CS268355B1 - Process for the preparation of 2-methyl-2-trifluoromethyl-ethyl-2-tert-butyro-2-furfuryl-3- (1-naphthyl) -propenoic acid - Google Patents

Abstract

The invention relates to a method for preparing 2-diethylaminoethyl ether of 2-/tetrahydro-2-furfuryl/-3-/1-naphthyl/propenoic acid from 2-diethylaminoethyl chloride and/or its salt by reaction with 2-/tetrahydro-2-furfuryl/-3-/1-naphthyl/propanoic acid under catalytic phase transfer conditions. The resulting base ester is a secondary and essential intermediate for the preparation of its hydrogen oxalate, which is used under the generic name naphthalene as a drug with peripheral and cerebral vasodilating and nootropic effects.

Description

The invention relates to the preparation of 2- (tetrahydro-2-furfuryl) -3- (1-phenyl) -propanoic acid 2-diethylaminoethyl ester (hereinafter compound I).

Substance I and its eoli, especially hydrogen oxalate, is a known chemotherapeutic of the generic name naphthidrofuryl. It has a peripheral and cerebral vasodilatory effect. It also shows nootropic effects / □ • Hronek et al., Cs. psychiatry 73, 239, 1977, S. Litoměřický et al., Farm, obzor 51, 309, 1982 /. Naphthidrofuryl is produced under a number of commercial names, such as Dusodril (Byk-Gulden, Konstance), Prexilene (Oberval, Lyon) and others (see Neg »Negwer, Organiech-chemlsche Arzneimlttel und ihre Synonyma, Cat. No. 5323, Vorlag Academy Berlin 1978 /.

The basic ester / substance 1 / ee is prepared by a number of methods. One of them is the azeotropic esterification of 2- (tetrahydro-2-fururyl) -3- (1-naphthyl) propanoic acid (II) with 2-diethylaminoethanol in xylene. However, this reaction does not give a yield higher than 38% even under p-toluenesulfonic acid catalysis. substances / E. Szarvesl et al., Bull. Soc. Chin. Fr. 1966, 1838) LIPHA, Fr. 1,363 948 (1964). A. L. Mendjoyan and V. E. Badaljan (Arm. Chim. Journal 22,677, 1969) mention the preparation of compound I by reacting the chloride of compound II with 2-diethylaminoethanol. C. Blesioli and A. Heymae (Fr. 2,444,033 (1980)) boiling 1- (tetrahydro-2-furyl) -3- (1-naphthyl) propane-2,2-dicarboxylic acid bis (2-diethylamino) ethyl ester for 10 hours in dimethylformamide they obtain the crude product of substance I, from which, after complicated purification, they obtain 30% t. According to another patent (C. Blasloli, A. Heymos, Fr. 244 034 (1980)), 3- (totrehydro-2-furyl) propanoic acid 2-diethylaminoethyl ester (compound III) is treated with butyllithium at -30 ° C. the lithium salt of III is obtained, which in hexamethylphosphoric triamide solution by treatment with 1-naphthylmethyl chloride at -30 ° C gives IE Szarvasi et al. (Bull. Soc. Chim. Fr., 1966, 1838) report the possibility of synthesizing compound I by reacting the 2-haloathyl ether of compound II with diethylamine. Esterification of compound II to compound I was carried out by E. Szarvasi et al. The same reaction was carried out by E. Szarvesl et al. In both feeds they reached a yield of 70% t. The substance I thus obtained was purified by distillation in vacuo at 190 DEG C. and 67 Pa. Substance I is sensitive to heat around 200 ° C, when it darkens and decomposes above 220 ° C.

Azeotropic reesterification of the de-methyl methyl ether of compound II (m.p. 176-180 ° C (67 Pa)) with 2-diethyleminoethenol in toluene (V.Volente et al., Coll. Czech. Chem. Commun., 52, 2534 (1987)) is obtained after 20 h. and isolation from the reaction mixture of substance I with a content of 97% in a yield of 92% t ·. From this product, the ee hydrogen of the substance I t-.t can be prepared without further purification. 109-111 ° C.

Preparations of substance I according to the methods known so far are not very advantageous for technical application! Bu3 and e are low yields or are carried out from technically demanding conditions by vacuum distillation or from low temperatures, or long reaction times are required to achieve good yields.

The process for the preparation of 2- (tetrahydro-2-furfuryl) -3- (1-naphthyl) propenoic acid 2-diethyleminoethyl ester is eliminated by the reaction of 2-diethylaminoethyl chloride with 2- (tetrehydro-2-furfuryl) -3- (1-naphthyl) propenoic acid according to of the invention, which consists in carrying out the reaction under phase catalytic transfer conditions.

The process is preferably carried out by the action of kvsrterníqh emoniových bases and / or _t eoll e.g. benzyltrlethylamonlumchlorldu, crown ethers, e.g. 1,4,7,10-tetraoxacyklododekanu or elkylfenylpolyethylenglykolů e in a system-kepellne kepellne or kepellna - solid .

The process according to the invention carries out that the synthesis of 2- (tetrahydro-2-furfuryl) -3- (1-naphthyl) propanoic acid 2-diethylaminoethyl ester can be carried out in two to four hours of reaction in a yield of at least 90%. under phase catalytic transfer conditions by reacting substance II and 2-diethylaminoethyl chloride or its salts to give an alkaline agent,

EN 268 355 Bl, preferably potassium carbonate, under the catalytic action of phase transfer catalysts and banzyltriethylamoniumchloridu preferably in an amount of 0.5 - 10 mol%, and preferably 6 mol%, with vigorous stirring at 30-140 ^fl C, preferably at 90 to 105 ° C, in a liquid-liquid system, preferably toluene-water, or in a liquid-solid system, preferably toluene-alkali carbonate. Oako phase transfer catalysts have proved to be, for example, tricrylylmathylammonium chloride, tetrabutylammonium hydrogen sulphate, banzyltriethylammonium chloride, dimethyl (27-dimethylamino-2,5, B, 11,14,17,20,23,26-nonehydroxyheptaeicosyl) (2-hydroxy-3-chloropropyl ) ammonium chloride, 1,4,7,10-tetraoxacyclododecane, 1,4,7,10,13,16-hexaoxacyclooctadecane, 29- (4-nonylphenoxy) -3,6,9,12,15,18,21,24 , 27-nonaoxanonaeikoeanol and others. When the reaction is carried out in a liquid-liquid system, preferably toluene-water, the gradual quaternization of 2-diethylaminoethyl chloride results in the formation of quaternary ammonium salts which already catalyze the reaction. However, without the addition of another catalyst, the reaction is slower. Conversion to 90% is achieved in 8 hours. The kinetics of the reaction were monitored by determining the increase in ionic chlorine in the aqueous-alkaline layer. After completion of the reaction, the product, i. substance I, isolated and its content was determined by titration methods. The identity of the substance was confirmed by thin-layer and high-pressure chromatography and on the basis of IR, UV and NMR spectra.

Rozpouštědla Substituted and / or unsubstituted aliphatic and / or aromatic compounds, for example octane, decane, cyclohexane, benzene, toluene, xylene, chlorobenzene and the like, can serve as solvents for the organic phase.

In the following examples, several possible processes for the synthesis of the basic ester I are given, without, however, exhausting all possible possibilities for the application of the invention. Example 1 'roztoku With a solution of 15.07 g (53 mmol) of acid II in 50 ml of toluene, 12.55 g (70 mmol) of 2-diethylaminoethyl chloride hydrochloride and 1.00 g (3.5 mmol) of mmol) benzyltriethylammonium chloride and stirred for 10 min. A solution of 55.00 g of anhydrous potassium carbonate in 50 ml of water is added to this suspension. The temperature in the reaction mixture was raised to reflux (90-94 ° C) by rapid heating. After 3.5 h of vigorous stirring from the raft of the reaction mixture, a conversion of 98% is achieved (as measured by the increase in ionic chlorine in the aqueous-alkaline phase). After cooling to room temperature, the organic layer was separated, washed with 3 x 25 ml of water, 3 x 25 ml of 10% aqueous sodium bicarbonate solution and again 3 x 25 ml of distilled water to neutral pH. At 40 ° C, the organic vortex is stirred for 10 min. with 0.5 g of activated carbon (Norrit, Ostakol) and filtered through a pad of 10 g of alumina (Brockmann II-III). The filter layer ee is washed with a further 10 ml of toluene. The combined toluene filtrates are evaporated under reduced pressure (3.3 kPs) from a water bath at a temperature of up to 80 ° C. The weight of the light oily residue is 20.32 g with a content of 93%, i.e. 18.89 g (49.25 mmol) of pure basic ester I. The yield is 93% of m.p.

In a conventional manner, reaction of this basic ester I with 7.53 g (60 mmol) of kyeellnyl oxalic dihydrate in 70 ml of anhydrous acetone gives 18.7 g (39.5 mmol), i.e. 80.1% by weight of hydrogen ester of basic ester I. tt 106-107 ° C, containing 100.2% ecidimetrically and 100.22% alkaline.

Example 2 roztoku With a solution of 13.7 g (48.2 mmol) of acid II in 50 ml of xylene, 12.55 g (70 mmol) of 2-diethylaminoethyl chloride hydrochloride and 1.4 g / 2 are introduced from vigorous stirring at 50 ° C. 5 mmol / Aliquat 336-Fluka. After 15 min. A solution of 55 g of anhydrous potassium carbonate in 50 ml of water is added with stirring. The temperature of the reaction mixture was raised to reflux (90-92 ° C) by rapid heating and thus maintained for 4 hours. 16.6 g of purified ether I. The yield is 90% of m.p.

Example 3

A solution of 21.8 g (76.7 mmol) of acid II in 90 ml of anhydrous xylene ee with stirring at

CS 268 355 81 3

At 25 DEG C., 11.7 g (84 mmol) of anhydrous finely ground potassium carbonate, 7.9 g (46 mmol) of 2-diethylaminoethyl chloride hydrochloride and 0.9 g (2.65 mmol) of tetrabutylammonium hydrogen sulfate are successively introduced. The suspension thus formed is rapidly heated to 100 DEG-105 DEG C. with vigorous stirring and maintained at this temperature for 1 hour. Then 11.7 g of potassium carbonate, 7.9 g of 2-diethylaminoethyl hydrochloride and 0.9 g of totrabutylammonium hydrogen sulphate. The reaction mixture is stirred vigorously at 100-105 [deg.] C. for a further 2 h. After cooling to 25 [deg.] C., the solid is filtered off with suction and washed with 50 ml and 2 * 20 ml of xylene. The combined xylene filtrates are washed with 50 ml of water and the product is extracted into 50 ml and then twice into 20 ml of 5 N hydrochloric acid. The combined aqueous-acidic extracts were salted with solid potassium hydroxide after overlaying with 50 ml of xylene from stirring and cooling to 25 ° C. After removing the water-silica layer, it is extracted twice more with 50 ml of xylene. The combined organic layers are washed with 3 x 30 ml of distilled water and concentrated in a rotary evaporator at 2.5 to 3.3 kPa on a water bath to a temperature of 80-90 ° C. The weight of the yellow oily residue is 30.6 g with a content of 87.6%. The yield of pure basic ester I is 26.8 g, i.e. 91.1% m.p. (69.9 mmol).

Example 4 ’

To a solution of 21.8 g (76.7 mmol) of acid II in 100 mL of anhydrous toluene was gradually added 11.70 g (84 mmol) of anhydrous finely ground potassium carbonate, 13.25 g (77 mmol) from stirring at 20-25 ° C. ) of 2-diethylaminoethyl chloride hydrochloride and 1.4 g (5 mmol) of benzyltriethylammonium chloride. The resulting eepepension was rapidly heated to 100-105 ° C with vigorous stirring and maintained at reflux for 2 h. After this time, 10 g (72 mmol) of anhydrous dressing carbonate and 3.44 g (20 g) of mmol) of 2-diethylaminoethyl chloride hydrochloride. The reaction mixture is stirred vigorously from reflux for 1.5 hours, cooled to room temperature, the solid is filtered off with suction and washed with 50 ml of 2 * 25 ml of toluene. The combined toluene filtrates are worked up either in the manner described in Example 1 or in Example 3. After concentration of the organic layer obtained in a rotary evaporator (3.3 kPo, at a bath temperature of up to 80 DEG C.), a yellow oily residue weighing 29.1 g remains. ge content of 93.4%, i.e. 27.2 g (70.92 mmol) of pure basic ester I. The reaction yield is 92.46% t.

Example 5 i

The procedure of this example is the same as in Example 4, except that 1.32 g (5 mmol) of 18-Crown-6 was used as the phase transfer catalyst. Work-up of the reaction mixture was carried out according to Example 3. After evaporation of the solvents in a rotary evaporator (3.3 kPe, to a water bath temperature of 80 °), a yellow oily residue weighing 28.8 g and containing 92.8%, i.e. 26.72 g (69.69 mmol) of pure basic ester I. The reaction yield is 90.86% m.p.

Claims (6)

OBJECT OF THE INVENTION A process for the preparation of 2- (tetrahydro-2-furfuryl) -3- (1-naphthyl) propanoic acid 2-diethylaminoethyl ether by the reaction of 2-diethylaminoethyl chloride and 2- (tetrahydro-2-furfuryl (-3- (1-naphthyl) propanoic acid), characterized in that provided that the ee reaction is performed under phase catalytic transfer conditions. 2. The process according to claim 1, characterized in that quaternary ammonium bases and / or their salts, for example benzyltriethylammonium chloride, are used as phase transfer catalysts. ' 3. The process according to item 1, characterized in that Crown ethers, for example 1,4,7,10,13,16-hexaoxacyclooctadecane, are used as phase transfer catalysts. 4. The process according to item 1, characterized in that alkylphenyl polyethylene glycols, for example 29- (4-nonylphenoxy) -3,6,9,12, 15,1Θ, 21,24,27-nonaoxanone eicosanol, are used as phase transfer catalysts. 5. The process of claim 1, wherein the reaction is carried out in a liquid-liquid system. 6. The method of claim 1, wherein the resection is performed in a liquid-solid system.