Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-09-22
1997-08-05
Reamer, James H.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07C30514
Patent
active
056544472
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention relates to a process for preparing 10-desacetoxytaxol, 10-desacetoxybaccatin III and derivatives of 10-desacetoxytaxol and 10-desacetoxybaccatin III.
Taxol is a natural product extracted from the bark of yew trees. 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. It is currently undergoing clinical trials against ovarian, breast and other types of cancer in the United States and France and preliminary results have confirmed it as a most promising chemotherapeutic agent. The structure of taxol and the numbering system conventionally used is shown below; this numbering system is also applicable to compounds used in the process of the present invention. ##STR1##
In Colin U.S. Pat. No. 4,814,470, it was reported that a taxol derivative, commonly referred to as taxotere, has an activity significantly greater than taxol. Taxotere has the following structure: ##STR2##
Although taxol and taxotere are promising chemotherapeutic agents, a need remains for additional chemotherapeutic agents. The tetracyclic core of taxol bears a C10 acetoxy substituent and taxotere bears a C10 hydroxy substituent which, if modified, would lead to the preparation of a series of taxol analogs. To date, however, the selective manipulation of the C10 acetoxy and hydroxy groups has presented a formidable problem.
SUMMARY OF THE INVENTION
Among the objects of the present invention, therefore, is the provision of an improved process for preparing 10-desacetoxytaxol, 10-desoxytaxotere, 10-desacetoxybaccatin III and derivatives of 10-desacetoxytaxol and 10-desacetoxybaccatin III.
Briefly, therefore, the present invention is directed to a process for the preparation of 10-desacetoxy and 10-desoxy taxanes. According to this process, a taxane having a C10 leaving group such as hydroxy, acyloxy or sulfonyloxy is reacted with samarium diiodide. The C10 leaving group is selectively and nearly quantitatively removed from the taxane.
Other objects and features of this invention will be in part apparent and in part pointed out hereinafter.
DETAILED DESCRIPTION OF THE INVENTION
As used herein "Ar" means aryl; "Ph" means phenyl; "Ac" means acetyl; "Et" means ethyl; "R" means alkyl unless otherwise defined; "Bu" means butyl; "Pr" means propyl; "TES" means triethylsilyl; "TMS" means trimethylsilyl; "TPAP" means tetrapropylammonium perruthenate; "DMAP" means p-dimethylamino pyridine; "DMF" means dimethylformamide; "LDA" means lithium diisopropylamide; "LHMDS" means lithium hexamethyldisilazide; "LAH" means lithium aluminum hydride; "Red-Al" means sodium bis(2-methoxyethoxy) aluminum hydride; "AIBN" means azo-(bis)-isobutyronitrile; "10-DAB" means 10-desacetylbaccatin III; FAR means 2-chloro-1,1,2-trifluorotriethylamine; protected hydroxy means --OR wherein R is a hydroxy protecting group; sulfhydryl protecting group" includes, but is not limited to, hemithioacetals such as 1-ethoxyethyl and methoxymethyl, thioesters, or thiocarbonates; "amine protecting group" includes, but is not limited to, carbamates, for example, 2,2,2-trichloroethylcarbamate or tertbutylcarbamate; and "hydroxy protecting group" includes, but is not limited to, ethers such as methyl, t-butyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, allyl, trityl, methoxymethyl, 2-methoxypropyl, methoxyethoxymethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrothiopyranyl, and trialkylsilyl ethers such as trimethylsilyl ether, triethylsilyl ether, dimethylarylsilyl ether, triisopropylsilyl ether and t-butyldimethylsilyl ether; esters such as benzoyl, acetyl, phenylacetyl, formyl, mono-, di-, and trihaloacetyl such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl; and carbonates including but not limited to alkyl carbonates having from one to six carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl; isobutyl, and n-pentyl; alkyl carbonates having
REFERENCES:
patent: 4814470 (1989-03-01), Colin et al.
patent: 4857653 (1989-08-01), Colin et al.
patent: 4876399 (1989-10-01), Holton et al.
patent: 4924011 (1990-05-01), Denis et al.
patent: 4924012 (1990-05-01), Colin et al.
patent: 4942184 (1990-07-01), Haugwitz et al.
patent: 4960790 (1990-10-01), Stella et al.
patent: 5015744 (1991-05-01), Holton
patent: 5059699 (1991-10-01), Kingston et al.
patent: 5136060 (1992-08-01), Holton
patent: 5175315 (1992-12-01), Holton
patent: 5200534 (1993-04-01), Rao
patent: 5243045 (1993-09-01), Holton et al.
patent: 5248796 (1993-09-01), Chen et al.
patent: 5250683 (1993-10-01), Holton et al.
patent: 5254580 (1993-10-01), Chen et al.
patent: 5254703 (1993-10-01), Holton
patent: 5264591 (1993-11-01), Bombardelli et al.
patent: 5272171 (1993-12-01), Ueda et al.
patent: 5277400 (1994-01-01), Holton et al.
patent: 5294637 (1994-03-01), Chen et al.
patent: 5299526 (1994-04-01), Holton
patent: 5336785 (1994-08-01), Holton
patent: 5338872 (1994-08-01), Holton et al.
patent: 5350866 (1994-09-01), Holton et al.
patent: 5384399 (1995-01-01), Holton
patent: 5399726 (1995-03-01), Holton et al.
patent: 5405972 (1995-04-01), Holton et al.
patent: 5430160 (1995-07-01), Holton
Bartholomew et al. "A Novel Rarrangement Reaction Conversion of 3-(chloromethyl)azetidin-2-ones to Azetidine-3-carboxylic Acid Esters", Tetrahedron Letters, vol. 32, No. 36, pp. 4795-4798 (1991).
Borman "New Family of Taxol, Taxotere Analogs Developed" Science & Technology, Chem. & Eng. News, pp. 36-37 (Apr. 12, 1993).
Chaudhary et al. "Synthesis of 10-Deacetoxytaxol and 10-Deoxytaxotere" Tetrahedron Letters, vol. 34, No. 31, pp. 4921-4924 (1993).
Chen et al. "Taxol Structure-Activity Relationships: Synthesis and Biological Evaluation of 2-Deoxytaxol" Tetrahedron Letters, vol. 34, No. 20, pp. 3205-3206 (1993).
Denis et al. "A Highly Efficient, Practical Approach to Natural Taxol" Journal of American Chemical Society, vol. 110, No. 17, pp. 5917-5919 (1988).
Farina et al. "The Chemistry of Taxanes: Unexpected Rearangement of Baccatin III During Chemoselective Debenzoylation with Bu.sub.3 SnOMe/LiCl" Tetrahedron Letters, vol. 33, No. 28 pp. 3979-3982 (1992).
Hanessian et al. "A Practical Synthesis of 2-Deoxy Aldonolacetones via a SmI.sub.2 -Mediated .alpha.-Deoxygenation Reaction" Tetrahedron Letters, vol. 33, No. 5, pp. 573-576 (1992).
Holton "Synthesis of the Taxane Ring System" Journal of the American Chemical Soc., vol. 106, pp. 5731-5732 (1984).
Holton et al. "A Synthesis of Taxusin" Journal of American Chemical Soc., vol. 110, pp. 6558-6560 (1988).
Holton et al. "A Novel Lanthanide-Induced Rearrangement" Journal of Organic Chemistry, vol. 53, No. 25, pp. 5981-5983 (1988).
Inanaga et al. "SmI.sub.2 -Promoted Deacetoxylation of O-Acetylsugar Lactones. An Easy Access to Deoxysugar Lactones" Chemical Letters, pp. 1025-1026 (1991).
Kaiser et al. "Synthesis of Esters of Acid-Unstable Alcohols by Means of n-butyllithium" Journal of Organic Chemistry, vol. 35, p. 1198 (1970).
Kingston et al. "Progress in the Chemistry of Organic Natural Products" Springer-Verlag, New York (1993) pp. 1-206.
Klein "Synthesis of 9-Dihydrotaxol: A Novel Bioactive Taxane" Tetrahedron Letters, vol. 34, No. 13, pp. 2047-2050 (1993).
Kusuda et al. "A Highly Effective Deoxygenation of .alpha.-oxygenated Esters Via SmI.sub.2 -Induced Electron Transfer Process" Tetrahedron Letters, vol. 30, No. 22, pp. 2945-2948 (1989).
Magri et al. "Modified Taxols, 4. Synthesis and Biological Activity of Taxols Modified in the Side Chain" Journal of Natural Products, vol. 51, No. 2, pp. 298-306 (1988).
Miller et al. "Antileukemic Alkaloids from Taxus Wallichiana Zucc." Journal of Organic Chemistry, vol. 46, No. 7, pp. 1469-1474 (1981).
Molander et al. "Lanthanides in Organic Synthesis. 2. Reduction of .alpha.-Heterosubstituted Ketones" Journal of Organic Chemistry, vol. 51, No. 7, pp. 1135-1138 (1986).
Mukerjee et al. ".beta.-Lactams: Retrospect and Prospect" Tetrahedron Letters, vol. 34, No. 52, pp. 1731-17
Holton Robert A.
Somoza Carmen
Florida State University
Reamer James H.
LandOfFree
Process for the preparation of 10-desacetoxybaccatin III does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process for the preparation of 10-desacetoxybaccatin III, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the preparation of 10-desacetoxybaccatin III will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1076111