Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Patent
1992-11-13
1994-03-08
Dees, Jose G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
560 27, 562444, 562450, C07C26900
Patent
active
052929213
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a process for the enantioselective preparation of phenylisoserine derivatives of the general formula
DESCRIPTION OF THE INVENTION
##STR2## in which R is a phenyl radical or a tert-butoxy radical and R.sub.1 is a protecting group for the hydroxyl group.
In general formula (I), R.sub.1 is more particularly a methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, (b-trimethylsilylethoxy)methyl, tetrahydropyranyl or 2,2,2-trichloroethoxycarbonyl radical. The radical R.sub.1 is preferably the 1-ethoxyethyl radical.
The products of general formula (I) are useful for preparing the baccatin III and 10-deacetylbaccatin III derivatives of the general formula ##STR3## 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 antitumoural 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 ##STR4## 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).
According to the present invention, the products of general formula (I) are obtained from S(+)-phenylglycine of the formula ##STR5## by treatment with a reducing agent and with a reagent for introducing a benzoyl or t-butoxycarbonyl group to give the alcohol of the formula ##STR6## in which R is a phenyl or tert-butoxy radical, which is oxidized and then reacted with a vinylmagnesium halide to give the product of the formula ##STR7## in which R is a phenyl or tert-butoxy radical, the hydroxyl group of which is then protected by a group R.sub.1 to give a product of the general formula ##STR8## in which R is a phenyl or tert-butoxy radical and R.sub.1 is as defined above, which is oxidized to the product of general formula (I).
According to the invention, the alcohol of formula (V) can be obtained: group with the amino alcohol obtained by reducing S(+)-phenylglycine, for introducing a benzoyl or t-butoxycarbonyl group with S(+)-phenylglycine.
Whichever variant of the process is used, it is not necessary to isolate the amino alcohol or the acid formed as an intermediate.
To carry out the process, it is particularly advantageous to reduce the S(+)-phenylglycine and then to react the product with the agent for introducing a benzoyl or t-butoxycarbonyl group.
As the reducing agent, it is preferred to use lithium aluminum hydride or borane (BH.sub.3), preferably in the form of a complex with dimethyl sulphide, in the presence of boron trifluoride etherate. The reaction is generally carried out in an inert organic solvent such as, for example, an ether like tetrahydrofuran or dimethoxyethane. The reduction is generally carried out at a temperature of between 50.degree. and 100.degree. C.
As the agent for introducing a benzoyl or t-butoxycarbonyl group, it is preferred to use 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. The reaction is generally carried out at between 0.degree. C. and the reflux temperature of the reaction mixture.
According to the invention, the alcohol
REFERENCES:
patent: 4501919 (1985-02-01), Koch et al.
patent: 4605759 (1986-08-01), Mita et al.
patent: 4695580 (1987-09-01), Ohashi et al.
Database WPIL, AN 83-31122k [13], Derwent Publications, Ltd., (London, GB), & JP-A-58 029 749, (H. Nohira), 22 Feb. 1983.
T. W. Greene, "Protective Groups in Organic Synthesis", 1981, pp. 16-22, 218-221, 261-263, Wiley-Interscience Pub., John Wiley & Sons.
The Journal of Organic Chemistry, vol. 49, No. 4, 24 Feb. 1984, American Chemical Society, Marx, et al.: "Reactivity-selectivity in the swern oxidation of alcohols using dimethyl sulfoxide-oxalyl chloride", pp. 788-793.
A. H. Haines: "Methods for the Oxidation of Organic Compounds", 1985, pp. 126-130, Academic Press, (London, GB).
The Journal of Organic Chemistry, v. 51, No. 1, 10 Jan. 1986, American Chem. Society, N. N. Denis, et al "An efficient, enantioselective synthesis of the taxol side chain", pp. 46-50.
Journal of the American Chemical Society, v. 110, No. 17, 17 Aug. 1988 Denis, et al., "A highly efficient, practical approach to natural taxol"; pp. 5917-5919.
Correa Arlene
Denis Jean-Noel
Greene Andrew-Elliot
Grierson David S.
Barts Samuel
Dees Jos,e G.
Rhone-Poulenc Rorer S.A.
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