Semi-synthesis of paclitaxel using dialkyldichlorosilanes

Details Semi-synthesis of paclitaxel using dialkyldichlorosilanes Semi-synthesis of paclitaxel using dialkyldichlorosilanes

2000-05-25

2001-06-05

Lambkin, Deborah C. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S510000

Reexamination Certificate

active

06242614

ABSTRACT:

BRIEF DESCRIPTION OF THE INVENTION
The present invention is directed to the synthesis of paclitaxel from 10-deacetylbaccatin-III which is protected at the 7-position with a dialkylalkoxysilyl protecting group.
BACKGROUND & SUMMARY OF THE INVENTION
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 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,
Pharmac. 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, Iwao 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. 379-416, CRC Press, Boca Raton, Fla. (1995) and the references cited therein.
Commercial pharmaceutical products containing paclitaxel are available, e.g. for the treatment of ovarian and breast cancer, and most recently, AIDS-related Kaposi's Sarcoma. Paclitaxel has also shown promising results in clinical studies for the treatment of other cancers. As a result, the demand for paclitaxel continues to escalate, and ever increasing amounts of paclitaxel are needed with each passing year for continued research and clinical studies. Paclitaxel is extracted with difficulty and in low yields for the bark of
Taxus brevifolia
(approximately 1 kg. of the drug is isolated from the bark of 3,000
T. brevifolia
trees). Because of the difficulty in extracting adequate yields, alternative sources for synthesizing paclitaxel are needed.
10-deacetylbaccatin-III (“10-DAB”) (1, Scheme-1) is currently the starting material for the semi-synthesis of paclitaxel, and may be readily extracted from the needles and twigs of the European Yew tree,
Taxus baccata
L. 10-DAB does not, however, exhibit the degree of anti-tumor activity demonstrated by paclitaxel. Accordingly, the semi-synthesis of paclitaxel from baccatin III. 10-DAB and other taxane compounds is of great interest and importance.
Three distinct approaches for making paclitaxel are known in the literature. Two approaches utilizes 7-O-TES-baccatin-III (3, Scheme-1) obtained from the selective silylation and acetylation of 10-DAB (1) (Greene et al.,
J. Am. Chem. Soc.
110, p. 5917 (1988). The first route, developed by Prof. Holton and disclosed in U.S. Pat. No. 5,274,124 (Scheme-2) reacts the lithium anion of 3 with a &bgr;-lactam to introduce the required amino acid side chain at the 13-position. The second route developed by Bristol-Myers Squibb Co. and disclosed in U.S. patent application Ser. No. 07/995,443, and by D. G. I. Kingston et al. in Tetrahedron Letters 35, p. 4483 (1994), (Scheme-3) couples 3 with an oxazolinecarboxylic acid ((4S-trans)-4,5-dihydro-2,4-diphenyl-5-oxazolecarboxylic acid) (4) using DCC or similar dehydrating agent. Using DCC, A Commercon et al. at Rhone Poulenc Rhorer (Tetrahedron Letters 33, pp.5185-5188 (1992), have developed a third synthesis of paclitaxel coupling 7-O-Troc-baccatin-III (5) with the protected &bgr;-phenylisoserine (6) shown in Scheme-4.
DETAILED DESCRIPTION OF THE INVENTION
It is an object of the present invention to provide a rapid, new, useful and efficient protocol for the semi-synthesis of paclitaxel from 7-O protected 10deacetylbaccatin-III derivatives, which generally comprises acetylation at the 10-position, followed by the attachment of a paclitaxel sidechain to the protected 10-deacetylbaccatin-III derivatives, and the subsequent deprotection of the 7-O-protected 10-deacetylbaccatin-III derivatives.
Another object of the present invention is the provision of methods of producing various 10-deacetylbaccatin-III derivatives having a protecting group at the C-7 site on the taxane structure, and which, after attachment of a sidechain and subsequent deprotection, yields paclitaxel in significant amounts.
An additional object of the present invention is the provision of a simple, efficient, and cost effective protocol for the semi-synthesis of paclitaxel.
Accordingly, the present invention encompasses a novel method by which 10-deacetylbaccatin-III can be efficiently converted to 7-O-protected 10-deacetylbaccatin-III using several different protecting groups. After attachment of a paclitaxel sidechain at the C-13 site, these 7-O-protected 10-deacetylbaccatin-III compounds can then be easily converted into paclitaxel making 10-deacetylbaccatin-III a valuable starting material for the semisynthesis of paclitaxel.
The present invention is broadly directed to a chemical process for the rapid and efficient production of paclitaxel, intermediates and precursors thereof. More specifically, the present invention is directed to the semi-synthesis of paclitaxel by protecting the 7-hydroxyl of paclitaxel precursor 10-deacetylbaccatin-III to provide 7-O-protected 10-deacetylbaccatin-III, using dialkyldichlorosilanes, followed by the selective acetylation at the C-10 position, the coupling of a paclitaxel sidechain at the C-13 position, and the subsequent deprotection at the C-7 position and replacement of the protecting group with a hydrogen. More particularly, the invention utilizes diakyldichlorosilane protecting groups such as Ph
2
SiCl
2
and i-Pr
2
Cl
2
at the C-7 site on the taxane during the coupling of the paclitaxel sidechain at the C-13 position.
The general process described herein involves the production of 7-O-protected-10-deacetylbaccatin-III derivatives, such as 7-OS(i-Pr)
2
(OMe)-10-deacetylbaccatin-III, selective acetylation at C-10 to form a compound such as, for example, 7-OSi(i-Pr)
2
(OMe)-baccatin-III, followed by the coupling of a sidechain at C-13, and the deprotection of the C-13 to form paclitaxel. A particularly advantageous dialkyldichlorosilane protecting group has the generic chemical formula: —Si(R)
2
(OR′), where R=Me, Et, i-Pr, Bu, Ph and R′=Me, Et, Pr, i-Pr, t-Bu, CH
2
CF
3
, CH
2
CF
2
CH
3
, CH(CF
3
)
2
and H. Protecting groups are discussed in detail in “Protective Groups in Organic Synthesis”, Second Ed., by Theodora W. Greene and Peter G. M. Wuts (1991, John Wiley & Sons, Inc.).
The specific examples which follow illustrate the synthesis of representative compounds of the instant invention and are not to be construed as limiting the invention in sphere or scope. The methods may be adapted to variations in order to produce intermediates and compounds embraced by this invention but not specifically disclosed. Further, variations of the methods to produce the same compounds in somewhat different fashion will also be evident to one skilled in the art.
(I) Silylation: 10-DAB (1) was reacted with a series of dialkyldichlorosilanes (e.g. Ph
2
SiCl
2
and i-Pr
2
SiCl
2
) in the presence imidazole in DMF under different reaction temperatures (RT to −53° C.) for 1-3.5 h. The resulting monochlorosilane intermediates were treated with alcohols, such as MeOH, EtOH, i-PrOH, PrOH, t-BuOH, CF
3
CH
2
OH, CF
3
CF
2
CH
2
OH, (CF
3
)
2
CHOH and water. The crude products obtained after workup were purified by either crys

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