DD234574A3 - PROCESS FOR PREPARING 3-AMINO-5- (PYRID-4-YL) -1,2-DIHYDRO-PYRID-2-ON - 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

in which X is hydrogen and Y is hydrogen or the COOH group or X and Y together represent the = CH-N (CH ₃ ) ₂ group, or corresponding pyridinium salts or mixtures of substances containing pyridine derivatives of the formula V or Picolinbasengemische with a complex of acid halides and dimethylformamide in the ratio of 2 to 2.9 moles of acid halide per mole of pyridine derivative to give compounds of formula II, the salt of formula II with cyanoacetamide in the presence of less than 3 moles, but at least 1 mole, base per mole of salt to the nitrile of formula III react, the nitrile hydrolyzed to the carboxamide of formula IV and degrades the amide with hypohalite or halogen to the amine of formula I.

2. The method according to item 1, characterized in that the mixture of technical Picolinbasengemische used, in particular those consisting essentially of 3-methyl-pyridine, 4-methyl-pyridine and 2,6-dimethyl-pyridine.

3. The method according to item 1, characterized in that one uses as the acid halide phosphorus oxychloride or phosgene.

4. The method according to items 1 and 3, characterized in that reacting 4-methyl-pyridine with a complex of phosgene and dimethylformamide, which is formed from 2.0 to 2.9 moles of phosgene per mole of 4-methyl-pyridine ,

5. The method according to item 1 or 4, characterized in that one carries out the reactions between the pyridine derivatives and the complex of phosgene and dimethylformamide at temperatures between 25 and 45 "C.

6. The method according to item 1, characterized in that reacting the salt of formula II without isolation with cyanoacetamide.

7. The method according to item 1 or 6, characterized in that one carries out the reaction of the salt of formula II with cyanoacetamide before the crystallization of the salt.

8. The method according to item 1, characterized in that alkali metal carbonates or alkali metal hydroxides or mixtures thereof used as the base.

9. The method according to item 1 and 8, characterized in that one carries out the reaction of the salt of formula II to the nitrile of formula III with 1.5 to 2.0 moles of alkali metal carbonate or alkali metal hydroxide and the alkali metal salts of the nitrile of formula III, optionally by adding further alkali compounds separates after completion of the reaction.

10. The method according to item 1, characterized in that isolating the amide of the formula IV by the addition of alkali metal hydroxide as alkali metal salt.

11. The method according to item 1, characterized in that one combines the amide of formula IV with the hypohalite at room temperature and degraded to the amine of formula I.

12. The method according to items 1 and 11, characterized in that one combines the hypohalite, Aikalilauge and the amide of formula IV at room temperature, 15 to 30 min at 50 to 70 ° C for the reaction and then the amine of formula I in weak alkaline range falls.

13. The method according to item 12, characterized in that reacting the alkali metal salt of the amide of the formula IV with halogen or hypohalite.

14. The method according to the items 12 and 13, characterized in that one brings the components according to 12 and 13 directly at a temperature of 50 to 60 ⁰ C to the reaction.

15. The method according to item 4, characterized in that one uses a complex which was formed from phosgene and dimethylformamide at temperatures of 25 to 45 ⁰ C.

For this 1 page formulas

Field of application of the invention

The invention relates to a process for the preparation of 3-amino-5- (pyrid-4'-yl) -1,2-dihydro-pyrid-2-one, which itself or in the form of its salts in the pharmaceutical industry due to its favorable circulatory properties, in particular as a cardiotonic with simultaneous antianaphylactic effect (bronchodilation), is applied.

Characteristic of the known technical solutions

It is known to produce by the action of acid chlorides on dimethylformamide and reaction of the resulting complex with 4-methyl-pyridine vinylogous pyridylsubstituierte formamidinium salts, these with cyanoacetamide to 3-cyano-5- (pyrid-4'-yl) -1,2-dihydro to cyclize -pyrid-2-one, to hydrolyze this to the 5-pyrid-4'-yl-1,2-dihydro-pyrid-2-one-3-carboxylic acid amide and to react the amide with hypobromite in 3-amino-5- ( pyrid-4'-yl) -1,2-dihydro-pyrid-2-one I (U.S. Patent No. 4,004,012; U.S. Patent No. 4,077,246; U.S. Patent No. 4,017,315; U.S. Patent No. 4,137,233; U.S. Patent No. 4,225,715; PS 4264609; GB-PS 2070008). The simplest preparation so far for the N, N-dimethyl-N- (3-dimethylamino-2-pyrid-4'-yl-prop-2-enylidene) ammonium chloride hydrochloride is the reaction of 4-methyl-pyridine with dimethylformamide in the presence of phosgene. From the hydrochloride can be represented by reaction with cyanoacetamide, the 3-cyano-5- (pyrid-4'-yl) -1,2-dihydro-pyrid-2-one (US-PS 4264609 ).

When using phosgene, at least 3 moles of this acid chloride are added dropwise at -10 to ^{0 0} C in 25 moles of dry dimethylformamide. With cooling, 1 mole of 4-methylpyridine is added, the temperature rises to 35 to 40 ⁰ C. After heating for 2 to 3 hours at 60 ° C is cooled, washed with dimethylformamide and ether and dried in vacuo. In this procedure, the handling of large quantities of liquid phosgene and the necessary cooling to -10 ⁰ C are complex and labor-safety problematic. The manner of isolation of the hydrochloride is very labor intensive. The likewise known procedure for the preparation of the vinylogous formamidinium salt by reacting 4-methylpyridine with dimethylformamide and phosphorus oxychloride also has significant disadvantages, in particular because of the high losses of dimethylformamide and a heavy load of the wastewater. According to US Pat. No. 4,264,609, the vinylogous formamidinium salt is heated with 110 mol% of cyanoacetamide in anhydrous dimethylformamide and at least 300 mol% of potassium carbonate on the steam bath for 1 hour and then cooled. The precipitated potassium salt is filtered off with suction, dried and dissolved in water. With acetic acid is adjusted to pH 5, filtered off and washed successively with water, ethanol and ether, with 40% of theory of 3-cyano-5- (pyrid-4'-yl) -1,2-dihydro-pyrid-2 on. By concentrating the mother liquors and working up as the main product, a further 45% of theory are obtained. The drying of the solvents and potassium carbonate is expensive. The large amount of potassium carbonate causes a very difficult stirrable reaction mixture. The work-up procedure is cumbersome. The proportion of quality mother liquor product is disproportionately large.

The saponification of 3-cyano-5- (pyrid-4'-yl) -1,2-dihydropyrid-2-one is best carried out by heating for 1 to 2 hours with 90% strength sulfuric acid on the steam bath (US Pat. No. 4,077,746). wherein it is heated in 18 times the amount of 90% sulfuric acid. The reaction mixture is poured onto ice, basified with aqueous sodium hydroxide solution and then with 10% potassium bicarbonate solution. The extracted, washed with water and dried product is recrystallized from dimethylformamide.

The very large amount of sulfuric acid causes a strong neutral salt loading of the mother liquor. Casting on ice, the necessary recrystallization and washing the pure product with various solvents are time-consuming Arbeitsgägne. The preparation of 3-amino-5- (pyrid-4'-yl) -1,2-dihydro-pyrid-2-one from 5-pyrid-4'-yl-1,2-dihydro-pyrid-2-one -3-Carbonsäureamid by means of hypobromite in alkaline solution (US-PS 4072746). At 0 ⁰ C bromine is added dropwise in about 7% sodium hydroxide solution, the amide was added and heated for 3 hours aufdem steam bath. After cooling to room temperature is treated with 6N hydrochloric acid / neutralized with 10% potassium bicarbonate solution. It is filtered off, washed with water, dried and recrystallized from dimethylformamide. The yield is 50% of theory. A major drawback of the known process is the use of sodium hypobromite, which is more volatile than hypochlorite, allows only low yields and causes undesirable by-products. The isolation and the subsequent recrystallization from dimethylformamide are very expensive, and the yield is low.

Object of the invention

The aim of the invention is, in contrast to the described procedures, which proceed exclusively from a pure 4-methylpyridine, in the reaction of a pyridine derivative of the general formula V (formula scheme) to the amine I also of 4-methyl-pyridine containing mixtures to save considerable amounts of raw materials, in particular dimethylformamide, washing solvents, acids and alkalis, to reduce cooling capacity, to significantly increase the volume yield by working at higher concentrations, to minimize the wastewater and exhaust air pollution, to increase the protection quality and despite saving of Process steps, in particular cleaning operations to arrive at a pure target product.

Explanation of the essence of the invention

The invention has for its object to develop an improved production process for 3-amino-5- (pyrid-4'-yl) -1,2-dihydropyrid-2-one. The object has been achieved by pyridine derivatives of the general formula V wherein X is hydrogen and Y is hydrogen or the COOH group or X and Y together represent the = CH-N- (CH ₃ ) ₂ group, or corresponding pyridinium salts or mixtures of substances containing pyridine derivatives of the formula V or Picolinbasengemische used as starting materials, the pyridine derivatives with a complex of acid halides and dimethylformamide in a ratio of 2 to 2.9 moles of acid halide per mole of pyridine derivative to compounds of formula II, the salt of formula II with cyanoacetamide in Presence of less than 3 moles, but at least 1 mole, base per mole of salt II reacts to the nitrile of formula III, the nitrile hydrolyzed to the carboxylic acid of formula IV and degrades the amide with hypohalite or halogen to the amine of formula I.

In the process according to the invention, the reaction of dimethylformamide with phosphorus oxychloride or phosgene takes place at temperatures between 25 and 45.degree. C. by introducing or passing the phosgene onto or into the dimethylformamide present in 5-fold excess. Subsequent addition of the pyridine derivative V, preferably a technical mixture of 4-methylpyridine, 3-methyl-pyridine and 2,6-dimethyl-pyridine, stirring for several hours at about 30 ° C and suction results in about 90% yield the salt II as a hydrate. It is surprising that gaseous phosgene is quantitatively taken up by dimethylformamide at these temperatures and does not enter the effluent CCV stream into the exhaust gas. Compared to the literature method of operation, the labor protection technically difficult handling of the liquid phosgene and necessary on an industrial scale brine cooling system is eliminated. The several hours of heating at 60 ⁰ C is also eliminated. Very astonishing is the inert behavior of the 3-methyl and especially the 2,6-dimethylpyridine over the complex formed from phosgene or phosphorus oxychloride and dimethylformamide. Thus, the immediate use of 4-methyl-pyridine from mixtures with

The process according to the invention requires substantially smaller amounts of phosgene, dimethylformamide and washing solvents than the known processes. Furthermore, drying capacity is saved, since it is advantageous to process the salt I moist or without isolation. Even when using phosphorus oxychloride as the acid halide over the known methods significant advantages in terms of saving of dimethylformamide, cooling capacity and in terms of reducing the wastewater load of dimethylformamide and chloride and phosphate ions are achieved. The vinylogous formamidinium salt II can be reacted directly with cyanoacetamide to form nitrile IM without isolation and purification. For this purpose, the still present in the dimethylformamide solution and not yet crystallized salt II can be cyclized directly with cyanoacetamide in the presence of a base to Nitrii. To obtain a particularly pure nitrile III, it is advisable to crystallize out the salt II, to remove the majority of the excess dimethylformamide, and to replace it with a suitable solvent for the cyclization. As solvents, especially dipolar aprotic, organic protic and water are suitable. For example, when using a reaction medium consisting essentially of water, it is possible to carry out the cyclization described in more detail below at room temperature. On the other hand, when dimethylformamide is used as the solvent, the ring closure can be carried out at elevated temperature. The cyclization is carried out with 1.0 to 2.0 moles of base per mole of salt II, preferably with 1.5 to 2.0 moles of base. The base used are alkali metal carbonates or alkali metal hydroxides or mixtures thereof. If the cyclization is carried out in aqueous solvent, sodium hydroxide or sodium carbonate is preferably used as the base, the nitrile III precipitating as alkali metal salt directly from the aqueous solution and is converted by acidification in the nitrile III.

When carrying out the ring closure in dimethylformamide, the nitrile III or its alkali metal salt is expediently isolated by partial distillative removal of the solvent. The recovered dimethylformamide, as well as that obtained by distilling the mother liquor of salt II, can be used to repeat these reactions. Advantages of the procedure according to the invention are the processing of the undried and dimethylformamide-containing salt II, the possible use of organic protic solvents and water and the reduction of the amount of base from 300 to about 100 mol .-%. This eliminates the drying of the solvent, the salt II and the alkali metal carbonates. Instead, the presence of water has been found to be beneficial so that it can even be used as a solvent. Instead of the separate work-up of main and mother liquor product, a uniform product III can be isolated by distilling off the solvent after the end of the reaction. The reduction of the amount of dimethylformamide and the amount of alkali leads to the reduction of wastewater pollution. The hydrolysis of the nitrile III is carried out by heating in 2 times the amount of 90% sulfuric acid at 60 to about 100 ° C, for example, 30 minutes to about 90 ° C. It is then diluted by adding water and neutralized with aqueous sodium hydroxide solution. A particular embodiment consists in the addition of further alkali and isolation of the sodium salt of compound IV, whereby an additional cleaning effect is achieved. The reduction of the amount of sulfuric acid to 79 of the known procedure (US-PS 4072746) reduces the environmental impact considerably. The pouring of the sulfuric acid solution on ice is replaced by the much simpler addition of water to the reaction mixture. The inventive form of insulation is much less labor-time and material-intensive than the previous Umkristaliisation of dimethylformamide. The amide IV is, without an intermediate purification is required, reacted at room temperature with alkali hypochlorite in the presence of excess alkali hydroxide and briefly heated to complete the reaction, preferably for 15 to 30 min to about 60 ^C C and the amine of formula I by addition precipitated by acids in the weakly alkaline range. This degradation of the amide to the amine may optionally proceed from the amide or its alkali metal salt, the latter also being able to be formed directly in the reaction solution before the actual reaction. The hypochlorite can be metered into the reaction mixture. It may also be formed directly during the reaction by the action of chlorine on excess alkali in the reaction solution. As a further process variant, it is possible to bring the required for the degradation of the amide IV to the amine I components directly at a temperature of 50 to 60 ⁰ C to react.

The use of sodium hypochlorite solution or chlorine is a significant advantage of the process of the invention. The hazards of handling corrosive bromine are avoided. The cost of using sodium hypochlorite solution drops to about Vio. At the same time cooling capacity is saved. The use of hypobromite increasingly occurring side reactions are bypassed and yields of 79 to 89% achieved. Instead of the complicated and volumenextensiven Umkristaliisation of dimethylformamide is purified by reprecipitation over the sodium salt. In detail, unrefined amine I is dissolved in molar amounts of sodium hydroxide solution with gentle heating, the sodium salt is separated off with suction and filtered with suction. The sodium salt is again dissolved in water with heating, treated with activated carbon and obtained by fractional precipitation of a very pure amine I.

The amine I is suitable, after appropriate galenic processing because of its proven by standard pharmacological studies and human circulatory properties, in particular as a cardiotonic with bronchodilator same effect, to be used.

This can be used both in the form of the free base and in the form of an acid addition salt. As acids, those are used which form pharmaceutically acceptable salts in combination with the free base. Overall, in the process according to the invention for the preparation of the 3-amino-5- (pyrid-4'-yl) -1,2-dihydro-pyrid-2-one, considerable amounts of raw materials and cooling capacity are thus saved compared to the known processes. and reduced exhaust air pollution to a minimum, by working at higher concentrations, the volume yield is significantly increased, increases the protection quality and receive a purer target product despite the saving of process steps. The invention will be explained in more detail with reference to embodiments.

Exemplary embodiments Example 1

19.8 g (0.2 mol) of phosgene were introduced in the course of 25 min at temperatures between 26 and 30 ° C in 77.4 ml (1 mol) of dimethylformamide. Subsequently, 13.0 g (0.1 mol) of 4-methyl-pyridine hydrochloride were added within 10 min at temperatures between 30 and 35 ° C. It was stirred at the same tempera door 4 h, inoculated with product, stirred for a further 2 h, filtered off, washed with 10 ml of dimethylformamide and air sucked to dryness. Yellow crystals. F.> 100 ° C (decomp.)

Yield: 28.1 g (90.0% of theory) of N, N-dimethyl-N-O-dimethylamino-pyridine-1-yl-prop-1-enylidene-1-ammonium chloride.

hydrochloride dihydrate (vinylogous formamidinium salt dihydrate)

C ₁₂ H ₁₉ Cl ₂ N ₃ -2H ₂ O (312.2)

Calc .: C 46.16 H 7.43 N 13.46 Cl 22.72 H ₂ 011.54

Found: C 46.50 H 7.74 N 13.04 Cl 22.89 H ₂ 011.30

Example 2

In the example! 1, 13.7 g (0.1 mol) of pyrid-4-yl-acetic acid were reacted with 24.7 g (0.25 mol) of phosgene in excess dimethylformamide.

Yield: 27.2 g (87.1% of theory) of vinylogous formamidinium salt dihydrate.

Example 3;

In the manner described in Example 1, 14.8 g (0.1 mol) of 4- (2-dimethylamino-vinyl) -pyridine were reacted with 19.8 g (0.2 mol) of phosgene in excess dimethylformamide.

Yield: 26.0 g (83.2% of theory) of vinylogous formamidinium salt dihydrate.

Example 4

24.7 g (0.25 mol) of phosgene were introduced in the course of 20 min at temperatures between 30 and 32 ° C in 97 ml (1.25 mol) of dimethylformamide. Subsequently, 9.3 g (0.1 mol) of 4-methyl-pyridine were added dropwise within 5 min. The mixture was stirred at 35 to 40 ^{C for} 5 h, cooled to room temperature and filtered off with suction

 Yield: 25.0 g (80.1% of theory) of vinylogous formamidinium salt dihydrate.

Example 5

24.7 (0.25 mol) of phosgene were introduced in the course of 20 min at temperatures between 30 and 35 ⁰ C in 97 ml (1.25 mol) of dimethylformamide. Subsequently, 28.3 g of technical Picolinbasengemisch with a content of 32% 3-methyl-pyridine, 33% 4-methyl-pyridine and 30.5% of 2,6-dimethyl-pyridine are added dropwise with stirring during 20min. It was, as described in Example 4, further worked

 Yield: 26.2 g (84.0%) of vinylogous formamidinium salt dihydrate, based on the content of 4-methyl-pyridine.

Example 6 *

34.6 g (0.35 mol) of phosgene were reacted with 136 ml (1.75 mol) of dimethylformamide and 29.0 g of technical Picolinbasengemisch, as in Example 5.

Yield: 27.8 g (86.5%) of vinylogous formamidinium salt dihydrate, based on the content of 4-methyl-pyridine.

Example 7

21.8 g (0.22 mol) of phosgene were introduced in the course of 20 min at temperatures between 34 and 36 ⁰ C in 85 ml (1.1 mol) of dimethylformamide. Subsequently, 9.3 g (0.1 mol) of 4-methyl-pyridine were added dropwise at 35 to 40 ⁰ C within 5min. It was stirred for 5 h, the crystal suspension with 45% sodium hydroxide solution to pH 8 and 9.2 g (0.11 mol) of cyanoacetamide and 21.2 g (0.2 mol) of sodium carbonate and 3 h with stirring to 85 to 90 ⁰ C heated. After cooling, the product was filtered off with suction, the residue was washed with 40 ml of dimethylformamide, suspended in 100 ml of water and treated with acetic acid to pH 5. It was filtered off, washed with water and dried at 8O ⁰ C in a drying oven. Yellowish solid

F. 360-365 ⁰ C Yield: 13.5 g (68.5% of theory) of 3-cyano-5- (pyrid-4'-yl) -1,2-dihydro-pyrid-2-one. Another 2.4 g (12.2% of theory) were taken from the

Mother liquor won

C ₁₁ H ₇ N ₃ O (197.2)

Calcd .: C66.99 H3.58 N 21.31

Found: C66.67 H3, 50 N, 21.64

Example 8

In the manner described in Example 3, 14.8 g (0.1 mol) of 4- (2-dimethylamino-vinyl) -pyridine were reacted with a complex of phosgene and dimethylformamide. After two hours of stirring at 35 ⁰ C, the solution with 9.2 g (0.11 mol) of cyanoacetamide and 21.2 g (0.2 mol) of sodium carbonate was added. It was stirred for 2.5 h at 90 ⁰ C and worked up as described in Example 7, worked up.

Yield: 12.4 g (62.9% of theory) of 3-cyano-5- (pyrid-4'-yl) -1,2-dihydro-pyrid-2-one. Another 3.0g (15.2% of theory) was recovered from the mother liquor.

Example 9

In place of 0.1 mol of 4-methylpyridine used in Example 7, 28.3 g of technical Picolinbasengemisch the composition given in Example 5 were used.

Yield: 13.1 g (66.4%) of 3-cyano-5- (pyrid-4'-yl) -1,2-dihydro-pyrid-2-one, based on the content of 4-methyl-pyridine. Another 2.7 g (13.7% of theory) were recovered from the mother liquor.

Example 10

38.3 g (0.25 mol) of phosphorus oxychloride were added dropwise over 30 min at temperatures between 30 and 35 ° C in 116ml (1.5 mol) of dimethylformamide. Subsequently, 28.3 g of technical Picolinbasengemisch the composition mentioned in Example 5 were added dropwise within 5 min at temperatures between 30 and 35 ⁰ C. After standing overnight, 160 ml of water were added to the reaction mixture and 45% sodium hydroxide solution was added to pH 8. The resulting precipitate was separated by filtration and discarded. In the filtrate, the content of vinylogous formamidinium salt was determined by UV spectroscopy to be 29.4 g (94.2%, based on the content of 4-methylpyridine).

Example 11

26.7 g (0.27 mol) of phosgene were charged in the course of 20min at temperatures between 30 and 35 ⁰ C to 126ml (1.62 mol) of dimethylformamide. Subsequently, 9.3 g (0.1 mol) of 4-methyl-pyridine were added dropwise at temperatures between 30 and 35 ⁰ C within 5min. The mixture was stirred for 6 h at room temperature, the crystal suspension with 63 ml of water and then treated with 9.2 g (0.11 mol) of cyanoacetamide. After addition of sodium carbonate to pH 7, 8.0 g (0.2 mol) of sodium hydroxide in 20 ml of water were added dropwise within 10 min. It was stirred for a further 5 h at room temperature. It was then concentrated to dryness in vacuo. After addition of 250 ml of water was adjusted with acetic acid to pH 7, filtered off with suction, washed with water and dried in vacuo at 80 ⁰ C.

 Yield: 17.7 g (89.6% of theory) of 3-cyano-5- (pyrid-4'-yl) -1,2-dihydro-pyrid-2-one

Example 12

In the manner described in Example 11, 9.3 g (0.1 mol) of 4-methyl-pyridine were reacted with the complex of phosgene and dimethylformamide. After stirring for 3 h, the still clear solution in the manner described in Example 11 with 63 ml of water was subsequently admixed with 9.2 g (0.11 mol) of cyanoacetamide. After adding sodium hydroxide to pH 7, 5.0 g (0.125 mol) of sodium hydroxide solution in 12 ml of water were added dropwise within 10 min, and it was stirred for 4 h at room temperature. The work-up was carried out as described in Example 11. Yield: 17.2 g (87.0% of theory) of 3-cyano-5- (pyrid-4'-yl) -1,2-dihydro-pyrid-2-one

Example 13 "

In the manner described in Example 11, 9.3 g (0.1 mol) of 4-methylpyridine were reacted with the complex of phosgene and dimethylformamide. After completion of the crystallization of the vinamidinium salt, the supernatant dimethylformamide solution was filtered off with suction from above and the remaining solid was dissolved in 120 ml of water. The solution was treated with 9.2 g (0.11 mol) of cyanoacetamide. After addition of 45% sodium hydroxide solution until a pH7 was reached, 5.0 g (0.125 mol) of sodium hydroxide solution in 12 ml of water were added dropwise within 10 min and the mixture was stirred at room temperature for 3 h. The work-up was carried out as described in Example 11

 Yield: 16.8 g (85, OD. Th.) Of 3-cyano-5- (pyrid-4'-yl) -1,2-dihydro-pyrid-2-one

Example 14

In the manner described in Example 11, 9.3 g of 4-methyl-pyridine were reacted with the complex of phosgene and dimethylformamide. The resulting crystal suspension was reacted with cyanoacetamide in the manner described, with a mixture of 3.0 g (0.075 mol) of sodium hydroxide solution and 7.9 g (0.075 mol) of sodium carbonate in 30 ml of water was added dropwise. The work-up was carried out as described in Example 11

 Yield: 17.6 g (89.0% of theory) of 3-cyano-5- (pyrid-4'-yl) -1,2-dihydro-pyrid-2-one

Example 15

In the manner described in Example 11, 28.3 g of technical Picolinbasengemisch the composition indicated in Example 5 were reacted with the complex of phosgene and dimethylformamide. The resulting crystal suspension was reacted with cyanoacetamide in the manner described, with 4.0 g (0.1 mol) of sodium hydroxide in 10 ml of water was added dropwise. It was stirred for 3 h at room temperature, treated with a further 4.0 g (0.1 mol) of sodium hydroxide solution and left for 15 min at the same temperature. The precipitated solid was filtered off with suction and dissolved in 200 ml of water of 50 ⁰ C. It was adjusted to pH 7 with acetic acid, filtered off, washed with water and dried in vacuo at 80 ° C. Yield: 15.6 g (79.0% of theory) of 3-cyano-5- (pyrid-4'-yl) -1,2-dihydro-pyrid-2-one. Another 2.2 g (11.0% of theory) were recovered from the mother liquor.

Example 16

31.2 g (0.1 mol) of vinylogous formamidinium salt dihydrate were added to 150 ml of dimethylformamide, 9.2 g (0.11 mol) of cyanoacetamide and 13.2 g (0.125 mol) of sodium carbonate were added and heated to 85-95 ° C for 3 hours. It was then evacuated and concentrated to dryness. After addition of 300 ml of water was adjusted with acetic acid to pH 7, filtered off with suction, washed with water and dried in vacuo at 80 ° C.

 Yield: 18.7 g (95% of theory) of 3-cyano-5- (pyr: d-4'yO-1,2-dihydro-pyrid-2-one

Example 17

19.7 g (0.1 mol) of 3-cyano-5- (pyrid-4'-yl) -1,2-dihydro-pyrid-2-one were added to 37 ml of 90% sulfuric acid, wherein the reaction mixture was on Heated to 85-95 ° C. It was stirred for 30 min at this temperature. After cooling to room temperature, 225 ml of water were added to the reaction mixture with stirring. Subsequently, the solution was brought to pH 8-9 by adding about 65 ml of 50% sodium hydroxide solution. The precipitate was filtered off, washed three times with 30 ml of water and dried at 11O ⁰ C. F.> 320 ° C

Yield: 20.6 g (96% of theory) of 5- (pyrid-4'-yl) -1,2-dihydro-pyrid-2-one-3-carboxamide C ₁₁ H ₉ N ₃ O ₂ (215, 2)

Calc .: C 61.39 H 4.22 N 14.87

Found: C, 61.34, H, 4.27, N, 14.84

Example 18

In the manner described in Example 17 19.7 g (0.1 mol) of 3-cyano-5- (pyrid-4'-yl) -1,2-dihydro-pyrid-2-one were reacted with 90% sulfuric acid and worked up. The resulting moist, crystalline powder was added without water in 100 ml of 2 molar sodium hydroxide solution and stirred for 15 min. Subsequently, it was suctioned off, washed three times with 20 ml of water and dried at 110.degree

 F.> 350 ° C (decomp.)

Yield: 22.1 g (93 _r 1% of theory) of the sodium salt of the 5- (pyrid-4'-yl) -1-dihydro-pyrid-1-S-carboxamide C ₁₁ H ₈ N ₃ O ₂ Na (237,2)

Calc .: C 55.69 H 3.44 N 17.72

C 55.53 H 3.44 N 17.31

Example 19

A mixture consisting of 20.0 g (0.50 mol) of caustic soda in 170 ml of water and 93 ml of a 1.5 molar sodium hypochlorite solution (0.14 mol) was mixed at temperatures between 25 and 30 ° C with 21.5 g (0.1 mol) Enter 5- (pyrid-4'-yl) -1,2-dihydro-pyrid-2-one-3-carboxylic acid amide with stirring. The mixture was stirred for 15 minutes at the same temperature and then heated to a temperature around 60 ° C. for 20 minutes. After cooling to room temperature, it was brought to pH 8.5-9.0 with about 65 ml of 6N hydrochloric acid. The precipitate was filtered off, washed twice with 30 ml of water and dried at 110 ⁰ C. Yield: 16.2 (86% of theory) of 3-amino-5- (pyrid-4'-yl) -1,2-dihydro-pyrid-2-one C ₁₀ H ₉ N ₃ O (187.2 )

Calc .: C 64.19 H 4.85 N 22.46

Found: C 63.90 H 4.77 N 22.43

Example 20

Instead of heating the reaction mixture to 6O ⁰ C described in Example 19, the stirring time was extended to 8 h at room temperature.

Yield: 14.8 g (79% of theory) of 3-amino-5- (pyrid-4'-yl) -1,2-dihydro-pyrid-2-one

Example 21

In a mixture of 12.0 g (0.3 mol) of caustic soda in 170 ml of water and 80 ml of a 1.5 molar sodium hypochlorite solution (0.12 mol) at temperatures between 25 and 30 ⁰ C 23.7 g (0.1 mol) Sodium salt of 5- (pyrid-4'-yl) -1,2-dihydro-pyrid-2-one-3-carboxylic acid amide added with stirring. It was further worked as described in Example 19. Yield: 16.6 g (89% of theory) of 3-amino-5- (pyrid-4'-yl) -1,2-dihydro-pyrid-2-one

Example 22

In a solution of 20.0 g (0.5 mol) of caustic soda in 170 ml of water was added 21.5 g (0.1 mol) of 5- (pyrid-4'-yl) -1,2-dihydro-pyrid-2 at room temperature. registered on-3-carboxamide. Subsequently, 8.5 g (0.24 mol) of chlorine were introduced with stirring at room temperature. The mixture was stirred for 30 minutes at room temperature and further worked as described in Example 19. Yield: 15.7 g (84% of theory) of 3-amino-5- (pyrid-4'-yl) -1,2-dihydro-pyrid-2-one

Example 23

In a solution of 20.0 g (0.5 mol) of caustic soda in 170 ml of water at 55-60 ° C, C2T, 5g (0.1 mol) of 5- (pyrid-4'-yl) -1,2-dihydropyrid-2-one was added. registered on-3-carboxamide. Subsequently, at temperatures between 55 and 70 ° C 93 ml of a 1.5 molar sodium hypochlorite solution (0.14 mol) was added. The mixture was stirred for a further 10 minutes at this temperature and worked up as described in Example 19

 Yield: 14.8 g (79% of theory) of 3-amino-5- (pyrid-4'-yl) -1,2-dihydro-pyrid-2-one

Example 24

10.0 g of crude 3-amino-5- (pyrid-4'-yl) -1,2-dihydro-pyrid-2-one were suspended in 60 ml of water and treated with 4.8 ml of concentrated sodium hydroxide solution. The mixture was heated to 50 ⁰ C, cooled, filtered off with suction and washed three times with Tomi dilute sodium hydroxide solution. The moist filter material was dissolved in 60 ml of water at 50 ⁰ C, stirred with 1 g of activated carbon and the filtrate with acetic acid to pH 11. After filtering off with suction and washing with water and drying at 80 ^° C., yellowish crystals were obtained. Yield: 8.0 g (80% of theory) of 3-amino-5- (pyrid-4'-yl) -1,2-dihydro-pyrid-2-one

Example 25

18.7 g (0.1 mol) of 3-amino-5- (pyrid-4'-yl) -1,2-dihydro-pyrid-2-one were dissolved in 1000 ml of 50% aqueous methanol and washed with a solution of 0.05 mol or 0.1 mol of the corresponding acid in methanol. The resulting precipitate was recrystallized from water, the salt was obtained in the form of the hydrate in high purity. Salt yield melting point

Fumarate 97.0% d. Th.> 250 ° C (decomp.)

Hydrogen fumarate 96.3% d. Th.> 250 ° C (decomp.)

Hydrogentartrate 97.5% of the theoretical > 210 ° C (dec.)

Ascorbate 98.0% d. Th.> 290 ° C (Zers.)

C HXV

CM,

fU

Ηα

CE ¹

Claims (1)

Inventive Aspirate: 1. A process for the preparation of 3-aminc-5- <pyrid-4'-yl) -1,2-dihydrc-pyrid-2-one of the formula I by reacting pyridine derivatives with acid halides and dimethylformamide to N, N-dimethyl N- (3-dimethylamino-2-pyrid-4'-yl-prop-2-enylidene) ammonium chloride hydrochloride of the forms! II, reaction of compounds of the formula II with cyanoacetamide in the presence of a base to give 3-cyano-δ-pyrid-4-yl) -1,2-dihydropyrid-2-one of the formula III, hydrolysis of the nitrites to the carboxamide of the formula IV and degradation of the carboxylic acid amides with hypophalogenite to the amine of the formula I, characterized in that pyridine derivatives of the formula V CHXY