Separation of isomers of furo (3,4-C) pyridine derivatives

Details Separation of isomers of furo (3,4-C) pyridine derivatives Separation of isomers of furo (3,4-C) pyridine derivatives

1990-10-18

1991-09-10

Dentz, Bernard

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C07D49148

Patent

active

050475371

DESCRIPTION:

BRIEF SUMMARY
The invention relates to a method for the separation of stereoisomers of furo[3,4-c]pyridine derivatives.
Furo[3,4-c]pyridine derivatives of the general formula I ##STR2## wherein R.sub.3 represents a hydrogen atom, a straight chain saturated hydrocarbon group having from 1 to 5 carbon atoms or unsaturated hydrocarbon group having from 2 to 5 carbon atoms, a heterocyclic group having up to 6 ring atoms, a phenyl group, a phenylalkyl or phenylalkenyl group, said groups being optionally substituted by one or more chlorine or fluorine atoms, trifluoromethyl groups, alkyl groups having from 1 to 5 carbon atoms, alkoxy groups having from 1 to 5 carbon atoms, alkylthio groups having from 1 to 5 carbon atoms, dialkylamino groups in which each alkyl group has from 1 to 5 carbon atoms, dialkylaminoalkoxy groups in which each of the two alkyl groups and the alkoxy group has from 1 to 5 carbon atoms or .alpha. or .beta.-alkoxy-N-pyrrolidinyl groups in which the alkoxy group has from 1 to 5 carbon atoms; R.sub.4 represents a hydrogen or chlorine atom and R.sub.6 represents a lower saturated or unsaturated hydrocarbon group up to C.sub.5, optionally substituted by a hydroxy radical, by a amino rest N(R).sub.2 wherein R stands for hydrogen or a lower alkyl up to C.sub.3. These compounds are known under their racemic form, for instance by our U. S. patent application Ser. Nos. 4,383,998, 4,585,776, 4,569,938, 4,569,939 and 4,581,362. They have various therapeutical activities, but it has been found that, for most of them, one stereoisomer is more active than the other. It is thus desirable to devise a method for the separation of their stereoisomers.
The invention provides a method for the separation of stereoisomers of 7-hydroxy-furo[3,4-c]pyridine derivatives which comprises reacting a fully O-acetylated monosaccharide halogenide with a racemate of the selected 7-hydroxy-furo[3,4-c]pyridine derivative, to form the (+) and (-) (O-acetylated monosaccharide) (furo[3,4-c]pyridine 7-yl derivative) ethers, then separating the (+) and the (-) ethers by selective crystallization, in an hydroalcoholic medium, either of the acetylated forms or of the corresponding desacetylated forms and, finally, working up each of the separated derivatives, optionally hydrolysing the ester function, and breaking the ether bond between monosaccharide and furo[3,4-c]pyridine derivative. The desacetylation is to be carried out before the selective crystallization when the desacetylated derivatives show a greater difference of solubility in the hydroalcoholic medium compared to the acetylated ones. The term monosaccharide is intended for a glucuronate ester or a glycoside; the term O-acetylated monosaccharide halogenide represents a bromide or a chloride of the said monosaccharide wherein all the hydroxy groups are acetylated. The hydroalcoholic medium used for the selective crystallization of the present invention consists of aqueous solution of a lower alkanol selected from the group consisting of methanol, ethanol and the propanols.


EXAMPLE 1

This example describes the separation of the stereoisomers of 1,3-dihydro-6-methyl-3-(p-chloro)phenyl-furo[3,4-c]pyridine. ##STR3##


REACTION NO. 1



Synthesis of (+)-1,3-dihydro-6-methyl-3-p-chlorophenylfuro[3,4-c]pyridine
7-O-(.beta.-D-glucuronate) methyl ester triacetate and (-)-1,3-dihydro-6-methyl-3-p-chlorophenylfuro[3,4-c]pyridine 7-O-(.beta. D-glucuronate) methyl ester triacetate.
4.06 g (0.015 mole) of 1,3-dihydro-6-methyl-3-p-chlorophenyl-7-hydroxy-furo[3,4-c]pyridine free base, 1.13 g (4 mmole) of mercuric chloride and 6.75 g of molecular sieve (4 .ANG.) were suspended in 85 ml of 1,2-dichloroethane, and refluxed for 15 minutes. 8.18 g (0.020 mole) of methyl (tri-O-acetyl-.alpha.-D-glucopyranosyl bromide)-uronate was then added in one portion and refluxing was continued under nitrogen for 15 hours. After cooling, the solvent was decanted into a separatory funnel, and the flask/sieves were rinsed five times with 50 ml aliquots of methylene dichloride. The organic layers were combined, and e

REFERENCES:
Lubineau et al., Tet. Letters, 26(14), pp. 1713-1716 (1985).
Gerding et al., HRC CC, J. High Resolution Chromatogr., Chromatogr. Commun., 10 (9), pp. 523-525, (1987), Chem. Abstracts, vol. 108, 119057n (1987).

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