Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-02-20
1998-06-16
Trinh, Ba K.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
548239, 549510, 549511, C07D26304, C07D30514
Patent
active
057672822
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP96/02408, dated Jun. 9, 1996.
The present invention refers to a process for the preparation of Taxol, to the oxazolidine or oxazoline involved in the process and to a process for preparing such oxazolidines or oxazolines.
Taxol, isolated from the bark or several yew species, is considered the most promising cancer chemotherapeutic agent and has recently been approved for treatment of metastatic carcinoma of the ovary. Taxol possesses unusually potent antileukemic and tumor inhibitory properties (Angew. Chem. Int. Ed. Engl. 1994, 33, 15-44). The scarcity and highly challenging structure have stimulated interest in its synthesis. Central to all synthetic strategies for Taxol is the attachment of the C-13 side chain to the baccatin III nucleus, since the presence of this side chain has proven to be essential for the biological activity of Taxol. ##STR1##
The chemical complexity of Taxol dictates that its commercial production by total synthesis is not likely to be economical, while the naturally derived 10-deacetylbaccatin III is readily available in relatively high yield from T. baccata. Preparation of quantities of Taxol economically by a semisynthetic approach which involves the condensation of suitably protected N-benzoyl-(2R,3S)-3-phenylisoserine with suitably protected 10-deacetylbaccatin III provides an alternative source of this important natural product and the access to semisynthetic analogues. ##STR2##
Therefore, the development of short and practical synthetic routes for phenylisoserine derivatives, as well as of procedures for attachment of the C-13 side chain to the baccatin III nucleus, which are adaptable for industrial-scale production, have become very important.
The numerous papers devoted to the preparation of enantiomerically enriched N-benzoyl-(2R,3S)-3-phenylisoserine include research on semisynthesis drawing from the chiral pool (J.Org.Chem. 1991, 56, 6939; Tetrahedron Lett. 1994, 35, 2845; Synthesis 1995, 181), enzymatic and/or microbial processes (Tetrahedron 1990, 46, 3841; J.Org.Chem. 1993, 58, 1068; J.Org.Chem. 1993, 58, 1287; Tetrahedron Lett. 1994, 35, 9289; Tetrahedron:Asymmetry 1993, 4, 2069; Biotechnol. Appl.Biochem. 1994, 20, 23-33), diastereoselective reactions with covalently-bound chiral auxiliaries or with chiral substrates (J.Org.Chem. 1991, 56, 1681; J.Am.Chem.Soc. 1988, 110, 5917; Tetrahedron Lett. 1991, 32, 3151; J.Chem.Soc., Perkin Trans.1 1993, 1375; Tetrahedron Lett. 1992, 33, 5185; Tetrahedron:Asymmetry 1992, 3, 1007; Tetrahedron 1992, 48, 6985; Synlett 1992, 761; J.Am.Chem.Soc. 1993, 115, 1151; J.Org.Chem. 1994, 59, 1238; J.Org.Chem. 1993, 58, 5889; PCT WO 93 17,997; Tetrahedron 1994, 50, 2785; Tetrahedron 1993, 49, 8323; J.Med.Chem. 1992, 35, 4230; Tetrahedron Lett. 1993, 34, 6049; Bioorg.Med.Chem.Let. 1993, 3, 2467; Bioorg.Med.Chem.Let. 1993, 3, 2475; Bioorg.Med.Chem.Let. 1994, 4, 1381; PCT WO 94 07,847; U.S. Pat. No. 5,294,737; J.Chem.Soc., Perkin Trans.1 1994, 2385), asymmetric catalysis (J.Org.Chem. 1986, 51, 46; J.Org.Chem. 1990, 55, 1957; J.Org.Chem. 1992, 57, 4320; J.Org.Chem. 1994, 59, 5104; Tetrahedron 1992, 48, 10515; J.Chem.Soc., Chem.Commun. 1994, 21; Tetrahedron 1994, 50, 4323; Tetrahedron Lett. 1995, 36, 2063), and chemical resolution of racemic acids (J.Org.Chem. 1993, 58, 255; Tetrahedron: Asymmetry 1994, 5, 1683).
On the other side, only a few reactions have been developed to is attach the "side chain" to the free C-13 OH group of baccatin derivatives. This esterification reaction appears to be hampered by the relevant steric hindrance around the C-13 OH group. Essentially only two general methods have been developed to solve this problem: the first one relies on the DCC Rhone-Poulenc/Gif protocol (J.Am.Chem.Soc. 1988, 110, 5917; Tetrahedron Lett. 1992, 33, 5185, EP 336840, 1989), and the second one on the .beta.-lactam Holton-Ojima protocol (European Patent Application 400971, 1990; U.S. Pat. No. 5,015,744, 1991; Chem. Abstr. 1990, 114, 164568q; U.S. Pat. No. 5,136,060, 1992; U.S. Pat. No. 5,175,315, 1992; P.
REFERENCES:
patent: 5476954 (1995-12-01), Bourzat et al.
Gennari Cesare
Mongelli Nicola
Vanotti Ermes
Vulpetti Anna
Pharmacia & Upjohn S.p.A.
Trinh Ba K.
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