DD263758A1 - PROCESS FOR PREPARING 2-AMINO-5- (PYRID-4-YL) -NICOTINSAEURE DERIVATIVES AND THEIR N-OXIDES - Google Patents

Abstract

The invention relates to a process for the preparation of 2-amino-5- (pyrid-4-yl) nicotinic acid derivatives of the formula I and their N-oxides by reacting N, N-dimethyl-N- & 3-dimethylamino-2- (pyrid-4-yl) prop-2-enylidene! ammonium chloride hydrochloride with malononitrile, cyanoacetamide, cyanthioacetamide or Cyyessigestern to the corresponding 1-cyano-4-dimethylamino-3- (pyrid-4-yl) -buta-1 , 3-diene-1-carboxylic acid derivatives and subsequent reaction with NH 3 or hydroxylammonium salts. Field of application of the invention is the pharmaceutical industry.

Description

Field of application of the invention

The invention relates to a process for the preparation of 2-amino-5- (pyrid-4-yl) nicotinic acid derivatives of the formula I and their N-oxides

wherein X is cyano, carbamoyl, thiocarbamoyl or alkoxycarbonyl.

The compounds are intermediates for the preparation of biologically active substances, in particular of pharmaceuticals and pesticides.

The invention is applicable in the pharmaceutical industry.

Characteristic of the known technical solutions

2-Alkylamino-3-cyano- and 2-alkylamino-3-c3rb3moyl-5-pyridyl-pyridines are already known (G.Y. Lesher, Ch. J. Opalka, D.F. Page 4362734 and US Patent 4374141). Also described are 2-amino, 2,3-diamino, 2-amino-3-chloro and 2-amino-3-nitro-5-pyridylpyridines (GY Lesher, Ch. J.Opalka, DFPage, U.S. Patent 4,420,617 and U.S. Patent 4,291,360). The introduction of the 2-amino group followed in principle by reacting corresponding 2-halopyridines with NHa or amines.

It is also known that unsubstituted, alkylsubstituted and aryl substituted 4-dialkylamino-buta-1,3-diene-1,1-dicarbonitriles can be cyclized with NH ₃ to 2-amino-3-cyano-pyridines (see BG Ege, HO Frey , E. Schuck, Synthesis 1979, 366; J. Liebscher, H. Hartmann, J. prakt. Chem. 318, 705 [1976]; H. Kurihara, H. Mishima, J. Heterocycl, Chem., 14, 1077 [1977]; RDAcker, G. Hamprecht EP-PS 57827, NISmetskaya, NAMuchina, WG Granik, Khim., Geterosikl soedin 1984, 799). JL Miesel (U.S. Patent 4,405,552, U.S. Patent No. 4,887,822 and European Patent No. 60071) describe the conversion of N, N-dimethyl-N- (3-dimethylamino-2- (4-chloro-phenyl) -prop-2-enylidene -3mmonium perchlorite in 2-amino-3-cyano-5- (4-chlorophenyl) -pyridine by reaction with malononitrile and sodium methylate, followed by reaction with ammonia In the latter patents, also the preparation of 3- (4-chlorophenyl) Ethyl 1-cyano-4-dimethyl-1-naphtha-1,3-diene-1-carboxylate and its reaction with hydroxylamine hydrochloride to 2-amino-5- (4-chloro-phenyl) -pyridine-3-carboxylic acid ethyl ester-1-oxide. On the other hand, it is known that, for example, the reaction of 1-cyano -dimethylamino-methyl-buta-IS-diene-1-carboxylic acid ethyl ester with NH _{3 to 3} -cyano-6-methyl-1,2-dihydro-pyrid-2 - mentions (NISmetsk3y3, NAMuchina, WG Granik, Khim, Geterosikl, Soedin, 1984, 799).

1-cyano-dimethyl-amino-S-pyridyl-buta-1,3-diene-1-carboxylic acid derivatives, 1,5-dicyan-3-pyridyl-penta-1,3-diene-1,5-dicarboxylic acid derivatives , 2-Amino-5-pyridyl-nicotinic acid derivatives and their N-oxides have not previously been described.

Object of the invention

The invention seeks to produce novel, useful as intermediates for the synthesis of biologically active compounds 2-amino-5- (pyrid-4-yl) -nicotinic acid derivatives and their N-oxides.

Explanation of the essence of the invention

Dor invention is the object of developing a process for the preparation of new 2-amino-5- (pyrid-4-yl) -pyridines. The object has been achieved by preparing 2-amino-5- (pyrid-4-yl) nicotinic acid derivatives and their N-oxides. According to the invention, compounds of the formula I in which X is cyano, carbamoyl, thiocarbamoyl or alkoxycarbonyl and their N-oxides are prepared by reacting N, N-dimethyl-N- [3-dimethylamino-2- (pyrid-4-yl) -prop -2-enylidene] ammonium chloride hydrochloride with malononitrile, cyanoacetamide, cyanoacetamide or cyanoacetic acid esters in suitable solvents, such as alcohols, water, pyridine, tertiary amines, dimethylformamide or mixtures of these solvents in the presence of bases, for example alkali metal alkoxides, alkali metal hydroxides, alkali metal carbonates, pyridine or trialkylamines to 1-cyano-4-dimethylamino-3- (pyridin-4-yl) -but3-1,3-diene-1-carboxylic acid derivatives are reacted and then by reaction with NH ₃ or its aqueous solution or Hydroxylammonium salts are converted into 2-amino-5- (pyrid-4-yl) -nicotinic acid derivatives or their N-oxides The 2-amino- ^c (pyrid-4-yl) nicotinic acid derivatives can be prepared in a particularly simple manner by dissolving N, N-dimethyl-N- [3-dimethyl lamino-2- (pyrid-4-yl) prop-2-enylidene] ammonium chloride hydrochloride in water and reaction with cyanoacetic acid derivatives and ammonia.

According to the invention, 4-dimethylamino-3- (pyrid-4-yl) -buta-1,3-diene-1,1-dicarbonitrile and i-cyano-dimethyl-amino-S- (pyrid-4-yl) -buta-1 , 3-diene-1-carboxylic acid esters are isolated as intermediates and are advantageously brought separately in a second stage with NH ₃ in water or Hydroxylammoniumsslzen in example pyridine to the reaction. The 2-amino-5- (pyrid-4-yl) -nicoic acid derivatives and their N-oxides are obtained in pure form and in high yields. Very advantageous are the mild reaction conditions and short reaction times.

In the reaction of N, N-dimethyl-N- [3-dimethylamino-2- (pyrid-4-yl) -prop-2-enylidene] ammonium chloride hydrochloride with malononitrile or cyanoacetic esters as by-products also 3- (pyrid -4-yl) -penta-1,3-diene-1,1,5,5-tetracarbonitrile and i.ö-dicyen-S-fpyrid ^ -ylJ-penta-is-diene-IS-dicarboxylic arise by Acidifying the reaction solution can be precipitated and also with aqueous NH ₃ or hydroxylammonium salts in z. B. pyridine 2-amino-5- (pyrid-4-yl) nicotinic acid nitrile or 2-amino-5- (pyrid-4-yl) nicotinic acid ester or their N-oxides.

The 2-amino-5- (pyrid-4-yl) -nicotinic acid derivatives of the formula I can also be prepared by reacting corresponding 2-chloro-5- (pyrid-4-yl) -nicotinic acid derivatives with NH ₃ .

The inventively prepared new 2-amino-5- (pyrid-4-yl) -nicotinic acid derivatives and their N-oxides are valuable intermediates for the preparation of z. B. cardiotonic pyridyl substituted heterocycles. The invention will be explained in more detail below with reference to exemplary embodiments.

embodiments

example 1

4-Dimethylamino-3- (pyrid-4-yl) -buta-1,3-dien-1,1-dicarbonitrilund3- (pyrid-4-yl) -penta-1,3-dien-1,1,5, 5-tetracarbonitrile To 3.78g (10mMoI) of N, N-dimethyl-N- [3-dimethylamino-2- (pyrid-4-yl) -prop-2-enylidene] -ammonium chloride hydrochloride (73% crude product) 10 ml of methanol with stirring 14mMol sodium methylate in 7ml of methanol and 0.60g (1OmMoI) of malononitrile in 5 ml of methanol. It is stirred for 1 hr. At room temperature, with 10 m! Water does not exist. acidified with 3 N HCl and the precipitated orange-red precipitate of 3- (pyrid-4-y!) - penta-1,3-diene-1,1,5,5-tetracarbonitrile aspirated. From the solution, the 4-dimethylamino-3- (pyrid-4-yl) -buta-1,3-diene-dicarbonitrile is obtained by adding with aqueous Na ₂ CO ₃ solution until the reaction is slightly alkaline and allowed to stand is purified by dissolving in 1 N HCl, adding activated carbon and re-precipitating with 1 N NaOH or Na ₂ CO ₃ solution.

3- (pyrid-4-yl) penta-1,3-diene-1,1,5,5-tetracarbonitril:

C ₁₄ H ₇ N ₅ calc. C 68.56 H 2.88 N 28.56

gef. C 68.31 H 3.00 N 28.2V

Yield: 0.44 g (18% of theory). M .: 263-270 ⁰ C (Zers.).

4-Dimothylamino-3- (pyrid-4-yl) -buta-1,3-diene-1,1-dicarbonitrile: C ₁₃ H ₁₂ N ₄ calc. C 69.62 H 5.39 N 24.98

gef. C 69.52 H 5.36 N 24.73

Yield: 1.17 g (52.2% of theory). Mp .: 222-224 ⁰ C.

Example 2

4-Dimiithylamino-3- (pyrid-4-yl) -L'jta-1,3-dien-1,1-dicarbonitrilund3- (pyrid-4-yl) penta-1,3-diene-1,1, 5,5-tetratarbonitrile 4, Og (10mMoI) N, N -dimethyl-N- (3-dimethylamino-2- (pyrid-4-yl) -prop-2-enylide (! NJ-ammonium chloride hydrochloride (69% eq Crude product) in 10 ml of methanol are added in portions with 0.848 g (8 mmol) of Na ₂ CO ₃ and then with 0.66 g (10 mmol) of malononitrile in 5% methanol.

3- (pyrid-4-yl) -penta-1,3-diene-l, 1,5,5-tetracarbonitrile Yield: 0.41 g (16.7% of th.).

4-Dimethylamino-3- (pyrid-4-yl) -buta-1,3-diene-1,1-dicarbonitrile Yield: 1.05 g (46.8% of theory).

Example 3

i-Cyano ^ -dimethylamino-S ^ -ylJ-fpyrid-buta-I.S-dien-i-carbons.iureethylesterundi.S-dicyano-S ^ fpyrid -YD-penta-I.S-dien-I.S-dicarbonsäureethylester

37.8 g (10 μmol) of N, N-dimethyl-N-IS-dimethylanilino-pyridyl-1-yl-propyl-enylidene-1-ammonium chloride hydrochloride (73% crude product) in 100 ml of abs. Ethanol are added under stirring with 15OmMoI sodium methylate in 70 ml of ethanol and then with 11.3 g (10OmMoI) of ethyl cyanoacetate. It is Ί Std. At room temperature, stirred with 100 ml of water and the yellow i-cyano ^ -dimethylamino-S-lpyrid ^ -yD-buta-I.S-diene-i-carbonsäureethyloster filtered off with suction. From the solution, the orange-red i.ö-dicyan-S-lpyrid ^ -yl-penta-I.S-dien-'l.ö-dicarboxylic acid ethyl ester is deposited by acidification with dil. HCI.

i-Cyano-dimethyl-stlpyrid-1-yl-buta-is-diene-i-carboxylic acid ethyl ester: C ₁₅ H ₁₇ N ₃ O ₂ calc. C66.40 H6.32 N, 15.49

gef. C 66.39 H 6.35 N 15.27

Yield: 14.1 g (52% of theory). M.p .: 186-188 ⁰ C.

Ethyl C, δ-dicyan-S-pyridyl-1-yl-penta-is-diene-IB-dicarboxylate: C ₁₆ H ₁₇ NjO ₄ calc. C 63.70 H 5.05 N 12.39

gef. C 63.06 H 4.87 N 12.56

Yield: 1.1 g (3.2% of theory). M .: 220-288 ° C.

Example 4

i-Cyano-dimethyl-s-tpyridyl-buta-is-diene-i-carboxylic acid butyl ester 20g (50mMoI) N, N-dimethyl-N-iso-dimethylamino ^ -fpyridyl-propyl-enylidene-ammonium chloride hydrochloride (69% crude product) in 50 ml of butanol are added with stirring 80 ml of sodium butoxide in 35 ml of butanol and then with 7.1 g (5OmMoI) cyanoacetic acid butyl ester. It is stirred for 3 hours at room temperature, concentrated, mixed with water and filtered with suction.

C ₁₇ H ₂₁ N ₃ O ₂ calc. C68.20 H7.07 N 14,04

gef. C68,10 H7.02 N 13,72

Yield: 8.26 g (55.2% of theory). M.p .: 147-148 ⁰ C.

Example 5

i-cyano-4-dimethylamir. butyl 3-3 (pyrid-4-yl) -buta-1,3-diene-1-carboxylate Analogous to Example 4 in methanol and using sodium methylate. Yield: 6.49 g (43.4% of theory). M.p .: 146-148 ³ C.

Example 6 2-Amino-3-cyano-5- (pyrid-4-yl) -pyridine 33.6g (10OmMoI) N, N-dimethyl-N-IS-dimethyloylamino ^ -pyridyl-propyl-enylidene-ammonium chloride hydrochloride in 100 ml of pyridine are cooled to ⁰ ° C., combined with 20 ml of sodium methylate in 100 ml of methanol and 6.6 g (10 μmol) of malononitrile in 50 ml of ethanol while stirring and stirred for 2 hours at room temperature. Thereafter, 40ml conc. NH ₃ solution is added and it is stirred for 2 hrs. At room temperature. The precipitated 2-amino-3-cyano-5- (pyrid-4-yl) -pyridine is filtered off with suction, the solution is acidified with dilute HCl, and the precipitated 3- (pyrid-4-yl) -penta-1,3-diene -1,1,5,5-tetracarbonitrile and filtered through 2 hrs. Heating with 40ml conc. NH ₃ solution in 6OX also converted into 3-amino-5- (pyrid-4-yl) -pyridine. The reaction products are combined and reprecipitated by dissolving in dilute HCl and neutralizing with NH ₃ solution.

C ₁₁ H ₈ N ₈ calc. C67.33 H4.11 N28.56

gef. C 67.36 H 4.09 N 28.63

Yield: 13.52 g (68.9% of theory). M.p .: 281-284 ⁰ C.

Example 7

2-Amtoyl-3-cyano-5- (pyr-4-yl) -pyridine 61.6 g 90% N, N-dimethyl-N-IS-dimethvlamino-1-pyrrole-1-yl-propyl-1-ylidene ammonium chloride hydrochloride ( 0.2 mol) are dissolved in 240 ml of water, 13.2 g of malononitrile (0.2 mol) added and 90ml concentrated. Ammonia solution was added dropwise.

The mixture is stirred for 2 hours at 60 ⁰ C cooled, filtered off and washed with water.

Yield: 26.7 g (68% I. Th.). M .: 230-285 ⁰ C.

Example 8 2-Amino-3-cyano-5- (pyrid-4-yl) -pyridine and 3 (pyrid-4-yl) -penta-1,3-diene-1,1,5,5-tetracarbonitrile 70g 69% NN- Dimethyl-N-IS-dimethylamino ^ -ipyrid ^ -d-prop ^ -enylidene-ammonium chloride hydrochloride (0.2 mol) are dissolved in a mixture of 120 ml of water and 120mL! Methanol suspended. Add 13.2 g of malononitrile (0.2 mol) and 41 ml of conc. Ammonia solution (0.5 MrI) too. It is heated for 2 hours to 60 ⁰ C and then 120 ml of methanol / water are distilled off in vacuo. The precipitated 2-amino-3-cyano-5- (pyrid-4-yl) -pyridine is filtered off with suction and washed with water. Yield: 23.6 g (60.2% of theory). M.p .: 283-285 ⁰ C.

The filtrate is brought to pH 6 with acetic acid and the precipitated crystals of 3- (pyrid-4-yl) -penta-1,3-diene-1,1,5,5-tetracarbonitrile are filtered off with suction and washed with water. Yield: 7.8 g (16.0% of theory). M .: 262-7 ^c C (Zers.).

Example 9

2-Amino-3-cyano-5- (pyrid-4-yl) -pyridine 70g 69% N, N-dimethyl-N-IS-dimethylamino-1-pyrrole, -YO-prop-1-enylidene-1-ammonium chloride hydrochloride (0, 2 moles) are suspended in a mixture of 120 ml of methanol and 120 ml of water. It will be 6.6 g of malononitrile (0.1 mol) and 41 m! conc. Ammonia solution (0.5 mol) was added. The mixture is stirred for 2 hours at 6O ⁰ C and distilled 120 ml of methanol / water. It is cooled and sucked off.

Yield: 18.8 g (48% of theory). M.p .: 273-28O ⁰ C.

Example 10

2-Arnino-3-cyano-5- (pyrid-4-yl) -pyridine 224 mg (1 mmol) 4-dimethylamino-3- (pyrid-4-yl) -buta-1,3-difn-1,1- dicarbonitrile are concentrated with 4ml. aqueous NH 3 solution for 0.5 hr. At room temperature. It is filtered off with suction and washed with water, alcohol and ether.

Yield: 220 mg (97% of theory). Mp .: 282-284 ⁰ C.

Example 11

2-Amino-3-cyano-5- (pyrid-4-yl) -pyriain-1-oxide 4, Og (10mMoI) N, N-dimethyl-N- [3-dimethylamino-2- (pyrid-4-yl ) -prop-2-enylidene-ammonium chloride hydrochloride (69% crude product) are stirred with 0.66 g (10 mM) of malononitrile in ¹ liter of pyridine for 1 h at room temperature and then with 0.83 g (12 mmol) of HONH ₂ . HCI offset. After about 1 hour, the formed N-oxide precipitates. The mixture is stirred for 2 hrs, filtered off and washed with water, ethanol and ether.

C _n H ₈ N ₄ O, calc. C 62.26 H 3.80 N 26.40

gef. C 62.02 H 3.97 N 25.98

Yield: 0.88 g (41.5% of theory). M .: 312-317 ⁰ C (Zers.).

Example 12

2-Amino-3-cyano-5- (pyrid-4-yl) -pyridine-1-oxide 2.24g (10mMoI) 4-dimethylamino-3- (pyrid-4-yl) -buta-1,3-diene 1,1,1-dicarbonitrile are stirred at room temperature with 695 mg (10 μmol) HONH ₂ HCMO min. It is filtered off with suction and washed with pyridine, water, ethanol and ether.

Yield: 2.05 g (96.7% of theory). M .: 312-316 ° C (Zers.).

Example 13

2-Amino-3-cyano-5- (pyridin-4-yl) -pyridine-1-oxide 6,3g (25,7mmol) 3- (pyrid-4-yl) -penta-1,3-diene-1 , 1,5,5-Tetracarbonit il are stirred in 35 ml of pyridine for 1 hr. With 2.09g (3OmMoI) HONH ₂ · HCl at 40-60 ⁰ C stirred. It is left standing overnight, mixed with water, aspirated and reprecipitated by dissolving in HCI and NH ₃ cases.

Yield: 1.97 g (36.1% of theory). M .: 310-317 ⁰ C (Zers.).

Example 14

2-Amino-3-carbamoyl-5- (pyrid-4-yl) -pyridine To 37.8g (10OmMoI) N, N-dimethyl-N-IS-dimethylamino-1-pyrrole-1-yl-propyl-enylidene-1-ammonium chloride hydrochloride (73% crude product) in 100 ml of pyridine are added under stirring at ^{0 0} C 20OmMoI sodium methylate in 100 ml of methanol and 8.4 g of cyanoacetamide. It is stirred for 2 hrs. At room temperature, with 80ml concentrated. NH ₃ solution, stirred for 2 hrs. At room temperature, mixed with water, the precipitate was filtered off and washed with water, ethanol and ether.

C _n H ₁₀ N ₄ O ₁ calc. C61.67 H4.71

gef. C 61.79 H 4.70

Yield: 15.4 g (72% of theory). M .: 277-282 ° C.

Example 15

2-Amino-3-carbamoyl-5- (pyrid-4-yl) -pyridine 61.6 g 90% N, N-dimethyl-N-isl-dimethylamino ^ -fpyridyl-propyl-enylidene-1-ammonium chloride hydrochloride ( 0.2 mol)

are dissolved in 150 ml of water, 18.5 g of cyanacetamide (0.22 mol) added and 38ml concentrated. Ammonia solution (0.5 mol) added and concentrated 38 ml. Ammonia solution (0.5 mol) was added dropwise. Is maintained for 1 hour at 4O ⁰ C and 2 hours at 60 ° C. It is cooled, filtered off and washed 4 times with 50 ml of water. Yield: 25.7 g (60.0% of theory). M .: 278-83 ° C.

Example 16 2-Amino-3-carbamoyl-5- (pyrid-4-yl) -pyridine-1-oxide 13.6g OemMoDN.N-dimethyl-N-IS-dimethylamino ^ -pyrid ^ -yD-prop ^ - enylidenl-ammonium chloride hydrochlüridiyS ^ oig crude product) in 35 ml of pyridine are added under stirring at 0 to -10 ⁰ C and 7OmMoI sodium methylate in 35ml methanol and 3,02g (36 mmol) of cyanoacetamide. It is stirred for 0.5 hr. At about 1O ⁰ C, cooled to 0 to -5 ° C, with 3.5g (50.4mMol) HONH ₂ · HCl, stirred for 3 hrs. At room temperature, mixed with a little water, allowed to stand, filtered off with suction, taken up in dilute HCl and again precipitated with dil. NaOI-I.

CiiH, ₀ N ₄ o2 calc. C 57.39 H 4.38 N 24.34

gef. C 56.99 H 4.44 N 23.65

Yield: 3.5 g (42.2% of theory). M.p .: 317-319 ° C (Zers.).

Example 17

2-Amino-3-thiocarbamoyl-5- (pyrid-4-yl) -pyridine To 3.36 g (10 mmol) of N, N-dimethyl-N, N-dimethylamino-1-pyridyl-N-propyl-enylidene-1-ammonium chloride hydrochloride (80 % crude product) in 20 ml of pyridine and 20 ml of methanol is added with stirring at -20 ⁰ C 1 g (1OmMoI) Cyanthioacetamid. It is stirred for 1 hr. At - 10 ⁰ C, with 6 ml of conc. NH ₃ solution and 1 g of ammonium acetate, stirred for 4 hrs. At room temperature, poured onto ice water, filtered off with suction and washed with water, ethanol and ether.

C ₁₁ H ₁₀ N ₄ S ₁ calc. C 57.37 H 4.38 N 24.33 S 13.92

gef. C 57.37 H 4.40 N 23.92 S 13.44

Yield: 1.28 g (56% of theory). M .: 279-283 C.

Example 18 2-Amino-3-thiocarbamoyl-5- (pyrid-4-yl) -pyridine-1-oxide Analogous to Example 16 from 3.78 g (10 μmol) of N, N-dimethyl-N-isl-dimethylamino ^ -pyridine-y-O -prop ^ -enyüdenl-ammonium chloride hydrochloride, 1g (10mMoI) cyanothioacetamide and 1g (14.3mmol) HONH ₂ • HCl. Purification is carried out by drawing off with about 1.5N NH ₃ solution, dissolving in 2N HCl and precipitating by alkalization with dilute NH ₃ solution.

C ₁₁ H ₁₀ N ₄ OiS, calc. C 53.64 H 4.09 N 22.75 S 13.02

gef. C 53.01 H 4.35 N 22.23 S 12.48

Yield: 0.34% (14% of theory). M .: 271-277 ⁰ C (Zers.).

Example 19

2-amino-3-ethoxy) -ycarbonyl-5- (pyrid-4-yl) -pyridine 2.71 g (10 μmol) of 1-cyano-dimethylamino-5-pyridine-1-yl-buta-1-isadiene-1-one Carboxylic acid ethyl ester are concentrated with 10ml. NH ₃ solution heated to 6O ⁰ C for a few minutes. After cooling to room temperature is filtered off with suction, extracted with dil. NaOH, dissolved in dilute HCI, precipitated by alkaline with dil. NaOH, washed with water and dried at 110 ⁰ C.

C ₁₃ H ₁₃ N ₃ O ₂ calc. C 64.18 H 5.39 N 17.27

gef. C63.93 H, 5.54 N, 17.17

Yield: 0.5 g (20.5% of theory). M .: 139-141 ⁰ C

Example 20

2-Amino-3-ethoxycarbonyl-5- (pyrid-4-yl) -pyridine-1-oxide 3.26g (12 mmol) i-cyano -dimethylamino-S-pyridyl-butyl-buta-IS-diene-i -carboxylic acid ethyl ester are stirred with 1.39 g (2OmMoI) HONH ₂ · HCl in 20 ml of pyridine for 0.5 hr. At room temperature. The precipitate is filtered off with suction and washed with a little water, ethanol and ether.

C ₁₃ H ₁₃ N ₃ O ₃ calc. C 60.22 H 5.05 N 16.21

gef. C 59.71 H 5.06 N 16.07

Yield: 2.64 g (84.9% of theory). M.p. 183-184X.

Example 21 2-Amino-3-butoxycarbonyl-5- (pyrid-4-yl-pyridine) 299.3 mg (1 mmol) of i-cyano-dimethyl-amino-S-pyridyl-butyl-buta-IS-disyl-i- carboxylic acid butyl ester are added with 6 ml of concentrated NH ₃ , warmed in a boiling water bath for 5 min, and allowed to stand for 15 min, the precipitate is filtered off with suction and washed with water.

C ₁₆ H ₁₇ N ₃ O ₂ at. C 66.40 H 6.32 N 15.49

gef. C66.18 H 6.32 N 14.91

Yield: 60 mg (22.1% of theory). Mp .: 109-11O ⁰ C.

Example 22 2-Amino-3-butoxycarbonyl-5- (pyrid-4-yl) -pyridine-1-oxide

1 g (3.3 mmol) of 1-cyano-4-dimethylamino-3- (pyrid-4-yl) -buta-1,3-diene-1-carboxylic acid butyl ester are mixed with 231 mg (3.3 mmol) of HONH ₂ .HCl in 1OmI pyridine stirred for 0.5 hours at room temperature. It is filtered off with suction, washed with pyridine, water, a little ethanol and ether.

C ₁₅ H ₁₇ N ₃ O ₃ calc. N 14.63 H5.96 C62 / 70

gef. N 14.26 H 5.95 C 62.94

Yield: 792 mg (83.5% of theory). M .: 183-184.5 ° C.

Example 23 2-Amino-3-cyano-5- (pyrid-4-yl) -pyridine

I1 g (51 mmol) of 2-chloro-3-cyano-5- (pyrid-4-yl) pyridine and 5 g of ammonium acetate are heated in 300 ml of methylene glycol at 95 ⁰ C and then 20 hours gaseous NH ₃ is introduced. It is concentrated, mixed with 400 ml of water, filtered off with suction, extracted with CHCl ₃ in the heat, the residue dissolved in 1 N HCl, treated with activated charcoal, filtered »precipitated with 6 N NH ₃ solution, filtered off with suction, washed with water and at Dried 120 ° C.

Yield: 5.9 g (58.9% of theory). Schm .: 279-285X.

Claims (4)

1. A process for the preparation of 2-amino-5- (pyrid-4-yl) -nicotinic acid derivatives of the formula I, in which X is cyano, carbamoyl, thiocarbamoyl or alkoxycarbonyl and their N-oxides, characterized in that N, N-dimethyl-N- [3-dimethylamino-2- (pyrid-4-yl) -prop-2-enylidene] - ammonium chloride hydrochloride a) with malodinitrile, cyanoacetamide, cyanthioacetamide or cyanoacetic esters to give i-cyano-4-dimethylamino-3- (pyrid-4-yl) -buta-1,3-diene-1-carboxylic acid derivatives and these, without them isolate, converted directly by the action of NH ₃ or hydroxylammonium salts in the 2-amino-5- (pyrid-4-yl) -nicotinic acid derivatives and their N-oxides b) reacting with malodinitrile or cyanoacetic esters, the resulting 4-dimethylamino-3- (pyrid-4-yl) -buta-1,3-diene-1,1-dicarbonitrile and i-cyano-dimethyl-amino-S-lpyrid ^ -Y-buta-IS-diene-icarbonsäureester and additionally formed 3- (pyrid-4-yl) -penta-1,3-diene-1,1,5,5-tetracarbonitrile or!, B-dicyan-S -lpyrid ^ -d-penta-is-diene-i.δ-dicarboxylic acid ester isolated and separately with NH ₃ or hydroxylammonium salts to the reaction brings. 2. The method according to item 1, characterized in that the reaction of N, N-dimethyl-N- [3-dimethylamino-2- (pyrid-4-yl) prop-2-enylidene] -ammoniumchlorid-hydiOchlorid jrederivaten with Cyanessigcf in suitable solvents, preferably pyridine, water, Trialkylam 'ien, alcohols, dimethylformamide or mixtures of these solvents vorgenorv NEN and using a non-basic solvent in Ggw. Of bases, such as alkali metal, alkali metal carbonates, pyridine or other tert. Amines or NH _{3 is} worked. 3. The method according to item 1, characterized in that the isolation of 4-Dimethylamino-3- (pyrid-4-yl) -buta-1,3-diene-1,1-dicarbonitrile and 1-cyano-4-dimethylamino-3- (pyrid-4-yl) -buta-1,3 -diene-1-carboxylic acid esters by adding water and filling at neutral to slightly alkaline pH of the solution and recovering 3- (pyrid-4-yl) -penta-1,3-diene-1,1,5, 5-tetracarbonitrile or 1,5-dicyano-3- (pyrid-4-yl) -penta-1,3-diene-1,5-dicarboxylic acid esters by acidification of the reaction solution.