CH492713A - Process for the preparation of esters - Google Patents

Description

  

      Process for the production of esters The invention relates to a process for the production of new esters which have anti-inflammatory, pain-relieving and antipyretic properties and are able to reduce the concentration of fibrinogen and of cholesterol and / or triglycerides in the blood and are therefore suitable for the treatment or prophylaxis of Ko - coronary artery disease and atherosclerosis are suitable.



  According to the invention, esters of the formula I
EMI0001.0005
    The one in which X is hydrogen or an alkyl or alkoxy radical with a maximum of 3 carbon atoms or a halogen atom, Y is a phenyl radical optionally substituted by one or two halogen atoms, R1 and R =, which can be the same or different from one another, each Hydrogen or an alkyl radical with a maximum of 3 carbon atoms and R3 denotes an alkyl radical with a maximum of 5 carbon atoms and the radicals Y and -CR1R2-COOR3 are not bonded to adjacent carbon atoms of the pyridine nucleus.



  Suitably, X can e.g. represent a hydrogen atom, a methyl or methoxy radical or a chlorine or bromine atom.



  As examples of the halogen atom or atoms which may be present in the Y radical, fluorine, chlorine and bromine atoms can be mentioned. The compounds in which the Y radical contains one or two halogen substituents are preferred compounds because they are generally more active than the corresponding unsubstituted phenyl derivatives.



  If R1 or R2 represents an alkyl radical, this can e.g. be a methyl radical. The alkyl radical R3 can e.g. be the methyl or ethyl radical. As salts of the pyridine derivatives, the pharmaceutically acceptable acid addition salts, such as e.g. Hydrochlorides, hydrobromides, sulfates or phosphates, are suitable.



       according to the invention is that a pyridylalkanecarboxylic acid of the formula II in which X, Y, R1 and R2 have the above meaning
EMI0001.0013
    sit, A is a carboxyl or functionally modified carboxyl group and the radicals Y and -CR1R2-A are not bound to adjacent carbon atoms of the pyridine nucleus, with an alcohol of the formula R3OH, in which R3 has the above meaning, or one reactive derivative thereof converts.



  The corresponding Ni trile and alkali metal salts can be used as the pyridylalkanecarboxylic acid with a functionally modified carboxyl group.



  The esterification can be carried out by reacting the carboxylic acid with the alcohol R3OH in the presence of an inorganic acid, e.g. Sulfuric acid, or of dicyclohexylcarbodiimide. The reaction can optionally be carried out in an organic solvent, e.g. Chloroform, carried out and accelerated or brought to completion by the addition of heat.

   On the other hand, the esterification can be carried out by the reaction of the carboxylic acid with a diazoalkane corresponding to the alcohol R3OH, e.g. Diazomethane, in an organic solvent, e.g. a mixture of methanol and ether. Or the esterification can be carried out by reacting an alkali metal salt of the carboxylic acid with a compound of the formula R3Hal, where R3 is an alkyl radical with at most 5 carbon atoms and Hal is a halogen atom, e.g. a chlorine or bromine atom. This reaction can optionally be carried out in an organic solvent, e.g.

   Dimethylformamide, carried out and, if necessary, accelerated or brought to a conclusion by supplying heat. The reaction of the nitrile corresponding to the carboxylic acid with the alcohol usually takes place under acidic conditions, e.g. in the presence of sulfuric acid; it can be accelerated or completed by adding heat.



  The compounds of the formula II used as starting materials can be prepared by methods known per se. The invention is explained in more detail in the fol lowing using exemplary embodiments. <I> Example 1 </I> 7 g of 6- (4-chlorophenyl) -2-methylpyrid-3-ylesetic acid were dissolved in 230 ml of methanol, and the solution was slowly turned into a solution of 1.1 g Diazomethane in 700 ml of ether was added, the solution being kept at 5 C during the addition.

   The solvents were evaporated off under reduced pressure and the solid residue was dissolved in 100 ml of ether and the solution was washed with 80 ml of a 5% aqueous sodium carbonate solution and then with 80 ml of water. The ethereal solution was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was recrystallized from petroleum ether (boiling point 60-80 ° C.). Thus methyl 6- (4-chlorophenyl) -2-methylpyrid-3-ylacetate was obtained, m.p. 75-76C.

      <I> Example 2 </I> A suspension of 6 g of 6- (4-chlorophenyl) -2-cyano-methylpyridine in 26 ml of dry methanol was brought to 0 ° C. in an ice bath. Then 17 g of concentrated sulfuric acid was slowly added and the resulting pale yellow solution was refluxed for 18 hours. The reaction mixture was added to 150 g of ice, and the pH of the solution was brought to 8 with a concentrated ammonium hydroxide solution (specific weight 0.88). The solution was extracted 3 times with 100 ml of ether, and the solvent was evaporated from the combined ethereal extracts. The solid residue was recrystallized from petroleum ether (boiling point 60-80 ° C.).

   This gave methyl 6- (4-chlorophenyl) pyrid-2-ylacetate, m.p. 45-46 C.



  The cyanomethyl compound used as starting material was produced as follows: A solution of 21 g of 6- (4-chlorophenyl) -2-methylpyridine in 400 ml of chloroform was brought to 0 ° C. in an ice bath. Then 30.9 g of m-chloroperbenzoic acid were slowly and partially added to the solution, and the solution was kept at 0-4 ° C. for 24 hours. The chloroform solution was shaken with 150 ml of a 15% aqueous potassium carbonate solution, and solid potassium carbonate was added until the pH of the aqueous layer was brought to 9.

   The chloroform layer was separated from the mixture and then dried, whereupon the solvent was evaporated. Thus, impure 6- (4-chlorophenyl) -2-methylpyridine-N-oxide was obtained. This can be purified by recrystallization from petroleum ether (b.p. 60-80 C) and then has a melting point of 92-94 C.



  25 g of the impure N-oxide were dissolved in 112 ml of acetyl chloride, and the mixture was refluxed for 6 hours. After evaporation of the excess acetyl chloride, the brown oily residue, which mainly consisted of 2-acetoxymethyl-6- (4-chlorophenyl) pyridine hydrochloride and 2-chloromethyl-6- (4-chlorophenyl) pyridine hydrochloride, was dissolved in 350 ml Dissolved methanol. A solution of 20 g sodium hydroxide in 20 g water was added and the mixture was kept at ambient temperature for 2 hours. The methanol was evaporated in vacuo and the residue mixed with ether and water. The ethereal layer was separated from the mixture and the ether was evaporated.

   This gave a mixture of 6- (4-chlorophenyl) -2-hydroxymethylpyridine and 2-chloromethyl-6- (4-chlorophenyl) pyridine, which was sufficiently pure for the next stage. 11 ml of thionyl chloride were slowly added to a solution of 22 g of this mixture in 300 ml of dry ethylene dichloride, the temperature of the reaction mixture not being allowed to rise above 35-40.degree. The suspension was stirred for 1.5 hours and then filtered. Thus 2-chloromethyl-6 - (4-chlorophenyl) pyridine hydrochloride was obtained. Recrystallization of this salt from isopropanol gave the corresponding base, mp 110-111 C. 15 g of 2-chloromethyl-6- (4-chlorophenyl) pyridine hydrochloride were dissolved in 150 ml of water.

   4 g of a concentrated ammonium hydroxide solution (specific weight 0.88) were added to the solution, and the mixture was extracted 3 times with chloroform. The combined chloroform extracts were dried and the solvent was evaporated. Thus, crystalline 2-chloromethyl-6- (4-chlorophenyl) pyridine was obtained. This solid was dissolved in 230 ml of dry methanol, whereupon 6.6 g of sodium cyanine was added and the mixture was refluxed for 10 hours in a nitrogen atmosphere. The reaction mixture was cooled and evaporated to dryness, whereupon the residue was mixed with ether and water. The organic layer was separated from the mixture and the solvent was evaporated.

   The solid residue was dissolved in 200 ml of ether and the solution was passed through 250 g of neutral clay (Woelm grain size 1). The solvent was evaporated from the eluate, and the residue was recrystallized from a mixture of ethyl acetate and petroleum ether (boiling point 60-80 ° C.). This gave 6- (4-chlorophenyl) -2-cyanomethylpyridine, m.p. 80-82 C.



  <I> Example 3 </I> A solution of 1.2 g of dimethyl-α-methyl-α - [4- (4-chlorophenyl) -6-methoxypyrid-2-yl] malonate in 12 ml of a methanolic 2N sodium hydroxide solution was refluxed for 1 hour and then evaporated in vacuo. The residue was dissolved in 12 ml of water. The clear solution was brought to pH 5 with glacial acetic acid and the whole was extracted with ethyl acetate. The extract was dried and evaporated. The residue was quickly triturated with petroleum ether (bp 40-60 ° C.) and the resulting mixture was filtered.

   This gave .a- [4- (4-chlorophenyl) - -6-methoxypyrid-2-yl] propionic acid, m.p. 84-87 ° C. with dec. A small sample of the starting product (acid) already described was esterified with diazomethane. The methyl ester was thus obtained, mp 65-67 ° C. [after recrystallization from petroleum ether (boiling point 40-60 ° C.)]. Example 4 6 g of 2- (4-chlorophenyl) -4-cyanomethylpyridine were dissolved in 30 ml of methanol containing 9.3 ml of concentrated sulfuric acid, and the pale yellow solution was refluxed for 24 hours.

   The solution was mixed with 150 g of ice and the pH was brought to 8 with 19 ml of an aqueous 18N ammonia solution, whereupon the desired ester was isolated by extraction with ether. The solvent was evaporated and the residue was recrystallized from petroleum ether (bp 40-60 ° C.). This gave methyl 2- (4-chlorophenyl) pyrid-4-ylacetate, m.p. 48-49 C.



  <I> Example 5 </I> 1.4 g of 2- (4-chlorophenyl) -4- (a-cyanoisopropyl) pyridine were hydrolyzed by treating it with 5N hydrochloric acid. Thus, a- [2- (4-chlorophenyl) pyrid-4-yl] isobutyric acid was obtained. A sample of this acid (0.58 g) was slowly added to a well-stirred solution of excess diazomethane in 50 ml of ether over 10 minutes while cooling with ice. After the evolution of nitrogen had ceased, the solvent was evaporated off in vacuo.

   This gave methyl a- [2- (4-chlorophenyl) pyrid-4-yl] isobutyrate, mp 71-72 ° C., after recrystallization from petroleum ether (boiling point 40-60 ° C.).



  The 2- (4-chlorophenyl) -4- (a-cyanoisopropyl) pyridine used as starting material was prepared as follows: 5.7 g of 2- (4-chlorophenyl) -4-cyanomethylpyridine were added to a sodium amide solution which, by dissolution of 0.595 g of sodium in 240 ml of liquid ammonia was added and the suspension was stirred until a clear green solution resulted. Then 4.7 ml of methyl iodide was added all at once and the solution was stirred for 30 minutes. After all the ammonia had evaporated, the solid residue was mixed with ether and a saturated aqueous sodium chloride solution. The organic phase was separated off, and the aqueous phase was extracted twice with ether.

   The combined ethereal extracts and the organic phase were evaporated to give a mixture of nitriles (5 g) which was separated by chromatography on neutral clay (Woelm grain size 1; 200 g. A solid fraction was obtained by elution with benzene (1.7 g) which was recrystallized from a mixture of benzene and petroleum ether (b.p. 60-80) to give 2- (4- chlorophenyl) -4- (a.-cyanoisopropyl) pyridine, m.p. 94 - 96 C.



  <I> Example 6 </I> A suspension of 1.55 g 6- (4-chlorophenyl) -2-methylpyrid-3-ylacetic acid and 0.498 g sodium bicarbonate in a 1: 1 water / methanol mixture (15 ml) was stirred vigorously until the effervescence had stopped and a clear solution was obtained. The solvents were evaporated off under reduced pressure, and the sodium salt was dried by adding and subsequent evaporation of 25 ml of benzene, the latter process being repeated 3 times.

   The anhydrous white solid was suspended in 15 ml of anhydrous dimethylformamide, whereupon 1 ml of ethyl bromide was added and the mixture was stirred at room temperature for 18 hours. 75 ml of water were added to the clear solution, and the whole thing was extracted 3 times with 25 ml each of a 1: 1 mixture of ether and petroleum ether (bp 40-60 ° C.). The combined organic layers were washed twice with 25 ml of water each time, dried over magnesium sulfate and evaporated in vacuo.

   Thus 1.64 g of ethyl 6- (4-chlorophenyl) -2-methylpyrid-3-ylacetate were obtained. This was recrystallized from petroleum ether (boiling point 40-60 ° C.) to crystallize, with fine white needles with melting point 54-55 ° C.

 

Claims (1)

PATENT CLAIM Process for the preparation of esters of the formula EMI0003.0034 in which X is hydrogen or an alkyl or alkoxy radical with at most 3 carbon atoms or a halogen atom, Y is a phenyl radical optionally substituted by one or two halogen atoms, RÚ and Rê, which can be identical to or different from one another, each hydrogen or an alkyl radical with a maximum of 3 carbon atoms and R3 an alkyl radical with a maximum of 5 carbon atoms and the radicals Y and -CRÚRê-COOR are not bonded to adjacent carbon atoms of the pyridine nucleus, characterized in that a pyridylalkanecarboxylic acid of formula 2 EMI0003.0039 in which X, Y, RÚ and Rê have the above meaning, A denotes a carboxyl or functionally modified carboxyl group and the radicals Y and -CRÚRê-A are not bound to adjacent carbon atoms of the pyridine nucleus, with an alcohol of the formula R3 OH, in which R3 has the above meaning, or a reac convertible derivative thereof. SUBClaims 1. The method according to claim, characterized in that the corresponding nitrile or an alkali metal salt is used as the pyridylalkanecarboxylic acid with a functionally modified carboxyl group. 2. Process according to claim, characterized in that the reaction of the pyridylalkanecarboxylic acid with the alcohol in the presence of dicyclohexylcarbodiimide or an inorganic acid is carried out. 3. The method according to claim, characterized in that the reaction of the pyridylalkanecarboxylic acid with a diazoalkane corresponding to the alcohol of the formula R30H is carried out in an organic solvent. 4. The method according to claim and sub-claim 1, characterized in that the reaction of an alkali metal salt of pyridylalkanecarboxylic acid with a halide corresponding to the alcohol of the formula R 0H is carried out. 5. The method according to claim and sub-claim 1, characterized in that the reaction of the nitrile with the alcohol is carried out under acidic conditions. 6. The method according to claim or the subordinate claims 2, 4 and 5, characterized in that the reaction is carried out in an organic solvent and / or accelerated or brought to completion by supplying heat. 7. The method according to claim, characterized in that the process products are converted into salts, in particular into pharmaceutically acceptable acid addition salts.