Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-02-29
2001-04-17
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
06218553
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of taxoid(s) including TAXOTÉRE and its analogs and the &bgr;-lactam intermediates useful in this process.
BACKGROUND OF THE INVENTION
Taxol (I) is a complex diterpene which is currently considered the most exciting lead in cancer chemotherapy. Taxol possesses high cytotoxicity and strong antitumor activity against different cancers which have not been effectively treated by existing antitumor drugs. For example, taxol is currently in phase III clinical trial for advanced ovarian cancer, phase II for breast cancer, and phase I for lung cancers, colon cancer and acute leukemia.
Although taxol is an extremely important “lead” in cancer chemotherapy, taxol has a problem with solubility in aqueous media, which may impose some serious limitation in its use. It is common for improved drugs to be derived from naturally occurring lead compounds. In fact, French researchers, Potier, Guéritte-Voegelein, Guénard et al. have discovered that a modification of the C-13 side chain of taxol brought about a new anticancer agent which seems to have antitumor activity superior to taxol with better bioavailability. This synthetic compound was named “TAXOTÉRE (II)”, which has t-butyoxycarbonyl instead of benzoyl on the amino group of (2R,3S)-phenylisoserine moiety at the C-13 position and a hydroxyl group instead of acetoxy group at C-10. [Colin, M. et al. Eur. Pat. Appl. EP25,738 (1988)]. Taxotére is currently in phase II clinical trial in both United States and Europe. TAXOTÉRE has been synthesized by a semisynthetic process, including a coupling of N-tert-butoxycarbonyl-(2R,3S)-3-phenylisoserine with 10-deacetylbaccatin III with proper protecting groups. (Denis, J. N. recently reported (Commercon, A. et al.,
Tetrahedron Letters,
1992, 33 5185).
It is known that the C-13 side chain of taxol, ie., N-benzoyl-(2R,3S)-3-phenylisoserine (III) moiety, is crucial for the strong antitumor activity of taxol. (Senilh et al.,
C. R. S{haeck over (e)}ances Acad. Sci. Ser.
2 1984, 299, 1039; Guéritte-Voegelein et al.,
Tetrahedron,
1986, 42, 4451, and Mangatal et al.,
Tetrahedron,
1989, 45, 4177; Guéritte-Voegelein et al.
J. Med. Chem.
1991, 34, 992; and Swindell et al.,
J. Med. Chem.
1992, 35, 145; Mathew, A. E. Et al.,
J. Med. Chem.
1992, 35, 145). Moreover, some modification of the C-13 side chain can provide a new series of taxol analogs which may have higher potency, better bioavailability and less unwanted toxicity, as exemplified by the discovery of TAXOTÉRE (II).
Accordingly, the development of an efficient method which can be applied to various analogs of taxol and TAXOTÉRE and analogs thereof, i.e., a method having flexibility and wide applicability, is extremely important and of current demand. It has been shown that such a new and efficient method with flexibility can be developed by using enantiomerically pure &bgr;-lactams as key-intermediates [Ojima, I. et al.,
J. Org. Chem.,
1991, 56, 1681; Ojima et al.,
Tetrahedron,
1992, 48, 6985; Holton, R. A., Eur. Patent Appl. EP 400,971 (1990)].
Lithium chiral ester enolate-imine cyclocondensation strategy has been applied to the asymmetric synthesis of the side chain of taxol via a (3R,4S)-3-hydroxy-4-phenylazetidin-2-one (IV) as the key-intermediate. (Ojima, I. et al.,
J. Org. Chem.,
1991, 56, 1681; Ojima et al.,
Tetrahedron,
1992, 48, 6985)
Based on this protocol, the side chain can be obtained in 3 steps in high yield with virtually 100% e.e. (Ojima, I. et al.
J. Org. Chem.
1991 56, 1681). Recently, it was found that 1-benzoyl-(3R,4S)-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one (V), readily derived from the hydroxy-&bgr;-lactam (IV), served as the key-intermediate for the synthesis of taxol [Holton, R. A. Eur. Pat. Appl. EP 400,971 (1990)]. Therefore, this &bgr;-lactam intermediate serves as the key-intermediate for both coupling methods.
In the published European application to Holton (hereinafter Holton), the &bgr;-lactam intermediate (V) was obtained through tedious optical resolution of the racemic cis-3-hydroxy-&bgr;-lactam. According to Holton's procedure, the coupling of the &bgr;-lactam (V) with 7-triethylsilylbaccatin III (VI) (7-TES-baccatin III) proceeds at 25° C. in the presence of dimethylaminopyridine (DMAP) and pyridine for 12 hours to give protected taxol in 92% yield, which was deprotected with
-.5
% hydrochloric acid in ethanol at 0° C. to afford taxol in ca. 90% yield.
However, the Holton procedure did not work at all when 1-tert-butoxycarbonyl-(3R,4S)-3-(1-ethoxylethoxy)-4-phenylazetidin-2-one (VII) was used for the attempted synthesis of TAXOTÉRE (II) by the present inventors.
It is believed that this may be due to the lack of reactivity of the 1-tert-butoxycarbonyl-&bgr;-lactam (VII) toward the c-13 hydroxyl group of a protected baccatin III (VI or VIII) under the conditions used by Holton. The lack of reactivity may be ascribed to the substantially weaker electron-withdrawing ability of tert-butoxycarbonyl group than that of benzoyl group.
Therefore, it was an objective of the present invention to develop a new method which can achieve the coupling of the 1-tert-butoxycarbonyl-&bgr;-lactam (VII) with the protected baccatin III (VIII) for the synthesis of TAXOTÉRE (II).
All of the references cited above and any reference which may be mentioned hereinbelow are expressly incorporated into the present disclosure.
It is an object of the present invention to provide new &bgr;-lactam useful in the synthesis of TAXOTÉRE (II) and analogs thereof.
It is further object of the present invention to provide a new coupling method for the syntheses of TAXOTÉRE (II) and analogs thereof.
SUMMARY OF THE INVENTION
A &bgr;-lactam of the formula (IX)
in which
R
2
, represents an RO-, RS- or RR′N- in which R represents an unsubstituted or substituted straight chain or branched alkyl, alkenyl or alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, carbocyclic aryl or heteroaryl, wherein substituents bearing one or more active hydrogens such as hydroxyl, amino, mercapto and carboxyl groups are protected; R′ is a hydrogen or R as defined above; R and R′ can be connected to form a cyclic structure; Examples of R
1
, include methoxy, ethoxy, isopropoxy, tert-butoxy, neopentyloxy, cyclohexyloxy, allyloxy, propargyloxy, adamantyloxy, phenyoxy, 4-methoxyphenoxy, 2-fluorophenoxy, 4-methoxycarbonylphenoxy, methylthio, ethylthio, isopropylthio, tert-butylthio, neopentylthio, cyclohexylthio, phenylthio, 3,4-dimethoxyphenylthio, methylamino, ethylamino, isopropylamino, tert-butylamino, neopentylamino, cyclohexylamino, dimethylamino, pyrrolidino, piperidino and morpholino group.
R
3
, represents an unsubstituted or substituted straight chain or branched alkyl, alkenyl or alkynyl radical, an unsubstituted or substituted cycloalkyl, or cycloalkenyl radical, an unsubstituted or substituted aryl radical wherein substituents bearing one or more active hydrogens such as hydroxyl, amino, mercapto and carboxyl groups are protected; Examples of R
3
, include phenyl, 4-methoxylphenyl, tolyl, 3,4-dimethoxylphenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 4-bromophenyl, naphthyl, cyclohexyl, cyclohexylmethyl, 2-phenylethenyl, 2-phenylethyl, benzyl, neopentyl, tert-butyl, isobutyl, isopropyl, allyl and propargyl;
G
1
represents a hydrogen or a hydroxyl protecting group such as methoxymethyl (MOM), methoxylethyl (MEM), 1-ethoxyethyl (EE) benzyloxymethyl, &bgr;-trimethylsilylethoxyl)methyl, tetrahydropyranyl, 2,2,2-trichloroethoxylcarbonyl (Troc), tert-butoxycarbonyl (t-BOC), 9-fluorenylmethoxycarbonyl (Fmoc) 2,2,2-trichloroethoxymethyl, trimethylsilyl, triethylsilyl, dimethylethylsilyl, dimethyl(t-butyl)silyl, diethylmethylsilyl, dimethylphenylsilyl and diphenylmethylsilyl;
Y is oxygen or sulfur.
The present inventors investigated the &bgr;-lactam coupling reaction with protected Baccatin III in detail and found that the coupling could be achieved by increasing the nucleophi
Finnegan, Henderson, Farrabow, Garrett & Dunner L.L.P.
The State University of New York at Stony Brook
Trinh Ba K.
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