Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-02-09
1997-02-25
Trinh, Ba K.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
549510, 549511, 562887, 562895, C07D26306, C07D30514
Patent
active
056060688
DESCRIPTION:
BRIEF SUMMARY
This application is a 35 USC 371 PCT/FR93/00111 dated Feb. 4, 1993.
DESCRIPTION OF THE INVENTION
The present invention relates to new anhydrides of general formula: ##STR3## to their preparation and to their use.
In the general formula (I), represents a hydrogen atom and R.sub.3 represents a protecting group of the hydroxyl functional group, together form a 5- or 6-membered saturated heterocycle.
More particularly, Ar represents an optionally substituted phenyl or .alpha.- or .beta.-naphthyl radical, it being possible for the substituents to be chosen from halogen atoms (fluorine, chlorine, bromine or iodine) and alkyl, aryl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxyl, mercapto, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl radicals, it being understood that the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 carbon atoms and the aryl radicals are phenyl or .alpha.- or .beta.-naphthyl radicals.
More particularly still, Ar represents a phenyl radical optionally substituted with a chlorine or fluorine atom, or with an alkyl(methyl), alkoxy(methoxy), dialkylamino(dimethylamino), acylamino(acetylamino) or alkoxycarbonylamino(tert-butoxycarbonylamino) radical.
More particularly, R.sub.3 represents a protecting group of the hydroxyl functional group chosen from methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, (.beta.-trimethylsilylethoxy)methyl, tetrahydropyranyl, 2,2,2-trichloroethoxymethyl or 2,2,2-trichloroethoxycarbonyl radicals.
More particularly, when R.sub.2 and R.sub.3 together form a 5- or 6-membered saturated heterocycle, the latter represents an oxazolidine ring which is optionally gem-disubstituted in the 2-position.
According to the present invention, the new anhydrides of general formula (I) can be obtained by reacting a dehydrating agent, such as an imide like dicyclohexylcarbodiimide, with the acid of general formula: ##STR4## in which Ar, R.sub.1, R.sub.2 and R.sub.3 are defined as above.
Generally, 0.5 to 1 mol of dehydrating agent is used per mole of acid used.
Generally, the reaction is carried out in an organic solvent chosen from halogenated aliphatic hydrocarbons, such as dichloromethane or chloroform, and aromatic hydrocarbons, such as benzene, toluene or xylenes.
Generally, the reaction is implemented at a temperature of between 0.degree. and 30.degree. C.
The anhydride obtained can be separated from the reaction mixture according to the usual techniques. However, it can be particularly advantageous to use the anhydride obtained prepared extemporaneously without isolation prior to its use in particular in esterification reactions.
The anhydrides of general formula (I) are generally more stable than the acids from which they derive in esterification reactions and they can lead to reactions which are more easily reproducible.
The new anhydrides of general formula (I) are particularly useful for preparing taxol or taxotere or their derivatives of general formula: ##STR5## in which R represents a hydrogen atom or an acetyl radical and R.sub.1 and Ar are defined as above, which exhibit particularly advantageous antitumour properties.
According to the invention, the products of general formula (III) can be obtained: defined as above, R.sub.1 represents a benzoyl or tert-butoxycarbonyl radical, R.sub.2 represents a hydrogen atom and R.sub.3 represents a protecting group of the hydroxyl functional group, with a derivative of baccatin III or of 10-deacetylbaccatin III of general formula: ##STR6## in which G.sub.1 represents a protecting group of the hydroxyl functional group, such as a 2,2,2-trichloroethoxycarbonyl radical or a trialkylsilyl radical, each alkyl part of which contains 1 to 4 carbon atoms, and G.sub.2 represents an acetyl radical or a protecting group of the hydroxyl functional group, such as a 2,2,2-trichloroethoxycarbonyl radical, in order to obtain a product of general formula: ##STR7## in which Ar, R.sub.1, R.sub.2, R.
REFERENCES:
March, J., "Advanced Organic Chemistry", pp. 369-370, 2nd edition, 1977.
Jerry March, Advanced Organic Chemistry-Reactions, Mechanism, and Structure (3d Edition) 346-348, 1977.
Denis et al., Journal of the American Chemical Society, 110 (17): 5917-5919 (Aug. 1988).
Denis et al., The Journal of Organic Chemistry, 51(1): 46-50 (Jan. 1986).
H. Pielartzik et al., "Carbons aure-ester", 656-684, May 1995.
Rhone-Poulenc Rorer S.A.
Trinh Ba K.
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