HU191847B - Process for producing 3-amino-5-/pyridin-4-yl/-1,2-dihydro-pyridin-2-one compound - Google Patents

Abstract

The invention relates to an improved production process for 3-amino-5- (pyrid-4-yl) -1,2-dihydro-pyrid-2-one (I). By means of the process according to the invention it becomes possible to save substantial quantities of raw materials, to increase the volume yield and to considerably reduce the wastewater load. Compound I, as well as its pharmaceutically acceptable salts, has aroused considerable interest because of its favorable circulatory properties, in particular as a potential cardiotonic with concurrent antianaphylactic activity. Field of application of the invention is the pharmaceutical industry.

Description

(57) EXTRAS

The present invention relates to a novel process for the preparation of 3-amino-5- (5-4'-pyridyl) -1,2-dihydro-2-pyridone by reacting pyridine derivatives with an acid halide and dimethylformamide. The process is characterized in that the pyridine derivative of formula (V) - in formula (V) - X is hydrogen and Y is hydrogen or carboxyl or X and Y together = CH-N (CH 3) 2 or the corresponding pyridinium salt or A compound of formula II is reacted with a complex of an acid halide and dimethylformamide to form a compound of formula II, a salt of a compound of formula II is converted to a nitrile of a compound of cyanoacetamide, the hydrolyzed nitrile to a carboxylic acid of formula IV is broken down into an amine of formula.

-1191847

The present invention relates to a novel process for the preparation of 3-amino-5- (4'-pyridyl) -1,2-dihydro-2-pyridone. This compound has an excellent effect on blood circulation and is therefore used, alone or in the form of its salts, for the preparation of medicaments which are heart stimulating and at the same time dilate the bronchi.

3-Amino-5- (4'-pyridyl) -1,2-dihydro-2-pyridone of formula (I) is currently prepared by forming complexes of acid chloride and dimethylformamide with 4-methylpyridine on a vinyl, pyridyl group is reacted with cyanoacetamide to form 3-cyano-5- (4'-pyridyl) -1,2-dihydro-2-pyridone, hydrolyzing to form the corresponding 3-carboxylic acid amide and then converting it with hypobromide to form the target compound of formula I U.S. Patent Nos. 4,004,012, 4,072,746, 4,017,315, 4,137,233, 4,225,715, 4,264,609, British Patent 2,070,008). The simplest known hitherto known for the preparation of N, N-dimethyl-N- (3-dimethylamino-2-pyrid-4'-yl-2-propenylidene) -ammonium chloride hydrochloride is 4-methylpyridine with dimethylformamide. in his presence. Reaction of the hydrochloride with cyanoacetamide affords 3-cyano-5- (4'-pyridyl) -1,2-dihydro-2-pyridone (U.S. Pat. No. 4,264,609).

When using phosgene, at least 3 moles of phosgene are added dropwise to 25 moles of dry dimethylformamide at -10 to 0 [deg.] C., and 1 mole of 4-methylpyridine is added under cooling to a temperature of 35-40 [deg.] C. After 2 to 3 hours at 60 ° C, the reaction mixture was cooled, washed with dimethylformamide and ether and dried in vacuo. The disadvantage of this process is that large quantities of liquid phosgene have to be treated and expensive equipment to cool to -10 ° C, and the isolation of the hydrochloride requires a lot of work. The preparation of the vinyl formamide salt (by reaction of 4-methylpyridine, dimethylformamide and phosphorous oxychloride) also has the disadvantage of high losses of dimethylformamide and wastewater treatment.

No. 4,264,609. As described in U.S. Pat. No. 4,600, the vinyl formamide salt is heated in a steam bath with a solution of 110 mol% of cyanoacetamide in anhydrous dimethylformamide and at least 300 mol% of potassium carbonate for 1 hour and then cooled. The precipitated potassium salt is filtered off, dried and dissolved in water. The solution is adjusted to pH 5 with acetic acid, the product is filtered off with suction and washed with water, ethanol and ether, respectively, to give 3-cyano-5- (4'-pyridyl) -1,2-dihydro-2-pyridone in 45% yield. receive. The disadvantage here is that the potassium carbonate and the solvent must be dried. Due to the large amount of potassium carbonate, the reaction mixture is poorly stirred. Processing of the mixture is cumbersome and the proportion of reduced quality product obtained from the mother liquor is high.

Most preferably, the saponification of 3-cyano-5- (4'-pyridyl) -1,2-dihydro-2-pyridone is accomplished by heating with 90% sulfuric acid for 1-2 hours (U.S. Pat. No. 4,072,746). patent specification); the required sulfuric acid is used in an 18-fold excess. The reaction mixture is poured onto ice and basified with aqueous sodium hydroxide solution followed by 10% potassium bicarbonate solution. The product is filtered off with suction, washed with water and then dried, and recrystallized from dimethylformamide.

In the mother liquor, since it is necessary to neutralize large amounts of conic acid, neutral salts are enriched. Pouring onto ice, recrystallization and multiple washing of the end product with various solvents takes time.

From 5-pyrid-4'-yl-1,2-dihydro-2-pyridone-3-carboxylic acid amide, 5- (4'-pyridyl) -1,2-dihydro-2-pyridone is prepared in alkaline solution with hypobromite (4,072). (U.S. Patent No. 746) by adding bromine to about 7% sodium hydroxide solution at 0 ° C, then adding the amide and heating the mixture in a steam bath for 3 hours. After cooling to room temperature, the mixture is acidified with 6N hydrochloric acid, neutralized with 10% potassium bicarbonate solution, filtered off with suction, washed with water, dried and recrystallized from dimethylformamide. The yield is 50% of the theoretical yield. The disadvantage of this procedure is that hypobromite must be used. Hypobromite is even more volatile than hypochlorite, so it provides only a small yield and produces unwanted by-products. Isolation of the product from recrystallization from dimethylformamide is a complex operation and the yield is not satisfactory.

SUMMARY OF THE INVENTION The object of the present invention is to provide a process which, in contrast to known processes starting from pure 4-methylpyridine, also allows the use of product mixtures containing 4-methylpyridine in the reaction of the pyridine derivative (V) with additional raw materials such as DMF , saves detergents, acids, alkalis, reduces cooling capacity, increases volume through use of higher concentrations and minimizes the formation of polluted air in sewage. Finally, it is an object of the present invention to reduce the number of process steps, particularly purification operations, and nevertheless to obtain a pure final product.

The above object is solved by the pyridine derivative of formula (V) - wherein in formula (V) X is hydrogen and Y is hydrogen or carboxyl or X and Y together = CH-N (CH 3) 2 - or the corresponding pyridinium salt or is of formula (V)

-2191847 reaction mixture of pyridine derivatives or picoline base with a complex of an acid halide and dimethylformamide (2: 1 to 2.9: 1 molar ratio of acid halide to pyridine derivative) to the compound of the formula II with 1 mol of cyanoacetamide in the presence of 1 to 3 moles of base per salt) to a nitrile of formula (III), hydrolyze the nitrile to the carboxylic acid amide (IV) and then decompose the amide to the amine of formula (I) with hypohalite or halogen.

In the process of the present invention, the dimethylformamide is reacted with phosphorus oxychloride or phosgene at 25-45 ° C by introducing the phosgene onto or into a five-fold excess of dimethylformamide, followed by the pyridine compound of formula (V). preferably a mixture of 4-methylpyridine, 3-methylpyridine and 2,6-dimethylpyridine is added and the mixture is stirred at about 30 ° C for several hours. The salt of formula (II) is then aspirated in the form of a hydrate. Surprisingly, at the given temperature, diraethylformamide completely absorbs the phosgene, meaning that the phosgene is not released into the air along with the carbon dioxide that is released. Contrary to the procedure known in the literature, there is no need to work with liquid phosgene that is difficult to handle for safety reasons and no industrial-scale refrigeration equipment is required. Nor is it necessary to maintain the temperature at 60 ° C for several hours. It is really surprising that 3-methylpyridine and 2,6-dimethylpyridine behave completely inert against the phosgene and phosphorus oxychloride and dimethylformamide complexes. This also permits the direct use of 4-methylpyridine which is present in combination with isomeric picolines and lutiolines.

The process of the present invention requires much less phosgene, dimethylformamide and solvent than the known processes. Further, drying capacity is saved because the salt of formula (II) is preferably reacted in the wet state or without isolation. Even when phosphorus oxychloride is used as the acid chloride, there are significant advantages over known processes in terms of dimethylformamide, cooling capacity, and reduced wastewater load (dimethylformamide, chloride and phosphate ions). The vinylogen formamidine salt of formula (II) can be reacted with cyanoacetamide to form the nitrile (III) without isolation and purification. For example, this step may be carried out by directly cyclizing the non-crystallized salt of formula (II) in a solution of dimethylformamide with cyanoacetamide in the presence of a base to a nitrile. In order to obtain a particularly pure nitrile of formula (III), it is preferable to allow the salt to crystallize by removing the major amount of the supernatant dimethylformamide and replacing it with a solvent suitable for ring closure. Dipolar aprotic organic proton solvents and water are particularly suitable for this purpose. Bottom Éber case of application of water _was rakcióközeg example possible that described in more detail below, ring closure is carried out at room temperature. By using dimethylformamide as a solvent, the ring closure can also be carried out at elevated temperatures.

For the ring closure, 1.0 to 2.0 moles of base, preferably 1.5 to 2.0 moles, of base are used per mole of the salt of formula II. As the base, alkali metal carbonates or alkali metal hydroxides or mixtures thereof may be used. When the ring closure is carried out in an aqueous medium, the base is preferably sodium hydroxide solution or sodium carbonate, in which case the alkali metal salt of nitrile (III) is precipitated from the aqueous solution and can be converted to nitrile (III) by acidification.

After ring closure in dimethylformamide medium, the nitrile III or its alkali metal salt is preferably isolated by partial distillation of the solvent. The recrystallized dimethylformamide, also dimethylformamide distilled from the mother liquor of the salt of formula II, can be reused for the reactions described.

Advantages of the present invention include the processability of the wet dimethylformamide salt of Formula II, the use of organic proton solvents and water, and the reduction of the base amount from 300 mol% to about 100 mol%. The solvent, the salt of formula (II) and the alkali metal carbonate need not be dried, and the presence of beer, water, has proven to be so advantageous that it can be used as a solvent. It is not necessary to process the main fraction and the product obtained from the mother liquor separately, but after distilling off the solvent, a uniform product of formula (III) is obtained. Reducing the amount of dimethylformamide 1 and base simplifies water purification problems.

The nitrile of formula (III) is hydrolyzed by heating twice in 90% sulfuric acid at 60-100 ° C, for example for about 30 minutes at about 90 ° C. The aqueous solution was then diluted with water and neutralized with aqueous sodium hydroxide solution. In a preferred embodiment of the process, more alkali metal hydroxide is added to the solution than is necessary for neutralization, and the compound of formula (IV) is isolated in the form of its alkali metal salt, resulting in greater purity. The amount of sulfuric acid required is 1/9 part of the amount of sulfuric acid disclosed in U.S. Patent No. 4,072,746. U.S. Pat. Pouring the sulfuric acid mixture onto ice is replaced by much simpler aqueous dilution.

The isolation of the product according to the invention requires less work and material than recrystallization from dimethylformamide.

The amide of formula (IV) is reacted with alkali metal hypochlorite at room temperature in the presence of an excess of alkali metal hydroxide without intermediate purification. To complete the reaction, the mixture is heated to a temperature of about 60 ° C for a short time, preferably 15 to 30 minutes, and the amine of formula (I) is precipitated by addition of an acid at a slightly basic pH. When the amide is decomposed into an amine, either the amide or its alkali metal salt may be used, which may be formed in solution in situ prior to the reaction. The hypochlorite may be added to the mixture, or vice versa, or may be formed in situ in the reaction mixture by reaction of chlorine with an alkali metal hydroxide. Alternatively, the components required to decompose the amide of formula IV into the amine of formula I are directly

The reaction is carried out at 50-60 ° C.

It is a significant advantage that the process according to the invention is worked with sodium hypochlorite solution or chlorine, thus avoiding the danger of using caustic bromine. ₂ 0 In addition, the cost of sodium hypochlorite solution makes up about one tenth of the bromo-cost and saves cooling capacity. Adverse reactions to hypobromite are avoided, yielding 79-89% yield. Instead of expensive and bulky recrystallization with dimethylformamide, purification is accomplished by purification through the sodium salt. To do this, the crude amine of formula (I) is dissolved in a equimolar amount of sodium hydroxide solution with gentle heating, and the sodium salt is precipitated by the addition of additional sodium hydroxide solution and filtered off with suction. The sodium salt was dissolved in water during heating, clarified with activated carbon and fractionated precipitation gave 35 very pure amines.

The amine of formula (I) can be used as a cardiac pacemaker and bronchodilator after preparation in a suitable dosage form. Both the free base and its acid addition salt are suitable as active ingredients. Suitable acid addition salts are salts of acids which form physiologically acceptable salts with the free base. 45

Summarizing the advantages of the process according to the invention, we can save a considerable amount of raw material, cooling capacity, reduce environmental pollution (water, air) to a minimum, increase the volume capacity by working at higher concentrations, make the process safer and despite the fewer process steps, a cleaner final product is obtained. 55

The invention will now be further illustrated by the following examples.

19184 Example 1 60

Phosgene (19.8 g, 0.2 mol) was introduced into dimethylformamide (77.4 ml, 1 mol) at 26-30 ° C over 25 minutes. To the solution, 13.0 g (0.1 mol) of 4-methylpyridine hydrochloride was added over 10 minutes at 30-35 ° C. The reaction mixture was stirred at the indicated temperature for 4 hours, quenched with product and stirred for a further 2 hours. The product is filtered off with suction, washed with 10 ml of dimethylformamide and air dried. Yellow crystals are obtained which melt above 100 DEG C. with decomposition. Yield: 28.1 g (90.0% of theory) of N, N-dimethyl-N- (3-dimethylamino-2-pyrid-4'-yl-prop-2-enylidene) -ammonium chloride hydrochloride dihydrate (formyl vinamidine salt).

Elemental analysis calculated for C12H19.9Cl2N3.2H2O (M = 312.2),% C 46.16 H 7.43 N 13.46 Cl 22.72 H2O 11.54 Found% C 46.50 H 7.74 N 13.04 Cl 22.89

H2O 11.30

Example 2

As described in Example 1, 13.7 g (0.1 mol) of 4-pyridylacetic acid are reacted with 24.7 g (0.25 mol) of phosgene in an excess of dimethylformamide. 27.2 g (87.1% of theory) of the vinyloglycidine intermediate dihydrate are obtained.

Example 3

As in Example 1, 14.8 g (0.1 mol) of 4- (2-dimethylaminovinyl) pyridine

19.8 g (0.2 mol) of phosgene were reacted. 26.0 g (83.2% of theory) of the vinyl analog formamidium salt hydrate are obtained.

Example 4

24.7 g (0.25 mol) of phosgene were absorbed with 97 ml (1.215 mol) of dimethylformamide over 20 minutes at 30-32 ° C. 9.3 g (0.1 mol) of 4-methylpyridine are then added dropwise over 5 minutes. The reaction mixture was stirred at 35-40 ° C for 5 hours, cooled to room temperature and the product was filtered off with suction. 25.0 g (80.1% of theory) of the vinyl analog formamidinium salt dihydrate are obtained.

Example 5

24.7 g (0.25 mole) of phosgene were swallowed in 97 ml (1.25 mole) of dimethylformamide over 20 minutes at 30-35 ° C. Then 28.3 g of a crude picoline base mixture containing 32% 3-methylpyridine, 33% 4-methylpyridine and 30.5% 2,6-dimethylpyridine are added with stirring for 20 minutes. Further processing was carried out as described in Example 4. 26.2 g (a

-4191847

Based on 4-methylpyridine (84.0% of theory), vinyl analog formamidium salt dihydrate is obtained.

Example 6

Phosgene (34.6 g, 0.35 mol) was treated with dimethylformamide (136 mL, 1.75 mol) and 29.0 g of the base mixture of Example 5 as in Example 5. 27.8 g (86.5% of the theoretical of 4-methylpyridine) are obtained in the form of the vinyl formoformidinium salt dihydrate.

Example 7

21.8 g (0.22 mol) of phosgene over 20 minutes

At 34-36 ° C, was swallowed in 85 mL (1.1 mol) of dimethylformamide. To the reaction mixture

At 35-40 ° C, 9.3 g (0.1 mol) of 4-methylpyridine was added dropwise over 5 minutes. After stirring for 5 hours, the resulting crystalline suspension was adjusted to pH 8 with 45% sodium hydroxide solution and

9.2 g (0.11 mol) of cyanoacetamide and 21.2 g (0.2 mol) of sodium carbonate are added. The mixture was stirred at 85-90 ° C for 3 hours. After cooling, the solid is filtered off with suction, washed with 40 ml of dimethylformamide, suspended in 100 ml of water and adjusted to pH 5 with acetic acid. The product is filtered off with suction, washed with water and dried in an oven at 80 ° C.

13.5 g (68.5% of theory) of 3-cyano-5- (4'-pyridyl) -1,2-dihydro-2-pyridone are obtained in the form of a yellowish solid, m.p. melted. An additional 2.4 g (12.2%) of product was obtained from the mother liquor.

Elemental Analysis (M = 197.2) calculated% found,%: C11H7N3O C, 66.99; H, 3.58 formula N, 21.31 N, 21.64. Based on C, 66.67 H, 3.50 Example 8 THE 3. Example written way 14.8 g (0.1 mol) 4- (2-Diroethylaminovinyl) - pyridine

with phosgene-dimethylformamide complex. The reaction mixture was stirred at 35 ° C for 2 hours and then 9.2 g (0.11 mol) of cyanoacetamide and 21.2 g (0.2 mol) of sodium carbonate were added. The mixture was stirred at 90 ° C for 2.5 hours and worked up as described in Example 7. 12.4 g (62.9% of theory) of 3-cyano-5- (4'-pyridyl) -1,2-dihydro-2-pyridone are obtained. An additional 3.0 g of product (15.2%) was isolated from the mother liquor.

Example 9

Example 7 was used, but instead of the 4-methylpyridine used therein, the pyridine base mixture of Example 5 was used.

28.3 g were used. 13.1 g (66.4%) of 3-cyano-5- (4'-pyridyl) -1,2-dihydro-2-pyridone are obtained. An additional 2.7 g (13.7%) of product was obtained from the mother liquor.

Example 10

Phosphorous oxychloride (38.3 g, 0.25 mol) was added dropwise to dimethylformamide (116 ml, 1.5 mol) at 30-35 ° C over 30 minutes. At the same temperature, 28.3 g of the picoline base mixture of Example 5 was added dropwise to the reaction mixture over 5 minutes. The solution was allowed to stand overnight, diluted with water (160 mL) and adjusted to pH8 with 45% sodium hydroxide solution. The precipitate was filtered off and discarded. The formamidine salt content of the filtrate was determined by UV spectroscopy, yielding 29.4 g (94.2% of theory of 4-methylpyridine).

Example 11

26.7 g (0.27 mole) of phosgene were absorbed at a temperature of 30-35 ° C over 20 minutes onto 126 ml (1.62 mole) of dimethylformamide. To the mixture was added dropwise 4-methylpyridine (9.3 g, 0.1 mol) at 30-35 ° C over 5 minutes. After stirring at room temperature for 6 hours, water (63 ml) was added to the crystalline suspension followed by cyanoacetamide (9.2 g, 0.11 mol). The pH is adjusted to 7 with sodium carbonate and a solution of 8.0 g (0.2 mol) of sodium hydroxide in 20 ml of water is added dropwise over 10 minutes. After stirring at room temperature for 5 hours, evaporate to dryness in vacuo, dissolve the residue in 250 mL of water and adjust the pH to 7 with acetic acid. The product was filtered off with suction, washed with water and dried in vacuo at 80 ° C. 17.7 g (89.6% of theory) of 3-cyano-5- (4'-pyridyl) -1,2-dihydro-2-pyridone are obtained.

Example 12

As described in Example 11, 9.3 g (0.1 mol) of 4-methylpyridine can be reacted with a phosgene-dimethylformamide complex. After 3 hours, add 63 ml of water to the clear solution and then

9.2 g (0.11 mol) of cyanoacetamide are added. A solution of sodium hydroxide (5.0 g, 0.125 mol) in water (12 ml) was added dropwise to the mixture adjusted to pH 7 with sodium hydroxide solution, and the mixture was stirred at room temperature for 4 hours. . 17.2 g (87.0% of theory) of 3-cyano-5- (4'-pyridyl) -1,2-dihydro-2-pyridine are obtained.

-511

Example 13

In the same manner as in Example 11, 9.3 g (0.1 mole) of 4-methylpyridine was reacted with a phosgene-dimethylformamide complex. After the vinamidinium salt crystallized, the supernatant dimethylformamide solution was filtered off with suction and the remaining solid was dissolved in 120 ml of water. 9.2 g (0.11 mol) of cyanoacetamide are added to the solution, the pH is adjusted to 7 with 45% sodium hydroxide solution, and 5.0 g (0.125 mol) of sodium hydroxide in 12 ml are added over 10 minutes. aqueous solution was added dropwise and stirring was continued at room temperature for 3 hours. Workup as in Example 11. 16.8 g (85.0% of theory) of 3-cyano-5- (4'-pyridyl) -1,2-dihydro-2-pyridone are obtained.

Example 14

In the same manner as in Example 11, 9.3 g of 4-methylpyridine was reacted with phosgene-dimethylformamide complex. To the crystalline suspension was added cyanoacetamide as described above, while a solution of 3.0 g (0.075 mol) of sodium hydroxide and 7.9 g (0.075 mol) of sodium carbonate in 30 ml of water was added dropwise. Work up as in Example 11 to give 17.6 g (89.0% of theory) of 3-cyano-5- (4'-pyridyl) -1,2-dihydro-2-pyridone.

Example 15

As described in Example 11, the picoline base mixture of Example 5 was prepared

28.3 g is reacted with phosgene-dimethylformamide complex. To the crystalline suspension was added cyanoacetamide in the same manner as a solution of 4.0 g of sodium hydroxide in 10 ml of water was added dropwise. After stirring at room temperature for 3 hours, additional sodium hydroxide (4.0 g, 0.1 mol) was added and after 15 minutes, the salt was filtered off, dissolved in 200 ml of water at 50 ° C and the pH of the solution was adjusted with acetic acid. Set it to 7. The product was filtered off with suction, washed with water and dried in vacuo at 80 ° C. 15.6 g (79.0% of theory) of 3-cyano-5- (4'-pyridyl) -1,2-dihydro-2-pyridone are obtained. A further 2.2 g (11.0%) of product was obtained from the mother liquor.

Example 16

For 150 ml of dimethylformamide, 31.2 g (0.1 mole) of vinyl analog formamidinium salt dihydrate followed by 9.2 g (0.11 mole) of cyanoacetamide and

Sodium carbonate (13.2 g, 0.125 mol) was added. After stirring for 3 hours at 85-95 ° C, the mixture was placed under vacuum and cured to dryness. Water (300 ml) was added to the residue, the pH of the solution was adjusted to 7 with acetic acid, the coins were filtered off with suction, washed with water and dried in vacuo at 80 ° C. 18.7 g (95% of theory) of 3-cyano-5- (4'-pyridyl) -1,2-dihydro-2-pyridone are obtained.

Example 17

3-Cyano-5- (4'-pyridyl) -1,2-dihydro-2-pyridone (19.7 g, 0.1 mol) was added to 90 ml sulfuric acid (37 ml) while the reaction mixture was stirred at 35-95 ° C. The mixture was stirred at the indicated temperature for 30 minutes and, after cooling, diluted with 225 ml of water with stirring. The pH of the solution was adjusted to 8-9 by adding about 65 ml of 50% sodium hydroxide solution. The precipitate was filtered off with suction, washed with water (3x30 ml) and dried at 110 ° C. 20.6 g (96% of theory) of 5- (4'-pyridyl) -1,2-dihydro-2-pyridone-3-carboxylic acid amide

moss that melts above 320 ° C. Analysis calculated,%: found,%: α C 11 H 9 N 3 O 2 (M = 215.2) C 61.39 H 4.22 C 61.34 H 4.27 formula N, 14.87 N, 14.84. Based on 18th example THE 17th of Example way 19.7 g

(0.1 mole) 3-cyano-5- (4'-pyridyl) -1,2-dihydro-2-pyridone was gelatinized with 90% sulfuric acid and worked up. The resulting wet crystalline powder was dissolved in 100 ml of 2M sodium hydroxide solution without water. added. The suspension is stirred for 15 minutes, then the product is filtered off with suction, washed three times with 20 ml of water and dried at 110 ° C. 22.1 g (93.1% of theory) of the sodium salt of 4- (4'-pyridyl) -1,2-dihydro-2-pyridone-3-carboxylic acid are obtained, m.p. H, 3.44; N, 17.72. Found: C, 55.53; H, 3.44; N, 17.31.

Example 19

20.0 g (0.50 mol) of a solution of sodium hydroxide in 170 ml of water and 93.0 ml of a 1.5 molar solution of sodium hypochlorite (0.14 mol) at 25-30 ° C with stirring

5- (4'-Pyridyl) -1,2-dihydro-2-pyridone-3-carboxylic acid amide (21.5 g, 0.1 mol) was added. The mixture was stirred at the indicated temperature for 15 minutes and then heated at 60 ° C for 20 minutes. After cooling, the pH is adjusted to 8.5 to 9 with about 65 mL of 6N hydrochloric acid. The precipitate is filtered off with suction. It is washed twice with 30-30 ml of water and dried at 110 ° C. 16.2 g (86% theory)

-a) 3-amino-5- (4'-pyridyl) -1,2-dihydro-2-pyridone is obtained.

Analysis calculated for C10 H9 N3 O (M = 187.2):% C, 64.19; H, 4.85; N, 22.46. Found: C, 63.90; H, 4.77; N, 22.43.

Example 20

The procedure of Example 19 was followed but the reaction mixture was not heated to 60 ° C but stirred at room temperature for 8 hours. Yield: 14.8 g (79%, 3-amino-5- (4'-pyridyl) -1,2-dihydro-2-pyridone).

Example 21

A solution of sodium hydroxide (12.0 g, 0.3 mol) in water (170 mL) and sodium hypochlorite (1.5 mL, 80 mL) (0.12 mol) was stirred at 25-30 ° C (23.7 ° C). 5- (4'-Pyridyl) -1,2-dihydro-2-pyridone-3-carbonavamide sodium salt (0.1 mol) was added. In the following, the procedure of Example 19 is followed. 16.6 g (89% of theory) of 3-amino-5- (4'-pyridyl) -1,2-dihydro-2-pyridone are obtained.

Example 22

To a solution of 20.0 g of sodium hydroxide (0.5 mol) in 170 ml of water at room temperature

5- (4'-Pyridyl) -1,2-dihydro-2-pyridone-3-carboxylic acid amide (21.5 g, 0.1 mol) was added. While stirring at room temperature, 8.5 g (0.24 mol) of gaseous chlorine were absorbed into the mixture. After stirring for 30 minutes at room temperature, the mixture was worked up as described in Example 19. 15.7 g (84% of theory) of 3-amino-5- (4'-pyridyl) -1,2-dihydro-2-pyridone are obtained.

Example 23

To a solution of 20.0 g (0.5 mol) of sodium hydroxide in 170 ml of water at 55-60 ° C is 21.5 g (0.1 mol) of 5- (4'-pyridyl) -1,2-dihydro- 2-Pyridone-3-carboxylic acid amide is added. To the mixture was added 93 ml of 1.5 M sodium hypochlorite (0.14 mol) at 55-70 ° C. The mixture was stirred at the indicated temperature for 10 minutes and worked up as in Example 19. 14.8 g (79% of theory) of 3-amino-5- (4'-pyridyl) -1,2-dihydro-2-pyridone are obtained.

Example 24

10.0 g of crude 3-amino-5- (4'-pyridyl) -1,2-dihydro-2-pyridone are suspended in 60 ml of water and 4.8 ml of concentrated sodium hydroxide solution are added to the suspension. The mixture was heated to 50 ° C, then cooled, the product was filtered off with suction and washed three times with 10 ml of dilute sodium hydroxide solution. The wet filtrate was dissolved in water (60 mL) at 50 ° C, clarified with charcoal (1 g), filtered and the pH of the filtrate adjusted to 11 with acetic acid. The product is filtered off with suction, washed with water and dried at 80 ° C. 8.0 g (80% of theory) of 3-amino-5- (4'-pyridyl) -1,2-dihydro-2-pyridone are obtained in the form of yellow crystals.

Example 25

18.7 g (0.1 mol) of 3-imino-5- (4'-pyridyl) -1,2-dihydro-2-pyridone are dissolved in 1000 ml of 50% aqueous methanol and 0.05 mol are added. and 0.1 molar solution of acid in methanol

Juk. The resulting precipitate recrystallize from water- granting the. They are formed in the big jana. purity salts hydrate Salt Yield% melting point fumarate 97.0 Above 250 ° C (decomposition) hidrogónfumarát 96.3 Above 250 ° C (decomposition) bitartrate 97.5 Above 210 ° C (decomposition) ascorbate 98.0 Above 290 ° C (decomposition).

PATENT CLAIMS

Claims (15)

A process for the preparation of the 3-amino-5- (4'-pyricyl) -1,2-dihydro-2-pyridone of formula (I) by reacting the pyridine derivatives with acid halides and dimethylformamide of formula N, N- dimethyl-N- (3-dimethylamino-2-pyrid-4'-yl-prop-2-enylidene) -ammonium chloride hydrochloride is reacted with cyanoacetaride 3-cyano (III) in the presence of a base. -5- (4'-Pyridyl) -1,2-dihydro-2-pyridone, the nitrile is hydrolyzed and the resulting carboxylic acid is cleaved with a hypohalogenite to form an amine of formula (I), characterized in that the pyridine derivative (V) - in formula (V), X is hydrogen and Y is hydrogen or carboxyl or X and Y together = CHN (CH3) z - either the corresponding pyridinium salt or a mixture of pyridine derivatives (V) or mixtures of picoline bases with an acid halide and with a dimethylformamide complex (2: 1 to 2.9: 1 molar ratio of the acid halide and pyridine derivative) to the compound of the formula II, the salt of the formula II being cyanoacetamide; in the presence of a base) is converted to the nitrile of formula (III), the nitrile is hydrolyzed to the carboxylic acid of formula (IV), and then the amide -715 decomposes with hypohalite or halogen to form the amine of formula (I). Process according to claim 1, characterized in that the starting material is a mixture of crude picoline bases, preferably mixtures of essentially 5 3-methylpyridine, 4-methylpyridine and 2,6-dimethylpyridine. 3. The process of claim 1 wherein the acid halide is phosphorus oxychloride or phosgene. Process according to claim 1 or 3, characterized in that the 4-methylpyridine is reacted with a complex consisting of 2.0-2.9 moles of phosgene per dimethylformamide and 1 mole of 4-methylpyridine. Process according to claim 1 or 4, characterized in that the pyridine derivatives and the dimethylformamide-phosgene complex are reacted at 25-45 ° C. 20 6. A process according to claim 1 wherein the salt of formula II is reacted with cyanoacetamide without isolation. The process according to claim 1 or 6, wherein the salt of formula (II) is reacted with cyanoacetamide prior to crystallization. 8. The process of claim 1, wherein the base is selected from the group consisting of alkali metal carbonate or alkali metal hydroxide or mixtures thereof. 9. A process according to claim 1 or 8, wherein the salt of formula II is converted to the nitrile of formula III in the presence of 1.5 to 2.0 times the equivalent amount of taste in the base, and optionally further alkali metal. The alkali metal salt of the nitrile is precipitated by the addition of. The process according to claim 1, wherein the carboxylic acid amide of formula (IV) is isolated as the alkali metal salt by addition of an alkali metal hydroxide. The process of claim 1, wherein the amide of formula (IV) is reacted with hypohalite at room temperature to form the amide of formula (I). Process according to claim 1 or 11, characterized in that the hypohalogenite, the alkali metal hydroxide and the amide of formula (IV) are mixed at room temperature and the mixture is reacted at 50-70 ° C for 15-30 minutes and The amide of formula (I) is precipitated in a slightly alkaline range. 13. The process according to claim 12, wherein the alkali metal salt of the amide of formula (IV) is reacted with halogen or hypohalite. The process of claim 12 or 13, wherein the components of claim 12 and 13 are reacted directly at 50-60 ° C. 15. The process of claim 4, wherein the complex is formed from phosgene and dimethylformamide at 25-45 ° C. 1 drawing The Director of Economic and Legal Publishing is responsible for the publication 88.547.66-4 Alföldi Nyomda Debrecen - Responsible leader: István Benkö CEO