Process for the Preparation of Eserethole

Details Process for the Preparation of Eserethole Process for the Preparation of Eserethole

1994-12-19

1996-05-21

McKane, Joseph K.

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

564214, C07D20956

Patent

active

055191444

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP93/01353 filed May 28, 1993.
The present invention relates to a process for the preparation of the compound of formula (II) ##STR2## which is an useful intermediate for the preparation of eserethole.
The invention also relates to a process for the preparation of eserethole starting from compound (II).
Eserethole of formula (VII) ##STR3## is in its turn the main intermediate for the synthesis of (-)eserine and the analogues thereof, used in human therapy for the treatment of various diseases, some of which are particularly severe and wide-spread, such as Alzheimer's disease.
(-)Eserine is a natural alkaloid which can be prepared either by extraction or synthetically.
Some of the described total synthesis involve the intermediate formation of (-) eserethole or (.+-.)eserethole.
The interest for an industrial process to prepare eserethole and the precursors thereof which is advantageous as far as yield, purity and costs are concerned is therefore evident.
The known preparation of the intermediate of formula (II) (J. Am. Chem. Soc., 57, 563, 1935) comprises five steps, according to the following scheme I: ##STR4##
Now a process has been found, and it is the first object of the invention, which allows to prepare compound (II) in only two steps, according to the following scheme (II): ##STR5##
4-(N-Methylamino)phenol is reacted with a 2-halogen-propionyl chloride to give the novel intermediates of formula (Ia) (X.dbd.C1) or (Ib) (X.dbd.Br), from which compound (II) can be obtained by cyclization in the presence of Lewis acids.
The reaction conditions and the solvents are those conventional for this kind of reactions. In the first step, toluene as the solvent and a reaction temperature of about 20.degree. C. are particularly preferred.
In the second step, aluminium chloride is particularly preferred as the Lewis acid, whereas suitable solvents are aromatic hydrocarbons, particularly chlorobenzene.
The preparation of eserethole from compound (II) was described by a number of Authors.
Common to all the known synthesis are the O-alkylation of the intermediate (II) with alkyl sulfates and the subsequent alkylation at the 3 position of the oxindole ring with chloroacetonitrile, which alkylation can be carried out with sodium ethoxide in ethanol (Julian et al. J. Am. Chem. Soc. 57, 563, 1935) or in liquid-liquid duoble phase in the presence of chiral phase transfer catalysts (PTC) (Wong et al. J. Org. Chem. 56, (2), 873 (1991).
From the resulting compound, two reaction pathways can be followed: transformation of the amine into (.+-.) eserethole (Julian et al., ibidem; Wong et al., ibidem; Brossi et al. Heterocycles, 27(7), 1709, 1988); or lithium aluminium hydride or with sodium and alcohols and subsequent alkylation of the NH on the third ring to give eserethole (Brossi et al., Heterocycles, 27(7), 1709, 1988; Brossi et al., Heterocycles, 27(3), 745, 1988).
Now an improved process has been found, and it is a second object of the invention, for the preparation of eserethole starting from compound (II), which process comprises: (III); 1,3-dimethyl-3-cyanomethyl-5-acyloxy-oxindole (IV); with ethyl halides or sulfate; bis-(methoxy-ethoxy)aluminum hydride, to give O-ethyl-nor-eseroline (VI);
Steps b), c) and e) are carried out essentially according to the already known procedures, whereas steps a) and d) are the novel aspects of the process of the invention.
The advantage of acylation compared with alkylation resides in the higher selectivity of the reaction, without formation of double alkylation products, with a resulting increase in the yield. Particularly preferred is acylation with acetic anhydride to give intermediates (II) and (IV) in which R is acetyl. Said intermediates are novel.
In step d), the use of sodium bis-(methoxyethoxy)aluminium hydride (VITRIDE.RTM.) in toluene, instead of
LiAlH.sub.4 or sodium and ethanol used in the known technique, decreases the risks of a reduction process and achieves higher global yields.
N-Methylation from O-ethyl-nor-eseroline to eserethole is

REFERENCES:
CA87:17297w Aliphatic . . . Fungicides. Misato et al., p. 165, 1977.
CA120:192066s Preparation . . . eserthole. Belli et al., p. 1086, 1994.
CA122:83232P EVA- . . . film. Vermeiren, p. 91, 1995.

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