Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1992-11-20
1994-03-01
Dentz, Bernard
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
560 29, 562418, 562444, C07D30514, C07C22936, C07C27122
Patent
active
052909573
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a process for the stereoselective preparation of phenylisoserine derivatives of the general formula ##STR1## in which R is a phenyl radical or a tert-butoxy radical and R.sub.1 is a protecting group for the hydroxyl group.
DESCRIPTION OF THE INVENTION
In general formula (I), R.sub.1 is more particularly a methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, (.beta.-trimethylsilylethoxy)methyl, tetrahydropyranyl or 2,2,2-trichloroethoxycarbonyl radical. The radical R.sub.1 is preferably the 1-ethoxyethyl radical.
The procedure of general formula (I) are useful for preparing the baccatin III and 10-deacetylbaccatin III derivatives of the general formula ##STR2## in which R is a phenyl radical or a tert-butoxy radical and R.sub.2 is a hydrogen atom or an acetyl radical.
The products of general formula (II) in which R is a phenyl radical correspond to taxol and 10-deacetyltaxol and the products of general formula (II) in which R is a tert-butoxy radical correspond to those described in European patent 253 738.
The products of general formula (II), and in particular the product of general formula (II) in which R.sub.2 is a hydrogen atom and which is in the 2'R,3'S form, have particularly valuable antitumoral and antileukaemic properties.
The products of general formula (II) can be obtained by reacting a product of general formula (I) with a taxane derivative of the general formula ##STR3## in which R.sub.3 is an acetyl radical or a protecting group for the hydroxyl group and R.sub.4 is a protecting group for the hydroxyl group, and then replacing the protecting groups R.sub.1 and R.sub.4 and, if appropriate, R.sub.3 with a hydrogen atom under the conditions described by J-N. DENIS et al., J. Amer. Chem. Soc., 110(17) 5917-5919 (1988).
It is possible to react the racemic product of general formula (I) and subsequently to separate the diastereoisomers of the product of general formula (II), or else to react each of the enantiomers of the product of general formula (I) separately with the product of general formula (III).
According to the present invention, the acid of general formula (I) (syn form, racemic mixture) can be obtained from benzylamine.
By reaction with an agent for introducing a benzoyl or t-butoxycarbonyl group, benzylamine is converted to a product of the general formula ##STR4## in which R is as defined above, which, after double anionisation, is reacted with acrolein to give the alcohol of the general formula ##STR5## in which R is as defined above, in the form of a syn and anti mixture containing essentially the syn form: ##STR6##
The alcohol of general formula (Va), previously separated from the mixture of the syn and anti forms, is oxidized to the acid of general formula (I) after protection of the hydroxyl group.
The product of general formula (IV) is generally obtained by reaction with an agent for introducing a benzoyl or t-butoxycarbonyl group, preferably benzoyl chloride or di-t-butyl dicarbonate, as the case may be. The reaction is generally carried out in an organic solvent such as methylene chloride, in the presence of an inorganic base such as sodium hydroxide or sodium bicarbonate or carbonate, or an organic base such as triethylamine or 4-dimethylaminopyridine, at a temperature of between 0.degree. and 50.degree. C.
The double anionization of the product of general formula (IV) is generally carried out using equivalents of an organolithium derivative such as s-butyllithium, in an anhydrous organic solvent such as tetrahydrofuran, at a temperature below -50.degree. C. and preferably of about -78.degree. C.
The reaction of acrolein with the dianion of the product of formula (IV) is generally carried out by adding acrolein, preferably freshly distilled, to the solution of the dianion, previously cooled to about 100.degree. C. After hydrolysis, the product of general formula (V) is obtained in the form of a mixture of the syn and anti diastereoisomers, from which the syn form of formula (Va) is separated by chromatography.
Protection
REFERENCES:
Jour. of Org. Chem, vol. 51, No. 1, 1986 Denis, et al. "An Efficient, Enantioselective Synthesis of the Taxol Side Chain", pp. 46-50.
Jour. of the Amer. Chem. Soc., vol. 110, No. 17, Aug. 17, 1988, Denis, et al, "A Highly Efficient, Practical Approach to Natural Taxol", pp. 5917-5919.
Archiv der Pharmazie, vol. 308, 1975, Kamandi, et al. "Die Synthese von Ammonolyse von Beta-Phenyl-Glycidestern, II", pp. 135-141.
Correa Arlene
Denis Jean-Noel
Greene Andrew-Elliot
Dentz Bernard
Rhone Poulenc Rorer S.A.
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