Method for preparing an optically pure benzofuran carboxylic aci

Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...

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5483114, C07D30785, C07D40504

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058802967

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BRIEF SUMMARY
This application is a 371 of PCT/FR96/00697 filed May 9, 1996.
The present invention relates to a process for the preparation of an optically pure 2-ethyl-2,3-dihydrobenzofurancarboxylic acid derivative, to the derivative obtained and to its use for the preparation of the corresponding optically pure particular efaroxan. particular efaroxan, are derivatives that antagonize .alpha.2-adrenergic receptors and are described in European patent application No. 0,071,368 (Reckitt & Colman) for the treatment of depression or migraine. They are also described for the treatment of Parkinson's disease and neurodegenerative disorders, such as Alzheimer's disease, in WO patent applications No. 95/00145 and No. 95/01791 (Pierre Fabre Medicament).
Their enantiomers are described in WO patent application No. 92/05171, (-)-efaroxan being described in particular for treating diabetes, as a potassium-channel blocker. They are obtained by racemic resolution with dibenzoyl tartaric acid, at the final stage of the synthesis.
The present invention relates to a novel process for the stereospecific synthesis of optically pure formula I ##STR2## in which R represents a hydrogen or halogen atom or a lower alkyl, lower alkoxy or hydroxyl radical, starting with a corresponding optically pure 2-ethyl-2,3-dihydrobenzofurancarboxylic acid derivative, and to the optically pure derivatives obtained by means of this process.
The synthesis of the derivatives of general formula I is more particularly described in patent application EP-A-0,071,368 and consists in converting the corresponding 2-ethyl-2,3-dihydrobenzofurancarboxylic acid derivative into an amide of general formula III ##STR3## in which R is defined above, and then into the corresponding cyano derivative of general formula IV, by dehydration, ##STR4## which compound is then converted into the derivative of general formula I, using the usual techniques, with ethylenediamine.
The specific synthetic process according to the invention repeats this general scheme, with the corresponding optically pure 2-ethyl-2,3-dihydrobenzofurancarboxylic acid derivative as starting acid.
The present invention thus relates firstly to the process for the preparation of the starting acid of general formula II ##STR5## in which R represents a hydrogen or halogen atom or a lower alkyl, lower alkoxy or hydroxyl radical, in which process the racemic mixture is resolved by selective crystallization with the appropriate optically pure enantiomer of 2-phenylglycinol, in a suitable solvent, after which the crystallized optically pure acid of formula II is recovered.
The expression "appropriate optically pure enantiomer of 2-phenylglycinol" is understood to refer to the enantiomer of the acid which allows good separation of the diastereoisomeric salts obtained, one being more stable than the other, and which crystallizing. Thus, the acid of general formula II of R configuration is obtained by selective crystallization with S-(+)-2-phenylglycinol and, conversely, the acid of S configuration is obtained with R-(-)-2-phenylglycinol.
The term "suitable solvent" is understood to refer to any solvent which is capable of assisting the selective crystallization of an enantiomeric salt, while at the same time keeping the other in solution. It will be chosen advantageously from acetone, ethyl acetate, methyl ethyl ketone and mixtures thereof.
The preparation of the racemic acid of general formula II is described in the Journal of Heterocyclic Chemistry (1987, 24, 495).
The principle of selective crystallization by formation of diestereoisomeric salts is a known principle. However, it is difficult and hazardous to carry out, in particular when it involves obtaining high optical purity, that is to say greater than or equal to 95%.
One method for separating enantiomers of acids such as the acid of general formula II has been described, and does not involve selective crystallization of diastereoisomeric salts but esterification with optically active menthol (Chem. Pharm. Bull., 1988, 36, 902), which requires an additional s

REFERENCES:
Lin, J. of Liquid Chromatography, vol. 18, No. 13, pp. 2611-2619, Jul. 1995.
C.R. Edwards et al.: "A Practical Synthesis of 2,3-Dihydro-2-benzofurancarboxylic Acid: A General Route to 2,3-Dihydrobenzofurans"; Journal of Heterocyclic Chemistry, vol. 24, No. 2, Mar./Apr. 1987, pp. 495-496.

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