Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1995-04-14
2004-04-27
Trinh, Ba K. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S214000, C549S228000, C549S510000, C549S511000
Reexamination Certificate
active
06727369
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a process for the preparation of baccatin III and 10-desacetylbaccatin III analogs having new C2 and/or C4 functional groups.
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.
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:
Taxol, taxotere and other biologically active tetracyclic taxanes may be prepared semisynthetically from baccatin III and 10-desacetyl baccatin III as set forth in U.S. Pat. Nos. 4,924,011 and 4,924,012 or by the reaction of a &bgr;-lactam and a suitably protected baccatin III or 10-desacetylbaccatin III (“10-DAB”) derivative as set forth in U.S. Pat. No. 5,175,315 or copending U.S. patent application Ser. No. 07/949,107 (which is incorporated herein by reference). Baccatin III 1 and 10-DAB 2 can be separated from mixtures extracted from natural sources such as the needles, stems, bark or heartwood of numerous Taxus species and have the following structures.
The tetracyclic core of taxol and taxotere bear six singly bonded oxygen substituents. Two of these (three in the case of taxotere) are present as hydroxyl groups, and the others-are esters of three different carboxylic acids. Selective manipulation of these groups presents a formidable problem which must be overcome before a series of taxol analogs can be prepared by a rational synthetic sequence. Hydrolytic and solvolytic methods have previously encountered complications. For example, it has been reported by that hydrolysis of taxol under mildly basic conditions yields a complex mixture of products. Miller et al.,
J. Org. Chem
. 1981, 46, 1469. Recently it has been found that solvolysis of baccatin (III) derivatives leads to rearrangement of the tetracyclic core. Farina, et al., Tetrahedron Lett. 1992, 33, 3979.
SUMMARY OF THE INVENTION
Among the objects of the present invention, therefore, is the provision of a process for selectively attaching different functional groups to the C2 and/or C4 oxygens of baccatin III and analogs or derivatives thereof; the provision of such a process which is relatively straightforward; the provision of such a process in which the C2 benzoate substituent of baccatin III and analogs or derivatives thereof may be selectively reduced or hydrolyzed and the provision of such a process in which the C4 acetate substituent may be selectively reduced.
Briefly, therefore, the present invention is directed to a process for the preparation of analogs or derivatives of baccatin III or 10-desacetyl baccatin III in which the C2 substituent and/or the C4 acetate substituent of baccatin III or 10-desacetoxy baccatin III or an analog thereof is selectively converted to the corresponding hydroxy group(s).
The present invention is additionally directed to a derivative of baccatin III or 10-desacetyl baccatin III having the formula
wherein R
4a
, R
7a
, R
10a
, and R
13a
are as defined elsewhere herein.
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; “Me” means methyl; “Et” means ethyl; “iPr” means isopropyl; “tBu” and “t-Bu” means tert-butyl; “R” means lower alkyl unless otherwise defined; “Ac” means acetyl; “py” means pyridine; “TES” means triethylsilyl; “TMS” means trimethyl-silyl; “TBS” means Me
2
t-BuSi—; “Tf” means —SO
2
CF
3
; “BMDA” means BrMgNiPr
2
; “Swern” means (COCl)
2
, Et
3
N; “LTMP” means lithium tetramethylpiperidide; “MOP” means 2-methoxy-2-propyl; “BOM” means benzyloxymethyl; “LDA” means lithium diisopropylamide; “LAH” means lithium aluminum hydride; “Red-Al” means sodium bis(2-methoxyethoxy) aluminum hydride; “Ms” means CH
3
SO
2
—; “TASF” means tris(diethylamino)sulfoniumdifluorotrimethylsilicate; “Ts” means toluenesulfonyl; “TBAF” means tetrabutyl ammonium hydride; “TPAP” means tetrapropyl-ammonium perruthenate; “DBU” means diazabicycloundecane; “DMAP” means p-dimethylamino pyridine; “LHMDS” means lithium hexamethyldisilazide; “DMF” means dimethylformamide; “AIBN” means azo-(bis)isobutyronitrile; “10-DAB” means l0-desacetylbaccatin III; “FAR” means 2-chloro-1,1,2-trifluorotriethylamine; “mCPBA” means metachloroperbenzoic acid; “DDQ” means dicyanodichloroquinone; “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; “protected hydroxy” means —OP wherein P is a hydroxy protecting group; and “hydroxy protecting group” includes, but is not limited to, acetals having two to ten carbons, ketals having two to ten carbons, ethers such as methyl, t-butyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, allyl, trityl, methoxymethyl, 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, trifluoro-acetyl; 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 from one to six carbon atoms and substituted with one or more halogen atoms such as 2,2,2-trichloroethoxymethyl and 2,2,2-tri-chloroethyl; alkenyl carbonates having from two to six carbon atoms such as vinyl and allyl; cycloalkyl carbonates having from three to six carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and phenyl or benzyl carbonates optionally substituted on the ring with one or more C
1-6
alkoxy, or nitro. Other hydroxyl, sulfhydryl and amine protecting groups may be found in “Protective Groups in Organic Synthesis” by T. W. Greene, John Wiley and Sons, 1981.
The alkyl groups described herein are preferably lower alkyl containing from one to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be straight or branched chain and include methyl, ethyl, propyl, isopropyl, butyl, hexyl and the like. They maybe hetero-substituted with the various substituents defined herein, including alkaryl.
The alkenyl groups described herein are preferably lower alkenyl containing from two to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be straight or branched chain and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like. They may be heterosubstituted with the various substituents defined herein, including alkenaryl.
The alkynyl groups described herein are preferably lower alkynyl containing from two to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like. They may be heterosubstituted with the various substituents defined herein, including alkynaryl.
The aryl moieties described herein contain from 6 to 15 carbon atoms and include phenyl. They may be hydro-carbon or heterosubstituted with the various substituents defined hereinbelow. Phenyl
Holton Robert A.
Kim Seokchan
Suzuki Yukio
Florida State University
Senniger Powers Leavitt & Roedel
Trinh Ba K.
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