CS258296B1 - Process for preparing 2-diethylaminoethyl ester of 2- (tetrahydrofurfuryl) -3- (1-naphthyl) propionic acid - Google Patents

Abstract

The solution falls into the field of drug synthesis. Its subject is a method for preparing 2-diethyl-aminoethyl ester of 2-(tetrahydrofurfuryl)-3-(1-naphthyl)propionic acid of formula I chcooch 2 ch 2 n ( c 2 h 8 | 2 (I) , whose salts, especially hydrogen oxalate, are used in gerontopsychiatry as cerebral vasodilators and intellectual performance-improving drugs. The method for preparing the substance of formula I according to the solution consists in the re-esterification of methyl ester of 2-(tetrahydrofurfuryl)-3-(1-naphthyl)propionic acid with 2-diethyl-aminoethanol in the presence of a small amount of sodium 2-diethylaminoethoxide as a catalyst in boiling toluene with slow distillation of the mixture of toluene with methanol and continuous replacement of the distillate with pure toluene.

Description

The present invention relates to a process for the preparation of 2- (tetrahydrofurfuryl) -3- (1-naphthyl) propionic acid 2-diethylaminoethyl ester of the formula I: chcooch ₂ ch ₂ n (c ₂ h _b ) ₂

The compound of formula I in the form of a hydrogen oxalate mixture of the two possible stereoisomers (racemates) is used in therapy under the generic name naphthyrdrofuryl, both in peripheral vascular disorders and in cerebral blood flow disorders. In addition to the vasodilatory effect, it improves microcirculation and has a positive effect on tissue metabolism. It has been shown to enhance cellular respiration, improve oxygen utilization, interfere with glucose supply and utilization, activate the citric acid cycle, and increase overall tissue energy potential. It has been shown to be sympatholytic, locally anesthetic and antiserotonin; is an antagonist »

bradykinin.

Increased blood flow to the brain was found both after single administration and after long-term treatment. It has been shown that in chronic diffuse arteriosclerotic brain disorders, it improves general condition, affective disorders, intellectual performance, and overall patient sociability. It is very well tolerated. It has been evaluated as a contribution to gerontopsychiatric practice (Judge T. G., Urquhart A .: Curr. Med, Res. Opin. 1, 166, 197 2; Bouvier J. B. et al .:

J. Int. Copper. Res. 2, 59, 1974; Lehmann Η. E .: Psychopharmacol. Bull. 12 (2), 49 (1976);

Hronek J. et al. Psychiat. 73, 239 (1977); Litomericky 5. et al :: Farm. Obzor 51,

309, 1982).

The preparation of the compound of formula I has been described by a number of methods. The oldest is the reaction of 2- (tetrahydrofurfuryl) -3- (1-naphthyl) propionic acid (a mixture of two racemates) with 2-diethylaminoethyl chloride in boiling 2-propanol. When 2-diethylaminoethyl chloride is used as the hydrochloride, the reaction in boiling 2-propanol is carried out in the presence of anhydrous potassium carbonate. 2- (tetrahydrofurfuryl) -3- (1-naphthyl) propionic acid can also be converted to the ester of formula I by azeotropic esterification with 2-diethylaminoethanol (Szarvasi E. et al .: Bull. Soc. Chim. Fr.

1966, 1838; Belg. U.S. Pat. 613 547; Fr. U.S. Pat. 1,363,948; Fr. U.S. Pat. M 3,843). In addition to these evident and fairly suitable methods, other more complex and technically less advantageous methods have been used to prepare the ester of formula I (Fr. pat. 2,444,033 and 2,444,034).

It has now been found that the preparation of the ester of the formula I can be very advantageously carried out by re-esterification of the known methyl ester of the formula 2- (tetrahydrofurfuryl) -3- (1-naphthyl) propionic acid of the formula II

(II) (Szarvasi E. et al .: Bull. Soc. Chim. Fr. 1963, 1181) by reaction with 2-diethylaminoethanol in boiling toluene in the presence of a small amount of sodium 2-diethylaminoethoxide as a catalyst. In the reaction, a mixture of toluene with methanol released is slowly distilled off and replaced with pure toluene. Since the methyl ester of formula (XI) can be prepared in high purity and the transesterification proceeds without side reactions, the ester of formula (I) obtained is already highly pure as a residue and does not need to be distilled to convert to hydrogen oxalate. The presently described process for preparing the ester of formula I is an object of the present invention.

The following example is merely illustrative of the possibilities of the invention and is not intended to fully describe all possibilities of the invention.

Example

0.23 g of sodium is dissolved in 25.8 g of 2-diethylaminoethanol, 50 ml of toluene and 31.7 g of methyl 2- (tetrahydrofurfuryl) -3- (1-naphthyl) propionic acid (XI) are added and the mixture is slowly added. A toluene / methanol mixture is distilled off through the column, which is continuously replaced with anhydrous toluene. After 20 hours of distillation, 165 ml of the above mixture were distilled off and replaced with an equal volume of toluene. The mixture was then diluted with 150 ml of toluene, washed at 35 ° C with water, dried over sodium sulfate and evaporated under reduced pressure. In a yield of 37.3 g (92%), the obtained residue is a crude, oily base of formula I which is a mixture of two racemates. This euro product is sufficiently pure to be converted to good quality hydrogen oxalate. For characterization and for measurement of spectra, samples may be purified by distillation; t.v. 204 ° C / 53 Pa or on a diffusion pump 189 to 193 ° C / 3-4 Pa. Analysis and spectra of this base of formula I confirm its identity.

Neutralization of the undistilled base with oxalic acid dihydrate in acetone affords crystalline hydrogen oxalate melting at 111-113.5 ° C. According to HPLC analysis, this salt contained 33.6% of racemates A and 66.4% of racemates B. Recrystallization from acetone shifts the ratio of components to favor racemates B; after a single recrystallization from acetone, the product contains 28.4% of racemates A and 71.6% of racemates B (see also European Patent Application 69,013).

Claims (1)

Process for preparing 2- (tetrahydrofurfuryl) -3- (1-naphthyl) propionic acid 2-diethylaminoethyl ester I W ~ ^CH \ Λ ' CX ^CH2Z (I) chcooch ₂ ch ₂ n (c ₂ h ₅ ) ₂ characterized in that 2- (tetrahydrofurfuryl) -3- (1-naphthyl) propionic acid methyl ester of formula II (II) is re-esterified with 2-diethylaminoethanol in boiling toluene in the presence of a small amount of sodium 2-diethylaminoethoxide as a catalyst and distilling off a mixture of toluene and methanol, the mixture being continuously replaced by a volume of toluene.