CS258293B1 - Method of furfuryl idenmalonic acid's diethyl ester preparation - Google Patents

Abstract

The solution lies in the field of drug synthesis. It relates to a process for the preparation of a diethyl ester furfurylidenemalonic acid is an intermediate in the manufacture of medicaments, in particular substances with cerebral vasodilator activity. The process for preparing the compound of formula I consists in the reaction of furfural with diethyl malonate in boiling toluene in the presence of piperidine acetate as catalyst and under continuous removal by reaction of the resulting water by distillation azeotropic mixture of toluene with water.

Description

The present invention relates to a process for preparing diethyl ester of forfurylidenemalonic acid of formula I.

/ COOClHb ^ COOClHg

The compound of formula (I) is an intermediate in the manufacture of medicaments, in particular substances with vasodilating, spasmolytic activity. Representative of this class of drugs is the naphthyrdrofuryl, i.e. 2- (tetrahydrofurfuryl) -3- (1-naphthyl) propionic acid 2-diethylaminoethyl ester, used in the form of hydrogen oxalate as a cerebral vasodilator in gerontology, especially gerontopsychiatry.

The compound of Formula I is accessible from furfural and diethylmalonate. The literature (Hinz A. et al., Ber. Dtsch. Chem. Ges. 76, 676, 1943) describes the preparation of a compound of formula I by refluxing a mixture of acetic anhydride, furfural and diethyl malonate. This embodiment of the preparation of the compound of formula I requires relatively harsh reaction conditions, in particular a high temperature, which is technologically disadvantageous.

The present invention represents a technically advantageous form of preparation of the compound of formula (I). The reaction of furfural with diethyl malonate is carried out under conditions not described herein, i.e. in boiling toluene in the presence of piperidine acetate as catalyst. The water produced by the reaction is continuously removed by distillation of the azeotropic mixture with toluene, which boils at 84 ° C.

Thus, at this stage, the temperature of the reaction mixture is only 100 to 104 ° C. Only after removal of water, the temperature of the mixture slowly increased to 110-120 ° C, and when the temperature of the distilling vapors reached 111 ° C, the reaction was completed because it distilled pure toluene.

Work-up of the reaction mixture yielded a very pure product (85.7%) which, according to gas chromatography, contained 99.7% of the desired compound. Thus, in comparison with the cited literature, the process of the present invention provides, under milder reaction conditions, a higher yield (the literature reports a maximum of 82% of the product of unspecified purity) over a product of a high degree of purity.

The following example is illustrative of the possibilities of the invention, but is not intended to exhaustively describe all possibilities of the invention.

Example

To a stirred solution of 288 g furfural in 300 ml toluene was added 480 g diethyl malonate,

10.2 g of piperidine and 36 g of acetic acid are heated to 100-104 ° C and the azeotropic mixture of toluene and water (bp 84 ° C) is slowly distilled off for 1.5 h. Thereafter the temperature of the mixture (within 4 h) is raised to 110 to 120 ° C, gradually increasing the boiling point of the mixture.

When it reaches 110 ° C, the anhydrous toluene is distilled and the reaction is complete. After cooling, the mixture is filtered through a column of 600 g of neutral alumina (activity II), the column is washed with 200 ml of toluene, the filtrate is evaporated under reduced pressure and the residue is distilled.

The crude product obtained (665 g), boiling at 118 to 122 ° C / 53 Pa, was redistilled through a cm column. 605 g (85%) of a product boiling at 116-118 ° C / 40 Pa are obtained. Its purity, determined by gas chromatography, is 99.7%. On standing for 2 days at 10 ° C, the product crystallizes and melts at 40-40.5 ° C. Its analysis is in accordance with the empirical composition of ^C 12 ^H 14 ° 5 ^{and and 1 H NMR} spectra fully confirm its identity as a compound of formula I.

Claims (1)

Process for preparing the furfurylidenemalonic acid diethyl ester of the formula I COOCjHg CH = C 2 ^x cooc ₂ h ₅ (I) by reaction of furfural with diethyl malonate, characterized in that the reaction is carried out in boiling toluene in the presence of piperidine acetate catalyst and continuously removing the resulting water by distilling off the azeotropic mixture of toluene and water.