Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-05-16
2001-02-06
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
06184395
ABSTRACT:
BRIEF DESCRIPTION OF THE INVENTION
The present invention is directed to reaction conditions for the cleavage of silyl ethers from silyl protected taxane precursors to afford paclitaxel (Taxol®) and paclitaxel analogues. More specifically, the invention is directed to a process for the preparation of paclitaxel from a taxane precursor which comprises the steps of treating the taxane precursor with a strong acid such as trifluoroacetic acid, in a weak aqueous acid, such as aqueous acetic acid, such that the amount and number of side reactions leading to undesirable taxane impurities are minimized, and isolating the product from a solvent that affords paclitaxel in either of the two crystal forms, Form A or Form B.
BACKGROUND OF THE INVENTION
Taxanes are diterpene compounds that find utility in the pharmaceutical field. For example, taxanes containing aryl heterocyclic or cycloalkyl groups on the C-13 sidechain find utility as anti-cancer agents. Taxanes include pacltitaxel, cephalomannine, taxol c, 10-deacetylpaclitaxel, 10-deacetylcephalomannine, 7-&bgr;-xylosylpaclitaxel, baccatin-III, 10-deacetylbaccatin III, 7-&bgr;-xylosyl-10-deacetyl cephalomannine, 7-&bgr;-xylosyl-10-deacetylbaccatin III, 7-&bgr;-xylosylbaccatin III, and 10-deacetyl-taxol c.
Paclitaxel (Taxol®), a diterpene taxane compound, is a natural product extracted from the bark of the Pacific yew tree,
Taxus Brevifolia
. It has been shown to have excellent antitumor activity in in vivo animal models, and recent studies have elucidated its unique mode of action, which involves abnormal polymerization of tubulin and disruption of mitosis during the cell cycle. Taxol® has recently been approved for the treatment of refractory advanced ovarian cancer, breast cancer, non-small cell lung cancer, and most recently, AIDS-related Kaposi's Sarcoma. The results of paclitaxel clinical studies are replete in scientific periodicals and have been reviewed by numerous authors, such as Rowinsky and Donehower in “The Clinical Pharmacology and Use of Antimicrotubule Agents in Cancer Chemotherapeutics”,
Phamac. Ther
., 52, pp. 35-84 (1991); Spencer and Faulds, Paclitaxel, A Review of its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Potential in the Treatment of Cancer,
Drugs
, 48 (5), pp. 794-847 (1994); K. C. Nicolau et al., Chemistry and Biology of Taxol,
Angew. Chem., Int. Ed. Eng
., 33, pp.15-44 (1994); F. A. Holmes, A. P. Kudelka, J. J. Kavanaugh, M. H. Huber, J. A. Ajani, and V. Valero, “Taxane Anticancer Agents—Basic Science and Current Status”, edited by Gunda I. Georg, Thomas C. Chen, lwao Ojima, and Dolotrai M. Vyas, pp. 31-57 American Chemical Society, Wash., D.C. (1995); Susan G. Arbuck and Barbara Blaylock, “Taxol® Science and Applications”, edited by Matthew Suffness, pp. 379416, CRC Press, Boca Raton, Fla. (1995) and the references cited therein.
The structure of Taxol® is shown below along with the conventional numbering system for molecules belonging to the Taxane class; such numbering system is also employed in this application:
With reference to the numbering of the taxane, reference to a particular carbon on the taxane structure shall be indicated throughout this application by a “C-number”, which signifies the carbon on the taxane according to the above numbering system. For example, “C-13” refers to the carbon at position 13 on the taxane ring as shown above, having a sidechain coupled thereto.
Naturally occurring taxanes such as paclitaxel, 10-deacetylpaclitaxel and baccatin III can be extracted from the trunk bark of different species of Taxus (yew). Paclitaxel, in particular, may be extracted from the inner bark of
Taxus brevifolia
. Although
T. brevifolia
is a relatively common tree in the Pacific Northwest, it is a slow growing plant and is indigenous to the ecologically threatened old-growth forests of this area, and harvesting is thus increasingly restricted because of environmental concerns.
As yields of paclitaxel extracted from
T. brevifolia
are generally low, of the order of 100 mg/kg, semisynthetic methods of producing paclitaxel from baccatin IlIl and 10-deacetylbaccatin have been developed. Baccatin III, 10-deacetylbaccatin, as well as other paclitaxel precursors may be isolated from the needles of the European yew, Taxus baccata in relatively larger quantities, e.g. approximately 300 mg/kg of 10-deacetylbaccatin may be obtained from yew leaves. Although yew needles generally provide an adequate supply of the necessary starting materials for synthesizing paclitaxel, the supply is not endless and other methods easing the supply dilemma and producing adequate amounts of paclitaxel has become a priority. The art has thus continued to search for synthetic, including semisynthetic routes for the preparation of naturally occurring taxanes such as paclitaxel, as well as the preparation of paclitaxel analogues and second and third generation paclitaxel-like compounds thereof.
Using a semi-synthethic process, paclitaxel may be prepared from numerous paclitaxel precursors, some having protecting groups thereon, particularly at the C-7 postion on the taxane ring and at the 2′ position on the sidechain which is connected at position C-13. Paclitaxel may be easily prepared by the deprotection of these paclitaxel precursors.
Several methods for cleaving the silyl ethers have been reported in the literature. However, when applied to silyl protected taxane precursors, most of these procedures generated side reactions and several impurities. In the case of paclitaxel, the most prominent impurity is 10-deacetyltaxol. Some of the other side-reactions known to occur are: opening of the oxetane ring, loss of the C-1 hydroxyl group followed by ring contraction to a 5-membered ring, and epimerization at C-7.
With reference to paclitaxel, this compound exhibits polymorphism. Crystal Form A is predominantly obtained from non-aqueous solvent systems and crystal Form B is predominantly obtained from aqueous solvent systems. Paclitaxel Form A is the preferred crystal form and has been filed with the U.S. Food and Drug Administration.
The present invention relates to novel reaction conditions for the cleavage of silyl ethers from silyl protected taxane precursors that afford high quality paclitaxel and paclitaxel analogues. Also included are crystallization protocols that can afford either of the two paclitaxel crystal forms, Form A or Form B.
DESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation of high quality paclitaxel and paclitaxel analogues from taxanes of formula I:
wherein:
R
1
=H
3
, c-C
6
H
11
, C
6
H
5
, p-CH
3
—C
6
H
4
or p-NO
2
—C
6
H
4
;
R
2
=CH
3
, CH
2
CH
3
, CH
2
CH
2
CH
3
, C(CH
3
)
3
, (CH
2
)
3
CH
3
, (CH
2
)
4
CH
3
, C
6
H
5
, p-NO
2
—C
6
H
4
, c-C
3
H
5
, c-C
4
H
7
, c-C
5
H
9
, or OCH
3
;
R
3
=(CH(CH
3
)
2
)
2
OCH
3
, (CH
2
CH
3
)
3
, (CH
3
)
3
or (C(CH
3
)
3
)(CH
3
)
2
;
R
4
=H, CH
3
, C
6
H
5
, COCH
3
, COC
6
H
5
or COC
4
H
9
;
R
6
=H, F, OH, OCH
3
, OSi(CH
2
CH
3
)
3
, OSi(C(CH
3
)
3
)(CH
3
)
2
or OC(CH
3
)
2
OCH
3
, provided that R
6
is other than OC(CH
3
)
2
OCH
3
when R
1
is C
6
H
5
, R
2
is CH
3
, R
3
is (CH
2
CH
3
)
3
, R
4
is COCH
3
, R
7
is C
6
H
5
and R
8
is C
6
H
5
;
R
7
=C
6
H
5
, C(CH
3
)
3
or CH(CH
3
)
2
; and
R
8
=C
6
H
5
, C(CH
3
)
3
, (CH
3
)
3
CO, (CH
3
)
3
CCH
2
, CH
3
(CH
2
)
3
O, cyclobutyl, cyclohexyloxy or 2-furyl.
In accordance herewith, paclitaxel and paclitaxel analogues may be prepared from silyl protected taxane precursors of formula I by a process which comprises the steps of:
(a) preparing a solution of a taxane precursor in a weak organic acid;
(b) preparing a solution comprised of a strong acid in said weak organic acid and water;
(c) adding the solution from step (b) to step (a);
(d) stirring the reaction mixture formed in step (c);
(e) quenching the reaction mixture (to prevent degradation of the product during subsequent processing);
(f) adding water and extracting the product using an organic solvent;
(g) separating the organic l
Powers Gerald L.
Rosso Victor W.
Singh Ambarish K.
Weaver Raymond E.
Babcock Timothy J.
Bristol--Myers Squibb Company
Trinh Ba K.
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