemes 1-3, 9-dihydro-13-acetylbaccatin III is first protected at the C-7 position by adding a protecting group such as a methoxybenzyl or tosyl group to form a protected intermediate such as compound 2, 7 or 16. Other suitable protecting groups are substituted benzyl, dihydropyran, benzylformate (CBZ), substituted benzylformate, methoxymethyl (MOM), benzoylmethyl (BOM) and substituted benzoylmethyl.
The protected intermediate is oxidized at the C-9 position with a suitable oxidizing agent such as tetra-n-propylammonium perruthenate (TPAP), Collin's reagent (chromium trioxide and pyridine in dichloromethane) or activated methyl sulfoxide (DMSO) to give an oxidized intermediate such as compound 3, 8 or 17. The oxidized intermediate may be deacetylated at the C-13 position by reaction with, for example butyllithium in hexane or methyllithium, to give a baccatin III analog such as compound 4 or 9. Depending of the desired product, the baccatin III analog can either be deprotected with, for example 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) to yield baccatin III (15) or further reacted to eventually obtain 10-deacetylbaccatin III (13) or taxol (18) or other desirable products.
To obtain 10-deacetylbaccatin III, the baccatin III analog (4) is next deacetylated at the C-10 position by reaction with, for example triethylamine in sodium hydride, to compound 12 which is further deprotected. To obtain taxol, the C-13 taxol side chain is added to the baccatin III analog by reaction with, for example (2R, 2S)-N-benzoyl-O-(1-ethoxyethyl)-3-phenylisoserine and lithium hexamethyldisilazide, to give a taxol analog such as compound 5 or 10. The taxol analog is next deprotected at the 2′ by reaction with, for example 1% hydrochloric aced, and C-7 position by reaction with, for example triethylamine and UV light, to give taxol. Other suitable C-13 side chains such as
(Marks & Clerk)
Liu Jian
Sharpe Paul S.
Trinh Ba K.
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