Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-04-18
2004-11-30
Trinh, Ba K. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S511000, C060S039440, C060S039440, C060S039440, C060S039440, C060S039440, C060S039440, C060S039440, C060S039440
Reexamination Certificate
active
06825365
ABSTRACT:
The present invention relates to novel intermediates for the hemisynthesis of taxanes and to their processes of preparation.
Taxanes, natural substances with a diterpene skeleton which is generally esterified by a &bgr;-amino acid side chain derived from N-alkyl- or N-aroylphenylisoserine, are known as anticancer agents. Several dozen taxanes have been isolated from Taxaceae of the genus Taxus, such as, for example, paclitaxel (R
1
=Ac, R
2
=Ph, R
3
═R
4
=H), cephalomanine, their derivatives deacetylated in the 10 position, or baccatins (derivatives without side chain) represented by the formulae 1 and 2 below.
To avoid rapidly exhausting its original source,
Taxus brevifolia
, French researchers have sought to isolate paclitaxel from renewable parts (leaves) of
T. baccata
, the European yew. They have thus demonstrated the probable biogenetic precursor of taxanes, 10-deacetylbaccatin III, the springboard of choice for the hemisynthesis because of its relative abundance in leaf extracts.
The hemisynthesis of taxanes, such as paclitaxel or docetaxel (R
1
=Ac, R
2
=t-butyloxy, R
3
═R
4
=H), thus consists in esterifying the 13-hydroxyl of a protected derivative of baccatin or of 10-deacetylbaccatin III with a &bgr;-amino acid derivative.
Various processes for the hemisynthesis of paclitaxel or of docetaxel are described in the state of the art (EP-0 253 738, EP-0 336 840, EP-0 336 841, EP-0 495 718, WO 92/09589, WO 94/07877, WO 94/07878, WO 94107879, WO 94/10169, WO 94/12482, EP-0 400 971, EP-0 428 376, WO 94/14787). Two recent works, I. Georg, T. T. Chen, I. Ojima, and D. M. Vyas, “Taxane Anticancer Agents, Basic Science and Current Status”, ACS Symposium Series 583, Washington (1995) and Matthew Suffness, “Taxol® Science and Applications” CRC Press (1995), 1500 references cited, comprise exhaustive compilations of hemisyntheses of taxanes.
The &bgr;-amino acid side chains derived from N-alkyl- or N-aroylphenylisoserine of paclitaxel or docetaxel are of (2R,3S) configuration and one of the main difficulties in the hemisynthesis of taxanes is to obtain an enantiomerically pure product. The first problem consists in obtaining a pure enantiomer of the phenylisoserine derivatives employed in the hemisynthesis of taxanes. The second problem consists in retaining this enantiomeric purity during the esterification of the baccatin derivative and the subsequent treatments of the products obtained including deprotection of the hydroxyls and similar treatments.
Many studies on asymmetric synthesis involving derivatives of &bgr;-amino acids have focused on the chemistry of isoserine and of its derivatives, &bgr;-amino acids for which a dehydrated cyclic form is a &bgr;-lactam (EP-0 525 589). The majority of the various syntheses of phenylisoserine derivatives useful as precursors of taxane side chains focus on a common intermediate, (2R,3R)-cis-&bgr;-phenylglycidic acid, which is subsequently converted to &bgr;-phenylisoserine by reaction with ammonia (EP-0 495 718) or a nucleophile (Gou et al.,
J. Org. Chem
., 1983, 58, 1287-89). These various processes require a large number of stages in order to produce &bgr;-phenylisoserine of (2R,3S) configuration, necessarily with a stage of racemic resolution by conventional selective crystallization techniques, either for cis-&bgr;-phenylglycidic acid or for &bgr;-phenylisoserine, or subsequently, after conversion. Furthermore, in order to retain the enantiomeric purity of taxane side chain precursors during the esterification of the baccatin derivative, various means have been provided, in particular by using cyclic intermediates of blocked configuration, which remove the risks of isomerization during esterification reactions under severe reaction conditions. In particular, they involve &bgr;-lactam (EP-0 400 971), oxazolidine (WO 92/09589, WO 94/07877, WO 94/07878, WO 94/07879, WO 94/10169, WO 94/12482), oxazinone (EP-0 428 376) or oxazoline (WO 94/14787) derivatives. These cyclic precursors are prepared from the corresponding &bgr;-phenylisoserine derivative. As for the latter, the processes provided involve a large number of stages and a necessary racemic resolution in order to obtain the desired taxane side chain precursor. It was thus important to develop a novel route for the improved synthesis of intermediates which are taxane side chain precursors, in particular of enantiomers of cis-&bgr;-phenylglycidic acid, of &bgr;-phenylisoserine and of their cyclic derivatives.
Finally, for the hemisynthesis of taxanes and in particular of paclitaxel, the sole appropriate baccatin derivative used until now is that for which the 7-hydroxy radical is protected by a trialkylsilyl (EP-0 336 840, WO 94/14787), the deprotection of which is carried out exclusively in acidic medium. It was thus also important to employ novel protective groups for the hydroxyl functional group which in particular make possible selective protection of the 7-hydroxy radical and in addition allow a wider choice of operating conditions for the deprotection stage.
The present invention relates first of all to an improved process for the preparation of taxane side chain precursors.
The process according to the invention comprises converting a cis-&bgr;-arylglycidate derivative of general formula I
in which
Ar represents an aryl, in particular phenyl, and
R represents a hydrocarbon radical, preferably a linear or branched alkyl or a cycloalkyl optionally substituted by one or more alkyl groups;
wherein said process is carried out so as to regio- and stereospecifically introduce the &bgr;-N-alkylamide and the &agr;-hydroxyl or their cyclic precursors in a single stage by a Ritter reaction. Depending on the reaction mixture, two types of Ritter reaction are thus distinguished: one with opening of the oxetane, resulting in a linear form of the chain which is directly and completely functionalized, the other resulting in the direct formation of an oxazoline. The “*” symbol indicates the presence of an asymmetric carbon, with an R or S configuration. In both cases, the Ritter reaction is stereospecific, with retention of C-2 configuration and inversion of C-3 configuration. The process according to the invention is advantageously carried out on one of the enantiomers of the cis-&bgr;arylglycidate derivative of general formula I, so as to obtain the corresponding enantiomer of the linear chain or of the oxazoline, without subsequently requiring a racemic resolution. According to the method of preparation of the cis-&bgr;-arylglycidate derivative of general formula I described below, R represents an optically pure enantiomer of a highly sterically hindered chiral hydrocarbon radical, advantageously a cycloalkyl substituted by one or more alkyl groups, in particular a cyclohexyl. R will then preferably be one of the enantiomers of the menthyl radical, in particular (+) menthyl.
1. Direct Synthesis of the Linear Chain
The direct synthesis of the linear chain by the Ritter reaction comprises reacting a cis-&bgr;-arylglycidate derivative of general formula I defined above with a nitrile of formula
R
2
—CN
in which
R
2
represents an aryl radical, preferably a phenyl,
in the presence of a proton acid, such as sulphuric acid, perchloric acid, tetrafluoroboric acid, and the like, and of water.
A &bgr;-arylisoserine derivative of general formula IIa
in which Ar, R and R
2
are defined above, is then obtained.
The reaction is carried out with inversion of the configuration of the C-3 of the cis-&bgr;-phenylglycidate derivative. Thus, starting from a (2R,3R)-cis-&bgr;-phenylglycidate derivative, the corresponding &bgr;-arylisoserine derivative of (2R,3S) configuration is obtained.
The Ritter reaction is carried out in an appropriate solvent, at a temperature ranging from −75 to +25° C.
The appropriate solvent can be the nitrile itself, when it is liquid at the reaction temperature, or alternatively the acid itself (sulphuric, perchloric or tetrafluoroboric), or a solvent, such as, for example, methylene chloride or ethyl ether
Chanteloup Luc
Chauveau Bruno
Corbin Christine
Dhal Robert
Guen Sonia Le
Millen White Zelano & Branigan P.C.
Novasep
Trinh Ba K.
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