Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
1995-06-07
2001-02-13
Berch, Mark L. (Department: 1611)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C540S357000, C540S360000, C549S510000, C549S511000
Reexamination Certificate
active
06187916
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of taxoid(s) including TAXOTÈRE 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, Potierf 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 bioavailiability. This synthetic compound was named “TAXOTÈRE (II)”, which has t-butoxycarbonyl 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. EP253,738 (1988)]. Taxotére is currently in phase II clinical trial in both United States and Europe. TAXOTÈRE 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 (Commerçon, A. et al., Tetrahedron Letters, 1992, 33 5185).
It is known that the C-13 side chain of taxol, i.e., N-benzoyl-(2R,3S)-3-phenylisoserine (III) moiety, is crucial for the strong antitumor activity of taxol. (Senilh et al., C. R. Séances 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 TAXOTÈRE (II).
Accordingly, the development of an efficient method which can be applied to various analogs of taxol and TAXOTÈRE 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 0.5% 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 TAXOTÈRE (II) by the present inventors.
It is believed that this may be due to the lack of reactivity of the l-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 TAXOTÈRE (II).
All of the references cited above and any reference which may be mentioned hereinbelow are expressly incorporated into the present diclosure.
It is an object of the present invention to provide new &bgr;-lactams useful in the syntheses of TAXOTÈRE (II) and analogs thereof.
It is further object of the present invention to provide a new coupling method for the syntheses of TAXOTÈRE (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
2′
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
2′
may also represent a radical RO—, RS— or RR′N— in which R represents a straight chain or branched alkyl radical containing 1 to 20 carbon atoms, a straight chain or branched alkenyl radical containing 2 to 20 carbon atoms, a straight chain or branched alkynyl radical containing 2 to 10 carbon atoms, a cycloakyl radical containing 3 to 10 carbon atoms, a heterocyclic radical containing 3 to 10 carbon atoms, a cycloalkenyl radical containing 3 to 10 carbon atoms, a heterocycloalkenyl radical containing 3 to 10 carbon atoms, a polycloaklyl radical containing 6 to 20 carbon atoms, an aryl radical containing 6 to 20 carbon atoms, or a heteroaryl radical containing 3 to 15 carbon atoms.
R
2′
may also represent a radical RO—, RS— or RR′N— in which R represents an unsubstituted or substituted alkyl radical selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl,hexyl, isohexyl, (2-methylpentyl), heptyl, isoheptyl (2-methylhexyl), octyl, isooctyl (2-methylheptyl); a 9-fluoroenylmethyl radical; a cycloalkyl radical selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, and adamantyl; an alkenyl radicak selected from vinyl and allyl; an aryl radical selected from phenyl and naphthyl; a benzyl radical; a hetrocyclic aromatic r
Berch Mark L.
Finnegan, Henderson & Farabow, Garrett & Dunner, L.L.P
Research Foundation of State University of New York
LandOfFree
Process for the preparation of taxane derivatives and... 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 taxane derivatives and..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the preparation of taxane derivatives and... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2578504