AT339482B - PROCESS FOR PRODUCING NEW ORGANIC AMIDE COMPOUNDS - Google Patents

Description

  

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   The invention relates to a process for the preparation of new chemical compounds which are useful as pharmacologically active ingredients, u. The invention relates to the preparation of new organic amide compounds of the general formula
 EMI1.1
 and pharmaceutically acceptable salts thereof, wherein.



   R is hydrogen or methyl, R1 and R2 are hydrogen, straight or branched lower alkyl groups of 1 to 6 carbon atoms, or RR N taken together is nitro, 4-R5-1-piperazinyl, 4-methyl-1-homopiperazinyl, 1-pyrrolidinyl , Morpholinyl, 1-piperridinyl, 4- (1-pyrrolidiny) -piperidiny or
4- (1-piperidinyl) -piperidinyl, where R5 is a lower alkyl group with 1 to 6 carbon atoms,
Cyclohexyl, benzyl, phenyl or halophenylist, where halo means chlorine, fluorine, bromine or iodine,
 EMI1.2
 
Is rrimidinyl) -thio or 1-pyridyl, provided that when R4 is 1-pyridyl, CO2 is H-CO "and X is hydrogen, chlorine or bromine and Y is hydrogen or bromine.
 EMI1.3
 
R1 is atomic atoms or benzyl and where R is phenyl or p-hydroxyphenyl.

   Most preferred compounds are those in which the RR N group is m-diethylamine and p- (4-methyl-1-piperazine).



  It should be noted here that in the German patent application 2322750 and the French. In U.S. Patent No. 2,165,744, compounds used with the compounds available according to the invention have been described which also have antimicrobial properties.



   In accordance with the invention, the compounds obtainable according to the invention are obtained by reacting a free amino acid of the formulas
 EMI1.4
 or the corresponding acid salt or silylated derivative thereof, wherein
R has the above meaning with a D-N- {6 - [(substituted amino) phenyl] -1,2-dihydro-2-oxonicotinyl] -2-phenylglycine of the general formula

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 EMI2.1
 or its acid addition salts or a reactive derivative thereof, wherein
R, R, R, R, X and Y have the meanings given above.



   A few examples of reactive derivatives of the D, N- (1, 2-dihydro-2-oxonikotinyl) -2-substituted glycine compounds suitable for the reaction are the acid halides, imidazolide, mixed anhydrides (in particular those which are derived from an alkyl chloroformate, such as ethyl chloroformate and isobutyl chloroformate) and activated esters such as B. pentachlorophenyl ester. Since racemization is more likely with the acid halides, the other forms are generally preferred. The reactants are normally used in approximately equimolar amounts, although an excess of any (oxonicotinic acid compound or amino acid compound) can be used if desired.

   The reaction can be carried out in any of a number of non-reactive solvents. When using the silylated derivative for the reaction, the solvent should be anhydrous and it can be tertiary amides (such as, for example, N, N-dimethylacetamide, dimethylformamide and N-methyl-2-pyrrolidinone), ethers
 EMI2.2
 roform and dichloromethane), as well as mixtures thereof. In addition to any of these solvents, 6-aminopenicillanic acid and 7-aminopenicillanic acid and 7-aminopenicillanic acid and 7-amino-SR CHceph-3-em-4-carboxylic acid can be mixed with an acid chloride or mixed acid anhydride in free acid or salt form using aqueous solutions under normal Schotten-Baumann -Conditions are implemented.

   The duration and temperature of the reaction are not critical. Usually temperatures in the range from -30 to + 300C are used for reaction times which are between a few hours up to a day or more. The product can be isolated in any suitable manner as the free acid or salt by appropriate adjustment of the pH.



   The N- {6 - [(substituted amino) phenyl] -1,2-dihydro-2-oxonicotinyl} -2-substituted glycines and their reactive derivatives, which are required as starting materials in the above-described process, can be prepared according to processes detailed below are described.



   The desired N- {6- [(substituted amino) phenyl] -1, 2-dihydro-2-oxonikotinyl} -Z-substituted glycines can be obtained by reacting the corresponding 6- [(substituted amino) phenyl] -1, 2 -dihydro-2-oxoniko- tinyl chloride with the appropriate DN- (trimethylsilyl) -2-substituted glycine, trimethylsilyl ester in the presence of triethylamine, followed by hydrolysis.



   The 6 - [(substituted amino) phenyl] -1,2-dihydro-2-oxolocotinyl chloride compounds and their reactive derivatives required as starting materials in the above-described process can be prepared according to any of a number of methods which are described in more detail below. getting produced.



   A compound of the general formula
 EMI2.3
 is made by alkylating a compound of the formula

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 EMI3.1
 with an alkylating agent, such as. B. alkyl iodide or dialkyl sulfate, or by reacting a compound of the formula
 EMI3.2
 wherein the fluorine is in the ortho or para position, with a compound of the general formula
 EMI3.3
 manufactured.



   In addition, the fluorine atom can be activated so that it can be removed more easily, in particular if it is in the meta position due to the presence of a nitro group.



   So becomes a compound of the formula
 EMI3.4
 nitrated in fuming nitric acid to form a compound of the formula
 EMI3.5
 to give which again with a compound of the general formula
 EMI3.6
 is reacted and a compound of the general formula

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 EMI4.1
 results.



   The nitro group is removed by catalytic reduction of the nitro group to an amino group, after which a salt of the resulting amine is treated with sodium nitrite and then with water.



   One process for the preparation of halo-substituted starting materials is that a compound of the general formula
 EMI4.2
 wherein X1 and X2 are either bromine or chlorine, is reacted with a compound of the general formula RRNH to
 EMI4.3
 to surrender.



   The compound of the general formula
 EMI4.4
 is reacted with a lower alkyl formate such as ethyl formate in the presence of a strong base such as sodium methoxide or sodium hydride to give the sodium salt of the following dicarbonyl compound of the general formula
 EMI4.5
 

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 to surrender.



   The compounds listed above are reacted again with 2-cyanoacetamide or N-methyl-2-cyanoacetamide in the presence of piperidine acetate to give the following nitrile of the general formula
 EMI5.1
 to reveal where
X3 is hydrogen, chlorine or bromine.



   The above nitrile, in which X is hydrogen and Y is hydrogen or bromine, can also be obtained by reacting a compound of the general formula
 EMI5.2
 wherein the fluorine is in the ortho or para position with a compound of the general formula
 EMI5.3
 getting produced.



   The nitriles prepared by the above methods are obtained by converting the cyano group to a carboxyl group using an aqueous solution of a strong base into the desired 6- [(sub-
 EMI5.4
 phenyl] -1, 2-dihydro-2-oxonicotinic acid chloride can be converted into its acid chloride.



   The starting materials for the silylated amino acid can be prepared by using an anhydrous compound of the formulas
 EMI5.5
   is reacted with a hexaalkyldisilazane. The preferred silylating agent is hexamethyldisilazane. Only the carboxyl group is silylated under the conditions used (e.g. 2 h reflux in dichloromethane).



  After acylation, the silyl group is simply removed by treatment with water.



   The free acids of the invention form carboxylate salts with any of a number of inorganic and organic bases. Pharmaceutically acceptable carboxylate salts are made by reacting the free acids with bases such as sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium 2-ethylhe-

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 EMI6.1
    Potassium 2-ethylhexanoate, carboxylate salts are converted into the free acids by acidification. The free acids and their carboxylate salts usually differ somewhat with regard to solubility properties, but in general they are equivalent for the purposes of the process of the invention. In addition, the compounds obtainable according to the invention can occur in the form of an acid addition salt.

   Pharmaceutically acceptable salts are formed by reacting the free base or a carboxylate salt with any of a number of inorganic and organic acids, which acids include but are not limited to the following: hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, benzoic acid, citric acid, maleic acid, malic acid, tartaric acid , Succinic acid, gluconic acid, ascorbic acid, sulfamic acid, pamoic acid, methanesulfonic acid, benzenesulfonic acid and related acids.



   The compounds prepared according to the invention can exist in anhydrous form as well as in dissolved, including hydrated, form. In general, the hydrated forms and the forms dissolved with pharmaceutically acceptable solvents are equivalent to the anhydrous or undissolved forms for purposes of the invention.



   The compounds produced according to the invention are new chemical compounds which are used as pharmacological active ingredients and in particular as antibacterial active ingredients with a broad spectrum. They are effective in vitro against strains of both gram positive and gram negative bacteria. The activity of the compounds is illustrated by the results presented in the table for the following preferred compounds.



   The compounds prepared according to the present invention and their nontoxic, pharmaceutically acceptable salts, therefore, are most useful as broad spectrum antibiotics for mammals when administered in amounts of from about 5 to about 100 mg / kg body weight / day. A preferred dosage for optimal results would be between about 10 and about 50 mg / kg body weight / day, and such dosage units are used so that a total of between about 700 and about 3500 mg of active ingredient for a subject of about 70 kg body weight over a period of time of 24 hours.



   While the compounds prepared according to the invention can be used orally in the form of tablets, capsules, syrups, etc. (for treating infections of the alimentary tract), the preferred mode of administration is parenteral for treating systemic infections.

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 EMI7.1
 
 EMI7.2
 

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 EMI8.1
 

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 EMI9.1
 

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 EMI10.1
 

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 EMI11.1
 

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 EMI12.1
 

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 EMI13.1
 
R R X Y Salt General Pseudomonas Enterobacter starting materials: The various starting materials used in the previous examples and intermediates required for their production are obtained by the following methods.



   A) (Substituted amino) acetophenones: a) p- (4-Methyl-1-piperazinyl) -acetophenone: A solution of 1120 g of N-methylpiperazine and 755 g of p-fluoroacetophenone in 1920 ml of dimethyl sulfoxide is heated for 16 hours at 950C and then evaporated at reduced pressure. The residue is poured into 8 l of water and the solution is made basic with 440 g of 50% aqueous sodium hydroxide and cooled. The precipitate of p- (4-methyl-1-piperazinyl) acetophenone is collected by filtration, washed with water and dried; M.p. 97 to 990C. b) p- (4-propyl-l-piperazinyl) -acetophenone: A mixture of 33,2gp-fluoroacetophenone, 48,3 g N-Pro-
 EMI13.2
 then cooled and poured into ice water.

   The precipitate of p- (4-propyl-1-piperazinyl) acetophenone is collected by filtration, washed with water and dried; Mp. 68 to 70 ° C. after crystallization from hexane. c) 0- (4-Methyl-1-piperazinyl) -acetophenone: A mixture of 55.2 g of o-fluoroacetophenone and 100 ml of N-methyl-piperazine is heated for 19 hours at 95 to 1000C, then cooled and poured into 1600 ml of water containing 22 ml of 50% aqueous sodium hydroxide, poured. The mixture is made with three 300 ml servings
 EMI13.3
 it was stirred for half an hour at 30C and then poured into 2.5 l of water. An oil forms which solidifies when standing for a long time. The product is collected and recrystallized from ethanol / water.



  94.9 g (70.8%) of 2'-nitro-5'-fluoroacetophenone are obtained; M.p. 49-520C.



   A solution of 54.9 g (0.3 mol) of 2'-nitro-5'-fluoroacetophenone in 500 ml of dimethyl sulfoxide is treated with 60 g (0.6 mol) of N-methylpiperazine. The solution warms up slightly and after stirring for one hour at room temperature, 225 ml of 2N sodium hydroxide (0.45 mol) is added and the solution is in an excess. Poured in water, a solid separates, which is collected and dried. Recrystallization from benzene / hexane gives 52.2g (66.2%) 2'-nitro-5'- (4-methyl-1-piperazinyl) acetophenone; Fp.



  91, 5 to 92, 50C.



   A solution of 51.4 g (0.195 mol) of 2'-nitro-5 '- (4-methyl-1-piperazinyl) -acetophenone in 500 ml of benzene is treated with 1 g of 5% Pt / C and stored at room temperature and 3, 516 atm. Reduced. The violent reduction causes the temperature to rise to 620C. When the required amount of hydrogen has been absorbed, the reaction mixture is filtered and the solvent is removed under reduced pressure, 45.5 g (100%) of a dark oil remaining, which oil solidifies on prolonged standing. The crude 2'-amino- 5'- (4-methyl-1-piperazinyl) -acetophenone is used directly in the following step.



   A solution of 8.46 g (0.036 mol) of crude 2'-amino-5 '- (4-methyl-1-piperazinyl) acetophenone in 85 ml of abs. Dissolve ethanol and 8, 5 ml of concentrated sulfuric acid are added. The mixture becomes rubbery. By refluxing the mixture for a few minutes, the gum dissolves and a brown solid appears. The boiling mixture is treated in portions with 5.0 g (0.072 mol) of solid sodium nitrite. After the entire amount has been added, the mixture is refluxed for 45 minutes.

   The mixture is poured into water, basified with 50% sodium hydroxide and extracted three times with chloroform. The combined chloroform extracts are washed with saturated sodium chloride, dried over sodium sulfate and the solvent is removed under reduced pressure to leave a dark oil.

   Two distillations under reduced pressure through a distillation column with a short channel using a heating lamp give 4.07 g (51.4%) of the pure m- (4-methyl-1-piperazinyl) -acetophenone as a golden oil, bp 150 up to 1800/0, 4 mm. e) m- (diethylamino) acetophenone: A solution of 100.3 g (0.744 mol) of m-aminoacetophenone in 600 ml of abs. Ethanol is treated with 85 ml of acetaldehyde, 10 ml of acetic acid and 3 g of platinum oxide and reduced in air at 430 ° C. and 4.640 ° C. The solution is then filtered and the ethanol is removed under reduced pressure. The residue is taken up in chloroform, washed with 5% sodium hydroxide and then washed with water.

   Dry over sodium sulfate and remove the solvent under reduced pressure

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 EMI14.1
 

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 an oil. i) m- (methylamino) acetophenone: A solution of 13.5 g (0.1 mol) m-aminoacetophenone in 100 ml pyridine is cooled in ice and treated dropwise with 14.9 ml (0.15 mol) trifluoroacetic anhydride. The solution is stirred in ice for 45 minutes and then poured into water. The crude solid is collected and dried. Recrystallization from ethanol / water using charcoal gives 14.0 g of a white solid m- (trifluoroacetamide) acetophenone, m.p. 130-131.50C.



   A solution of 14.0 g (0.06 mol) m- (trifluoroacetamide) acetophenone in 300 ml acetone containing 15.6 ml (0.25 mol) methyl iodide is heated almost to boiling and 14.0 g (0 , 25 mol) powdered potassium hydroxide are added. After the solution has been refluxed for 10 minutes, it is decanted from the potassium hydroxide and excess acetone and methyl iodide are removed under reduced pressure. The residue is treated with a solution of 14 g of potassium hydroxide in 300 ml of water and refluxed for 10 minutes. The solution is extracted twice with chloroform and the chloroform is washed with water. After drying over magnesium sulfate, the solvent is removed under reduced pressure, leaving an oil.

   This is distilled at 98 to 1050/0.5 mm, with 8.0 g
 EMI15.1
 Ethanol is treated with 5.8 g of propionaldehyde and stirred for 1 hour at room temperature. 0.5 g of 5% platinum-on-carbon is added and the mixture is reduced at 240 ° C. and 3.516 atm. As soon as the required amount of hydrogen has been taken up, the reduction is stopped and the mixture is filtered to remove the catalyst. The methanol is removed under reduced pressure and the residue is taken up in chloroform. This is washed first with 5% sodium hydroxide and then with water. Drying over magnesium sulfate and removing the solvent under reduced pressure gives the crude product.

   Distillation at 108 to 1220/0.5 mm gives 13.8 g of m- (propylamino) -aoetophenone as a yellow oil.
 EMI15.2
 820 g of sodium methoxide in 7.5 l of tetrahydrofuran is added dropwise to a solution of 918 g of ethyl formate and 2.7 kg of p- (4-methyl-l-piperazinyl) acetophenone in 7 l of tetrahydrofuran, while the temperature is kept below 11 oc. The mixture is diluted further with 4 l of tetrahydrofuran and stirred for 16 h at room temperature. The resulting precipitate of the sodium salt of p- (4-methyl-1-piperazinyl) -benzoyl-acetaldehyde is collected by filtration, washed with tetrahydrofuran and dried.

   A solution of this sodium salt in 12 l of water is treated with 1050 g of 2-cyanoacetamide and with a solution consisting of 130 ml of acetic acid, 300 ml of water and 230 ml of piperidine. The solution is stirred and heated while the tetrahydrofuran is allowed to distill until the temperature reaches 920 ° C. and the solution is held at that temperature for 3 hours and then allowed to stand at room temperature for 16 hours. The mixture
 EMI15.3
 
6 acidified and then collected with saturation by filtration, washed with water and dried; M.p.> 3100C (decay).



   The following nitriles are prepared in a similar manner: b) 6- [p- (Dimethylamino) phenyl] -1,2-dihydro-2-oxonicotinonitrile From a solution of the sodium salt
 EMI15.4
 

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 (Dimethylamino) benzoylacetaldehyde4, 1 ml of piperidine gives 6- (p-piperidinophenyl) -1,2-dihydro-2-oxonicotinonitrile. f) 6- (p-Morpholinophenyl) -1, 2-dihydro-2-oxonicotinonitrile: a stirred mixture of 38.8 g of a 57% sodium hydride dispersion in mineral oil and 500 ml of benzene is added dropwise with cooling a solution
 EMI16.1
 p- (Morpholino) -acetophenone ethanol in 300 ml benzene added. An additional 400 ml of benzene are added and the suspension is stirred for 16 h at room temperature and then treated with 1.5 l of cold water.

   The aqueous phase, which contains the sodium salt of p- (morpholino) -benzoylacetaldehyde, is separated and treated in turn with 28.6 ml of acetic acid, 10 ml of piperidine and 34 g of 2-cyanoacetamide. The mixture is stirred and heated under reflux for 3 h, cooled and acidified to pH 5.0 with acetic acid. The resulting precipitate of
6- [p-Morpholinophenyl) -1,2-dihydro-2-oxonicotinonitrile is collected and triturated with ethyl acetate; Fp.



  272 to 2750C after two crystallizations from ethanol. g) 6- [p- (4-Piperidinopiperidino) phenyl] -1,2-dihydro-2-oxonicotinonitrile: A mixture of 10.7 g of 6- (p-fluorophenyl) -1,2-dihydro-2-oxonicotinonitrile ( J.Med.Chem.14 [1971], pages 342 and 16, 8 g of 4-piperidino - piperidine in 149 ml of dimethyl sulfoxide is stirred for 50 hours and heated at 95 to 1000 ° C. The mixture is cooled and 450 ml of 95% strength The resulting precipitate of 6- [p- (4-piperidinopiperidin) phenyl] -1,2-dihydro-2-oxonicotinonitrile is collected by filtration, washed with 95% ethanol and dried, mp 288 bis 293 C (decay).



   The following nitriles are prepared in a similar manner: h) 6- [p- (4-Cyclohexyl-1-piperazinyl) phenyl] -l, 2-dihydro-2-oxonicotinone III: From 11.7g 6- (p-fluorophenyl ) -1, 2-dihydro-2-oxonicotinonitrile and 18.4 g of N-cyclohexylpiperazine in 150 ml of dimethyl sulfoxide give 6- [p-4-cyclohexyl-1-piperazinyl) phenyl] -1,2-dihydro-2-oxonicotinonitrile ; M.p. 306 to 3120C (decay). i) 6- [p- (4-Benzyl-1-piperazinyl) phenyl] -1,2-dihydro-2-oxonicotinonitrile: From 11.7 g of 6- (p-fluorophenyl) -1,2-dihydro-2 -oxonicotinonitrile and 19.1 g of N-benzylpiperazine in 150 ml of dimethyl sulfoxide, 6- [p- (4-benzyl-1-piperazinyl) phenyl] -1,2-dihydro-2-oxonicotinonitrile is obtained; 275 to 2860C (decay). j) 6- [p- (4-Ethyl-1-piperazinyl) pheyl] -1,2-dihydro-2-oxonicotinonitrile:

   From 21.4 g of 6- (p-fluorophenyl) - - 1, 2-dihydro-2-oxonicotinonitrile and 22.8 g of N-ethylpiperazine in 200 ml of dimethyl sulfoxide, 6- [p- (4-ethyl- -1-piperazinyl) phenyl] -1,2-dihydro-2-oxonicotinonitrile obtained; m.p. 283 to 2850C (decomposition).
 EMI16.2
 m) 6- [p- [4- (1-pyrrolidinyl) -piperklinolphenyl} -1,2-dihydro-2-oxonicotinonitrile: From 11.7 g 6- (p-fluorophenyl) -1, 2-dihydro- 2-oxonicotinonitrile and 16,7g4- (1-pyrrolidinyl) -piperdine in 150 ml of dimethylsulfoxide give 6- {p- [4 (1-pyrrolidinyl) -peperidinolphenyl} -1,2-dihydro-2-oxonicotinonitrile; M.p. 318 to 3260C (decay). n) 6- [p- (Hexahydro-4-methyl-lH-1,4-diazepln-l-yl) phenyl] -l, 3-dihydro-2-oxonlkotlnonitrll:

   From 12.9 g of 6- (p-fluorophenyl) -1,2-dihydro-2-oxonicotinonitrile and 13.8 g of N-methylhomopiperazine in 180 ml of dimethyl sulfoxide, 6- [p- (hexahydro-4-methyl-1H-1 , 4-diazepin-1-yl) phenyl] -1,2-dihydro-2-oxonicotinonitrile. o) 6- [m- (4-Methyl-1-peperazinyl) phenyl] -1,2-dihydro-2-oxonicotinonitrile: A suspension of 5.3 g (0.098 mol) of sodium methoxide in 100 ml of ethyl ether under nitrogen cooled to 30C and treated dropwise with a solution of 18.4 g (0.084 mol) m- (4-methyl-l-piperazinyl) acetophenone and 6.25 g (0.084 mol) ethyl formate in 100 ml ethyl ether, while keeping the temperature below 50C. When the addition is complete, the mixture is allowed to stir at room temperature overnight. 100 ml of water are then added and the layers are separated.

   The ethyl ether layer is washed with an additional 75 ml of water. The pi of the aqueous layer is adjusted to pH 9 with acetic acid. 10.6 g (0.126 mol) of cyanoacetamide are then added and the solution is heated at 90 ° C. for 6 hours. A solid forms, which is collected and dried.

   Recrystallization from DMSO / water gives 14.8 g (60.2%) of pure 6- [m- (4-methyl-1-piperazinyl) phenyl] -1,2-dihydro-2-oxonicotinonitrile; Mp. 264 to 2670C (decomposition) as a yellow solid.
 EMI16.3
    (4-methyl-1-piperazinyl) phenyl] -1, extracted. The combined aqueous extract, which contains the sodium salt of 0- (4-methyl-1-piperazinyl) - -benzoylacetaldehyde, is adjusted to pH 9 with acetic acid and treated with 45.8 g of 2-cyanoacetamide

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 EMI17.1
 
95 C for 6 hours and heated.

   The mixture is cooled and washed and dried; Mp. 202 to 2030C after crystallization from ethyl acetate. q) 6- [m- (Diethylamino) phenyl] -l, 2-dihydro-2-oxonicotinonitrile: A suspension of 10.9 g (0.22 mol) of sodium methoxide in 200 ml of ethyl ether is cooled to 30 ° C. and a solution is added dropwise from 35.2 g
 EMI17.2
 delt, keeping the temperature below 50C. After the addition is complete, the mixture is allowed to stir overnight at room temperature.



   200 ml of water are then added and the aqueous phase is separated. The ethyl ether phase is extracted with an additional 150 ml of water and the combined aqueous extracts are brought to pH 9.2 with acetic acid. 23.2 g (0.276 mol) cyanoacetamide are added and the solution is kept at 90 ° C. for 6 h. After the solution has stood at room temperature overnight, the crude pyridonenitrile is collected on a filter.

   Recrystallization from ethanol / DMSO gives 16 g of pure 6- [m- (diethylamino) phenyl] -1, 2-dihydro-2-oxonicotinonitrile; M.p. 229 to 2320C. r) 6- [p- (4-methyl-1-piperazinyl) phenyl] -1,2-dihydro-1-methyl-2-oxonicotinonitrile: 29 g of 95.5% sodium methoxide are suspended in 250 ml of tetrahydrofuran, stirred and chilled. 50 ml of ethyl formate and 109 g of p- (4-methyl-1-piperazinyl) -acetophenone are dissolved in 600 ml of tetrahydrofuran and this solution is slowly added to the above suspension, the temperature being kept at about 110C. The mixture is stirred overnight at room temperature and the solid product is separated by filtration, washed first with tetrahydrofuran and then with ether.



   The above-mentioned solid is immediately dissolved in 1 liter of water and then 12 ml of piperidine, 6.4 ml of acetic acid and 49 g of N-methylcyanoacetamide are added. The PH is mixed with a little acetic acid (2 to 3 ml)
 EMI17.3
 
5 dried, filtered, evaporated to dryness and dissolved in tetrahydrofuran. The semi-solid product is precipitated by two successive additions of 11 petroleum ether each.

   The combined semi-solid product is triturated with 25 ml of tetrahydrofuran, the yellow solid is filtered off and in a high vacuum overnight
 EMI17.4
    PO dried, dissolved nol / tetrahydrofuran and filtered through the insert of a filter aid. The product [p- (4-methyl-1-piperazinyl) phenyl] -1,2-dihydro-1-methyl-2-oxonicotinonitrile slowly crystallizes from the cooled filtrate, yield 2.35 g; Mp. 238 to 2420C (decay).
 EMI17.5
 (4-methyl-1-piperazinyl) phenyI] -1, 2-dihydro-2-oxonicotinonitrile: 2.03 g (0.0844 mol) are suspended in 200 ml of benzene and this suspension is a solution in
60 ml benzene, 10.25 g (0.0422 mol) 3'-chloro-4 '- (4-methyl-1-piperazinyl) -acetophenone and 4 ml ethyl formate were added.

   After a quarter has been added, a few drops of ethanol are added and the temperature is raised to 500C to initiate hydrogen evolution. The addition is stopped at 50 ° C. and stirring is continued overnight at room temperature. 100 ml of water are added to the stirred suspension and the two layers are separated. The benzene layer is washed a few times with about 50 ml of water each time.



   The combined water layers are adjusted to 9 to 9.1 with acetic acid and piperidine and a clear solution results. 5.3 g of cyanoacetamide (50% excess) are introduced and the mixture is refluxed at 950C overnight. The precipitate of 6- [3-chloro-4- (4-methyl-1-piperazinyl) phenyl] -1,2-dihydro-2-oxonicotinonitrile is collected, washed with water and dried to give 11.5 g. A 5 g sample is further purified by dissolving it in hot, dilute acetic acid and by precipitation at pH 6 to 7 by partial neutralization with N alkali. 4.5 g of material are obtained which are found to be pure by thin-layer chromatography.

   X 369 EI = 686 (methanol). t) 6- (m-Nitrophenyl) -1,2-dihydro-2-oxonicotinonitrile: 11.9 g (0.22 mol, 10% excess) sodium methylate are suspended in 100 ml benzene. The suspension is cooled and a previously prepared solution of 20 ml of ethyl formate (0.25 mol, 25% excess) and m-nitroacetophenone 33 g (0.2 mol) in 260 ml of benzene is quickly added dropwise (20 min). The temperature is kept at 8: 1: 20C by means of an ice bath. The suspension is stirred overnight and 800 ml of water are added to the reaction mixture. Two layers with a suspended solid form. The solid is removed by filtration, the layers are separated and to the aqueous filtrate is added 16.8 g of 2-cyanoacetamide.

   The mixture, adjusted to pH 8.5 to 9, is refluxed overnight when the pH has fallen to 6.8 and a tanning solid has precipitated. The product 6- (m-nitrophenyl) -1,2-dihydro-2-oxonikoHnonitril is collected, washed with water and dried at 60 C in a vacuum for 3 hours, yield 11.34 g,

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 EMI18.1
 1 ml of ethanol is added and the reaction mixture is heated to 40 ° C. This temperature is maintained until all reactants have been added. Stirring at room temperature is continued overnight. Next, 50 ml of water is added, the layers are separated and the benzene layer is washed a few times with water.

   The combined aqueous solution is adjusted to% 9 to 9.1 with acetic acid and 3.12 g (50% excess) 2-cyanoacetamide is added to the solution and the mixture is refluxed overnight. The precipitated solid is filtered off, washed with acetonitrile and hot ethanol and dried to give 6- [m- (1-pyrrolidinyl) phenyl]] - 1,2-dihydro-2-oxonicotinonitrile as a yellow solid melting above 2900C. # - 354 EI = 482 (methanol). v) 6- (m-Piperidinylphenyl) -1,2-dihydro-2-oxonicotinonitrile:

   A solution of 10.2 g (0.05 mol) of m-piperidinylacetophenone and 7.1 ml (0.075 mol) of ethyl formate in 50 ml of ethyl ether is a stirred suspension of 5.4 g (0.1 mol) of sodium methoxide in 250 ml of ethyl ether was added, the temperature being kept below 50C. Stirring is continued overnight at room temperature. Cold water is added to the mixture, the layers are separated and washed with water. The combined aqueous ex-
 EMI18.2
 held under reflux at 950C for 4 h. The suspension is cooled, the product is filtered off and washed first with 100 ml of water and then with 200 ml of acetonitrile.

   The pale yellow solid 6- (m-piperidinylphenyl) -1, 2-dihydro-2-oxonicotinonitrile is dried and this gives 6.92 g. 71st = 355 EI = 682 (methanol). w) 6- [m- (Methylamino) phenyl] -1,2-dihydro-2-oxonicotinonitrile: A suspension of 3.1 g (0.057 mol, 10% excess) of sodium methoxide in 60 ml of ethyl ether and under nitrogen is in Ice cooled and treated dropwise with a solution of 7.77 g (0.052 mol) of m- (methylamino) acetophenone and 4.25 ml (0.052 mol) of ethyl formate in 60 ml of ethyl ether. The cooling is maintained throughout the addition. When the addition is complete, the cooling is stopped and the suspension is allowed to stir overnight at room temperature.



   The suspension is treated with 60 ml of water and the layer is separated. The ethyl ether layer is washed with an additional 45 ml of water. The combined aqueous phase is brought to pH 9.1 with acetic acid and 6.6 g (0.078 mol) of 2-cyanoacetamide are added. The solution is kept at 90 ° C. for 6 hours and then cooled. The crude solid is collected and recrystallized from DMSO / water to give 4.1 g of 6- [m- (methylamino) phenyl] -1,2-dihydro-2-oxonicotinoniturl as a yellow solid; Fp.



  288 to 2900C (decay). x) 6- [m- (Propylamino) phenyl] -1,2-dihydro-2-oxonicotinonitrile: A suspension of 4.48 g (0.083 mol, 10% excess) sodium methoxyd in 100 ml of ethyl ether is cooled in ice and added dropwise a solution of 13.3 g (0.075 mol) of m- (propylamino) acetophenone and 6.05 ml (0.075 mol) of ethyl formate in 100 ml of ethyl ether treated under nitrogen. Cooling was maintained during the addition. When the addition is complete, the cooling is stopped and the suspension is allowed to stir overnight at room temperature.



   The suspension is treated with 100 ml of water and the layers are separated. The ethyl ether layer is washed with an additional 50 ml of water. The combined aqueous layers are brought to: H 9 with acetic acid and are treated with 9.51 g (0.113 mol) of 2-cyanoacetamide. The solution is kept at 90 ° C. for 6 hours and then cooled. The crude precipitated product is collected and dried. Recrystallization from DMSO / water gives 6.1 g of 6- [m- (propylamino) phenyl] -1,2-dihydro-2-oxonicotinonitrile as a yellow-brown solid; M.p. 215 to 2200C (decay).



   C) 6-Substituted-1,2-dihydro-2-oxonicotinic acids:
 EMI18.3
    (4-Methyl-1-piperazinyl) phenyl] -1, 2-dihydro-2-oxonicotinic acid: Umhydroxyd is heated at 1050C for 40 hours in a shaken stainless steel autoclave and then poured into a mixture of 1.4 kg of ice and 1.4 l of conc. Poured hydrochloric acid. The pH of the resulting mixture is adjusted to 6.5 with 5% aqueous sodium hydroxide and the precipitate of 6- [p- (4-methyl-1-piperazinyl) phenyl] -1,2-dihydro-2-oxonicotinic acid is removed by filtration collected, washed first with water and then with 95% ethanol and dried; M.p. 3000C (disintegration).



   In a similar manner the following acids are prepared, i.a. or by hydrolysis of the corresponding nitrile with ten times its weight of 20% aqueous potassium hydroxide, followed by acidification and suitable adjustment of the pH.

 <Desc / Clms Page number 19>

 b) 6- [p- (dimethylamino) phenyl] -1,2-dihydro-2-oxonicotinic acid, e) 6- [m- (dimethylamino) phenyl] -1,2-dihydro-2-oxonicotinic acid,
M.p. 275 to 2800C (decomposition) after crystallization from aqueous dimethyl sulfoxide, d) 6- [p- (4-propyl-1-pierazinyl) phenyl] -1,2-dihydro-2-oxonicotinic acid,
Fp.

   268 to 2690C (decay),
 EMI19.1
 
A mixture of 14.7 g of 6- [o- (4-methyl-1-piperazinyl) phenyl] -1,2-dihydro-2-oxonicotinonitrile and 246 ml of 17% aqueous sodium hydroxide is stirred and heated under reflux for 43 h then filtered hot. The filtrate is concentrated in a solution of 63 ml. Hydrochloric acid poured into 350 ml of ice water.

   The resulting precipitate of 6- [o- (4-methyl-1-piperazinyl) phenyl] -1,2-dihydro-2-oxonicotinic acid is collected by filtration, washed with water and dried; Mp. 214.5 to 215.50 ° C. (decomposition) after crystallization from toluene-cyclohexane. q) 6- [m- (4-Methyl-1-piperazinyl) phenyl] -1,2-dihydro-2-oxonicotinic acid: A stainless steel autoclave is filled with 14.8 g of 6- [m- (4-methyl- 1-piperazinyl) phenyl] -1,2-dihydro-2-nicotinonitrile and a solution of 30 g of potassium hydroxide in 120 ml of water is added. The mixture is heated for 41 h at 1050 ° C. and then poured over ice and hydrochloric acid.

   The% is adjusted to 6.4 and 15.6 g (89%) 6- [m- (4-methyl-1-piperazinyl) phenyl] -1,2-dihydro-2-oxonicotinic acid hydrochloride becomes a yellow solid collected; Mp 309-3100C (decay).
 EMI19.2
 [m- (diethylamino) phenyl] -l, 2-dihydro-2-oxonicotinic acid: hydro-2-oxonicotinic acid; Mp. 256 to 2580C (decay). s) 6- [p- (4-methyl-1-piperazinyl) phenyl] 1,2-dihydro-1-methyl-2-oxonicotinic acid: 6- [p- (4-methyl-1-piperazinyl) phenyl] -1 , 2-dihydro-1-methyl-2-oxonicotinonitrile (2 g) is heated in 16 ml of water containing 4 g of potassium hydroxide at 1050 ° C. for 40 hours. The hydrolysis is incomplete.

   The recovered, partially hydrolyzed material (1.74 g, melting point 291 to 2300 ° C.) is treated for 38 hours at 1700 ° C. in a pressure vessel in 4 ml of water, 12 ml of ethyl glycol and 4 g of potassium hydroxide. The reaction mixture is concentrated in 6, 5 ml. Poured hydrochloric acid and 7 g of ice. The slightly cloudy solution is filtered and the filtrate is brought to dryness on a steam bath using a rotary evaporator under vacuum. The residue is mixed with 12 ml of cold water (pH about 3.3) and filtered.

   The filtrate later deposits additional solid, which is also filtered off and combined to make a total of 0.58 g of 6- [p- (4-methyl-1-piperazinyl) phenyl] -1,2-dihydro-1-methyl-2-oxonicotinic acid to give after drying over phosphorus pentoxide in vacuo. t) 6- [3-Chloro-4- (4-methyl-1-piperazinyl) phenyl] -1, 2-dihydro-2-oxonicotinic acid: 6- [3-chloro-4- (4-methyl-1 -piperazinyl) ¯phenyl] -1, 2-dihydro-2-oxonicotinonitrile (3.3 g) is heated for 40 hours at 105 ° C. in about 25 ml of 20% potassium hydroxide. The acidified solution (prj 5 to 7) is filtered, the collected precipitate is dissolved in dilute hydrochloric acid (<10%) and reprecipitated by bringing the P to 5 to 7.5 with 1N sodium hydroxide.

   The precipitate of 6- [3-chloro-4- (4-methyl-1-piperrazinyl) phenyl] - -1,2-dihydro-2-oxonicotinic acid is collected and crystallized from DMSO plus tetrahydrofuran / CH CN 1-1, whereby result 1, 8g. A. 329 µm Egg = 596 (methanol). u) 6- [3-Bromo-4- (4-methyl-1-piperazinyl) phenyl] -4 (or 5) -bromo-1,2-dihydro-2-oxonicotinic acid: 3.13 g

 <Desc / Clms Page number 20>

 (0.01 mol) 6- [p- (4-methyl-1-piperazinyl) phenyl] -1,2-dihydro-2-oxonicotinic acid are dissolved in 100 ml of 2N sulfuric acid with stirring at room temperature. 3.2 g (1.1 ml, 0.02 mole) of bromine are added to the solution dropwise, which causes a solid to precipitate.

   The suspension is stirred for 1 hour and then filtered. The fine yellow precipitate is washed with ethanol and dissolved in water with the addition of sodium hydroxide (Pa = 12). The basic solution is filtered to remove insoluble solids and the filtrate is acidified to pH 5.5 to 6.0 with 2N sulfuric acid.

   The product 6- [3-bromo-4- (4-methyl- -1-piperazinyl) phenyl] -4 (or 5) -bromo-1,2-dihydro-2-oxonicotinic acid is precipitated and collected by filtration with water washed and dried. v) 6- (m-Nitrophenyl) -1, 2-dihydro-2-oxonicotinic acid: A suspension of 147 g (0.608 mol) 6- (m-nitrophenyl) -1, 2-dihydro-2-oxonicotinonitrile in 3, 7 l of 5% potassium hydroxide is heated on a steam bath for 46 hours (solution is complete before 42 hours have elapsed). The solution is treated vigorously twice with charcoal and the filtrate is concentrated in about 2 kg of ice containing 250 ml. Hydrochloric acid, poured.

   The yellowish precipitate is collected by filtration and washed twice with water, twice with methanol and finally with ethyl ether, 69.8 g (60.6%) being obtained (after drying in vacuo for 72 h). The product 6- (m-nitrophenyl) -1,2-dihydro-2-oxonicotinic acid is further crystallized from icy acetic acid with charcoal, washed with acetic acid and then with ethyl ether, melting point 303-304C. w) 6- [m- (l-pyrrolidinyl) phenyU-l, 2-dihydro-2-oxonicotinic acid: 6- [m- (l-pyrrolidinyl) phenyl] -l, 2-dihydro-2-oxonicotinonitrile (2 , 08g) is heated for 40 hours at 1050C under pressure in 20 ml of 20% potassium hydroxide.



  The reaction mixture is concentrated in 6, 5 ml. Poured hydrochloric acid and 10 g of ice. The product 6- [m- (1-pyrroli-
 EMI20.1
    phenyl] -l, 2-dihydro-2-oxonicotinic acid pH 7 buffer). x) 6- (m-piperidinylphenyl) -1, 2-dihydro-2-oxonicotinic acid: 6- (m-piperidinylphenyl) -1, 2-dihydro-2-oxonicotinonitrile (5.6 g, 20 mmol) are in 300 ml of 6% potassium hydroxide dissolved in a stainless steel container and heated on a steam bath over the weekend. The heating is switched to a Glascol jacket and the solution is refluxed for an additional 3 hours at 1000C. The solution is poured into 200 ml of ice-water mixture and acidified to pH 3 with hydrochloric acid.

   The collected solid 6- (m-piperidinylphenyl) -1,2-dihydro-2-oxonicotinic acid is washed first with water and then with acetonitrile (250 ml); Yield 5.35 g of a light yellow solid, À = 324, Ei = 482 (in pH 7 buffer). y) 6- [m- (Methylamino) phenyl] -1,2-dihydro-2-oxonicotinic acid: A stainless steel autoclave is filled with 4.03 g of 6- [m- (methylamino) phenyl] -1,2-dihydro -2-oxonicotinonitrile loaded and a solution of 8, 0 g
 EMI20.2
 
4 gives 3.83 g of 6- [m - (methylamino) phenyl] -l, 2-dihydro-2-oxonicotinic acid as a yellow solid;

   Mp. 283-2840C (decay).
 EMI20.3
 

 <Desc / Clms Page number 21>

 
 EMI21.1
 rid. n) 6- [p- (4-Methyl-1-piperazinyl) phenyl] -1, 2-dihydro-1-methyl-2-oxonicotinyl chloride hydrochloride. o) 6- [o- (4-pentyl-1-piperazinyl) phenyl] -1,2-dihydro-2-oxonicotinyl chloride hydrochloride.



   A mixture of 3.44 g of finely divided 6- [o- (4-methyl-1-peperazinyl) phenyl] -1,2-dihydro-2-oxonicotinic acid and 35 ml of thionyl chloride is stirred for 16 h at room temperature and then with 150 ml Diluted dichloromethane. The resulting solution is evaporated under reduced pressure, and the obtained precipitate of 6- [o- (4-methyl-1-piperazinyl) phenyl] -1,2-dihydro-2-oxonicotinyl chloride hydrochloride is collected by filtration, washed with dichloromethane and dried. p) 6- [m- (4-Methyl-1-piperazinyl) phenyl] -1,2-dihydro-2-oxonicotinyl chloride hydrochloride: 6- [m- (4-Methyl-1-piperazinyl) phenyl] -1,2- dihydro-2-oxonicotinic acid hydrochloride (1.5 g) is added to 75 ml of SOCl containing 20 drops of N, N-dimethylformamide. The material appears to be partially soluble. and after a few minutes a new solid begins to appear.

   The suspension is stirred at room temperature overnight. Dichloromethane is then added and the pale yellow solid is collected and washed with dichloromethane. 1.44 g of 6- [m- (4-methyl-1-piperazinyl) phenyl] -1,2-dihydro-2-oxonicotinyl chloride hydrochloride are obtained.
 EMI21.2
 and washed with dichloromethane. 3.28 g of the acid chloride hydrochloride are obtained. r) 6- [p- (4-Methyl-1-piperazinyl) phenyl] -1, 2-dihydro-1-methyl-2-oxonicotinyl chloride hydrochloride: 0.5 g of 6- [p- (4-methyl-1-piperazinyl ) phenyl] -1,2-dihydro-1-methyl-2-oxonicotinic acid is added to 5 ml of thionyl chloride. The solid quickly dissolves with an effervescence and the resulting solution is stirred for 3 hours.

   The product is precipitated by adding 10 parts by volume of hexane and the solid 6- [p- (4-methyl-1-piperazinyl) phenyl] -1,2-dihydro-1-methyl-2-oxonicotinyl chloride hydrochloride is passed through Decant separately. Washing with hexane by decanting is repeated several times and the product is finally suspended in tetrahydrofuran and used as a suspension in the preparation of the compounds obtainable according to the invention.
 EMI21.3
 [3 - chloro -4 - (4 - methyl-1-piperazinyl) phenyl] -1, 2 - dihydro-2-oxonicotinyl chloride hydrochloride: ethyl-1-piperazinyl) phenyl] -1,2-dihydro-2-oxonicotinyl chloride hydrochloride is obtained by filtration collected and dried over phosphorus pentoxide in a high vacuum.

   The product is used directly in the preparation of the compounds obtainable according to the invention.
 EMI21.4
 acid, 25 ml of thionyl chloride are added and the mixture is allowed to stir overnight at room temperature. A trace of solid is filtered off the solution and the product is precipitated by adding hexane (large volume). The gum solidifies on standing and is filtered off and dried over phosphorus pentoxide to give 6- [3-bromo-4- (4-methyl-1-piperazinyl) phenyl] -4 (or 5) -bromo-1,2-dihydro- To give 2-oxonicotinyl chloride hydrochloride. u) 6- (m-Nitrophenyl) -1,2-dihydro-2-oxonicotinyl chloride: A 5 g sample of 6- (m-nitrophenyl) -1,2-dihydro-2-oxonicotinic acid is suspended in 100 ml of thionyl chloride and stirred overnight at room temperature.

   The product 6- (m-nitrophenyl) -1,2-ddihydro-2-oxonicotinyl chloride is carefully filtered off and washed with hexane and used directly in the preparation of compounds obtainable according to the invention. v) 6- [m - (1- pyrrolidinyl) phenyl] -1, 2-dihydro-2-oxonicotinyl chloride hydrochloride: 1.9 g 6- [m - (1- pyrrolidinyl) phenyl] -1, 2-dihydro- 2-oxonicotinic acid is suspended in 40 ml of thionyl chloride and stirred for 4 hours at room temperature. A trace of undissolved solid is removed by filtration and the filtrate is diluted with 500 ml of hexane. A gum that initially forms turns into a tanning solid with continued stirring.

   The solid 6- [m- (1-pyrrolidinyl) phenyl] -1, 2-dihydro-2-oxonicotinyl chloride hydrochloride is quickly collected by filtration and dried over phosphorus pentoxide in vacuo overnight. The 1, 8 g of the product obtained in this way are without further purification in the

 <Desc / Clms Page number 22>

 
 EMI22.1
 (m - piperidinylphenyl) -1, 2-dihydro-2-oxonicotinyl chloride hydrochloride: 5, 22-peridinylphenyl) -1,2-dihydro-2-oxoniocotinic acid are added to 100 ml of thionyl chloride and the mixture is stirred overnight at room temperature. The solid 6- (m-piperidinylphenyl) -1, 2-dihydro-2-oxonikotinyl chloride hydrochloride is separated by filtration, washed three times with 100 ml of hexane and dried in vacuo over phosphorus pentoxide.

   The product can be used directly in the next step. x) 6- [m - (methylamino) phenyl] -1, 2-dihydro-2-oxonicotinyl chloride hydrochloride: 1.0g 6- [m- (methylamino) phenyl] -l, 2-dihydro-2-oxonicotinic acid become 10 ml SOC1. containing 10 drops of dimethylformamide, added. Solution soon occurred and after about 15 minutes a new solid began to appear. The mixture is diluted with methylene chloride and the 6- [m- (methylamino) phenyl] phenyl] -1,2-dihydro-2-oxonicotinyl chloride hydrochloride is collected and washed with methylene chloride.
 EMI22.2
 amide, added. Solution soon occurs and after half an hour a new solid begins to appear.

   The mixture is diluted with methylene chloride and the 6- [m- (prop6yolamino) phenyl] -1,2-dihydro-2-oxonicotinyl chloride hydrochloride is collected and washed with methylene chloride. z) 6- [0- (4-Methyl-1-piperazinyl) phenyl] -1, 2-dihydro-2-oxonicotinyl chloride hydrochloride: A mixture of 3.44 g of finely divided 6- [o (4-methyl-1-piperazinyl) phenyl ] -1,2-dihydro-2-oxonicotinic acid and 35 ml of thionyl chloride are stirred for 16 hours at room temperature and then diluted with 150 ml of dichloromethane. Which he-
 EMI22.3
 washed with dichloromethane and dried.



   E) D-N- (trimethylsilyl) -2-phenylglcine, trimethylsilyl ester:
A mixture of 16.6 g of D- (-) - 2-phenylglycine, 30 ml of trimethylsilyl chloride and 35 ml of triethylamine in oil-dichloromefhan is stirred at reduced pressure and a solution is obtained which contains D-N- (tri
 EMI22.4
 -2-phenylglycine, trimethylsilyl ester N- [6- [p- (4-methyl-1-piperazinyl) phenyl] -1,2-dihydro-2-oxonicotinyl} chloride is added in portions with vigorous stirring. A solution of 35 ml of triethylamine in 50 ml of dichloromethane is then added dropwise with stirring for one hour. The resulting mixture is left to stand at room temperature for 3 hours and then diluted with 5 ml of water in 100 ml of dimethylformamide. The mixture obtained is
 EMI22.5
 Pyridine).

** WARNING ** End of DESC field may overlap beginning of CLMS **.

 

Claims (1)

PATENT CLAIMS: 1. Process for the preparation of new compounds of the general formula EMI22.6 ind of salts thereof, characterized in that a compound of the general formula <Desc / Clms Page number 23> EMI23.1 or a salt or a reactive derivative thereof with a compound of the formula EMI23.2 or the general formula EMI23.3 or an acid salt or a silylated derivative thereof is reacted and the product is isolated as a free amino acid or as a salt, wherein R is hydrogen or methyl, EMI23.4 R1dinyl) -piperidinyl is where R5 is a lower alkyl group with 1 to 6 carbon atoms, Is cyclohexyl, benzyl, phenyl or halophenyl, R is phenyl, p-hydroxyphenyl, 2-thienyl or cyclohexa-1,4-dien-1-yl, R6 is -C (CH3) 2 or -CH2-C (CH2R4) = and R4 hydrogen, acetoxy, (5-methyl-1,3,4-thiadiazol-2-yl) thio, (2-pyrimidinyl) thio or 1-pyridyl, with the proviso that when R1 is pyridyl, it is CO 2 H-CO ", and X hydrogen, chlorine or bromine and Y is hydrogen or bromine. 2. The method according to claim 1, characterized in that in the initial compound R1R2N is nitro and the product obtained is reacted with a reducing agent, whereby B, R, N is converted into a primary amino group.