DK153476B - 3-CARBAMYL-5-PYRIDINYL-2 (1H) -PYRIDINON COMPOUNDS FOR USE AS INTERMEDIATES IN THE PREPARATION OF CARDIOTONIC EFFECTIVE 3-AMINO-5-PYRIDINYL-2-PYRIDELINE-PYRIDED - Google Patents

Description

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This invention relates to novel 3-carbamyl-5-pyridinyl-2 (1H) -pyridinone compounds for use as intermediates in the preparation of cardiotonically active 3-amino-5-pyridinyl-2 (1H) -pyridinone compounds having the composition of claim 1. 1 of the general formula I.

GB-A-1 322 318 discloses, as intermediates, 1,2-dihydro-2-oxo-6- (4- or 3-pyridinyl) nicotinonitrile, 6- (4- or 3-pyridinyl) -2 ( 1H) -pyridinone and 6- (4- or 3-pyridinyl) -2-pyridinamine. U.S. Patent No. 3,838,156 discloses as intermediates 1,2-dihydro-2-oxo-e-Q'1-nicotinic acids, wherein Q11 'is 4- (or 3) -pyridinyl, optionally having one or two lower-alkyl substituents. In JP patent specification no.

20 295/67, published October 11, 1967, discloses 1- (x1-amino-2'-pyridinyl) -2-pyridinones as having "analgesic and antiphlogistic activity". Specifically, 1- (5'-amino-2'-pyridinyl) -2-pyridinone is disclosed.

Danish Patent Application No. 4558/76 discloses an analogous process for the preparation of 5-pyridinyl-2 (1H) -20 pyridinone compounds of the general formula

Q

vs

R

wherein PY means 4- or 3- or 2-pyridinyl optionally having one or two alkyl substituents of 1-6 carbon atoms, R means hydrogen, alkyl of 1-6 carbon atoms or hydroxyalkyl of 2-6 carbon atoms, and Q means cyano, hydrogen, amino, alkylamino having 1-6 carbon atoms, dialkylamino having 1-6 carbon atoms in each alkyl moiety, -NHAc, where Ac means alkanoyl having 1-6 carbon atoms or alkoxycarbonyl having 1-6 carbons

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b-atoms in the alkoxy moiety, or -NHCH-C (COQR 4) ', where g ^ R means alkyl of 1-6 carbon atoms, or pharmaceutically acceptable acid addition salts thereof.

These compounds are useful as cardiotonic agents 5 and, when Q is hydrogen, also as bronchodilators, determined by standard pharmacological assessment procedures. Preferred embodiments are those compounds of formula I wherein Q is amino, R is hydrogen, and PY is 4-pyridinyl or 3-pyridinyl. A particularly preferred embodiment 10 is 3-amino-5- (4-pyridinyl) -2 (1H) -pyridinone. Furthermore, a preferred embodiment is diethyl N- [1,2-dihydro-2-oxo-5- (4-pyridinyl) 3-pyridinyl] amino methylene malonate.

Those in DK ans. No. 4558/76 discloses compounds of formula I wherein Q is amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms in each alkyl moiety, -NHAc or -NHCH = C (COOR Ac and R 2 have the above meaning, can be prepared from the 3-c ar bamyl. 5-pyridinyl-2 (1H) -pyridinone compounds of the present invention, which are peculiar 2D in that they are compounds with the Claim 1 is characterized by the general formula I 'or acid addition salts thereof.

The compounds of the invention wherein R is hydrogen may be prepared by reacting ot -PY-β - (RRN) acrolein 25 (II) wherein PY has the above meaning and R 1 and 2 R are each alkyl with 1-6 carbon atoms, preferably methyl or ethyl, with malonamide to form 1,2-dihydro-2-oxo-5-PY-nicotinamide (I ', R = H).

Another procedure consists of reacting either α-PY- (3- (30) (R ^ R ^ N) acrolein (II) or α-PY-malonaldehyde (II1), where PY has the above meaning, and R and R each is alkyl of 1-6 carbon atoms, preferably 3

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methyl or ethyl, with α-cyanacetamide to form 1,2-dihydro-2-oxo-5-PY-nicotinonitrile (IIa = I, where Q is CN and R is H) and partially hydrolyze this to form 1, 2-dihydro-2-oxo-5-PY-nicotinamide (I ').

Compounds I1 wherein R is hydrogen can be alkylated to form the corresponding compounds wherein R is alkyl of 1-6 carbon atoms or hydroxyalkyl of 2-6 carbon atoms, by reaction with an alkylating agent of formula R'-An to form of 1-R'-3-carbamyl-5-PY-2 (1H) -pyridinone (I '), where PY has the above meaning, R' is alkyl of 1-6 carbon atoms or hydroxyalkyl of 2-6 carbon atoms, and An is an anion of a strong inorganic acid or organic sulfonic acid. Alternatively, the alkylation step may be carried out on the compound IIIa or on any of the compounds of formula I wherein R is hydrogen to form the corresponding compound wherein R is R ', e.g. prior to any of the conversion steps described.

The compounds of the invention of formula 1 'are converted to the therapeutically valuable compounds of formula I by reaction with a reagent capable of converting carbamyl to amino to form 1R-3-amino-5-PY-2 (1H ) -pyridinone (Ib), wherein PY and R have the above meaning.

This compound can be converted to the corresponding 1-R-3- (alkylamino or dialkylamino) -5-PY-2 (1H) -pyridinone (Ic) by reaction with one or two molar equivalents of an alkylating agent. A preferred embodiment of this alternative procedure consists of reacting 1-R-3-amino-5-PY-2 (1H) -pyridinone with a methylation mixture of formic acid and formaldehyde to form 3-dimethylamino-5 PY-2 (1H) -pyridinone, where PY has the above meaning.

4

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Alternatively, compound Ib may be reacted with an alkanoylating agent or alkoxycarbonylating agent to prepare an 1- R-3-NHAc-5-PY-2 (1H) -pyridinone (Id), wherein PY, R and Ac have the aforementioned meaning.

Finally, compound Ib can be converted to dialkyl-N- [1,2-dihydro-1R-2-oxo-5-PY-3-pyridinyl] aminomethylene malonate (1e) by reaction with dialkyl-α-alkoxymethylene malonate of the formula R C (C00R4)?, Where PY and R have the above-mentioned meaning, and R and R individually represent alkyl of 1-6 carbon atoms.

The above procedures are illustrated by the following reaction scheme:

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✓ CHO / CH0 PY-CH Pv_CV 1? \ CHO- S ^ CHNR 'R *

f I

NC-CH2CONH2 NC-CH2GCMi2 CH2 (CONH2) 2 PY CN P Y 2

Yes, wife. H2SO4.

χΚ'-Λη * Si "\ /" III and III b I 1

[XIX, R = R '] Br 2 + OH

R3 ψ <alkylation

1 I

R R

le / Ib v / acylene r5 and = C (COOR6) 2 \ / ▼ PY \ - ^ v ^ -NHAc P'y \ Xv / NHCH = C (COOR6) 2 I i, R R '

In the formulas of the above reaction scheme, PY, R and Ac have the above meaning, R 'is alkyl of 1-6 carbon atoms or hydroxyalkyl of 2-6 carbon atoms, 6

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An is an anion of a strong inorganic acid or organic sulfonic acid, R 1, R 2, R 2, R 2 and R 2 are each alkyl 4 of 1-6 carbon atoms and R is hydrogen or alkyl of 1-6 carbon atoms.

The utility of the compounds of formula I wherein Q is amino (preferred), alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms in each alkyl moiety, -NHAc or -NHCH = C (COOR 2) 2, where Ac and R 1 has the significance previously stated as cardiotonic agents documented by test results of standard pharmacological test procedures in Danish Patent Application No. 4558/76.

In this specification "alkyl of 1-6 carbon atoms" means straight or branched chain alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, n-amyl and n hexyl.

The term "hydroxyalkyl of 2-6 carbon atoms" means hydroxyalkyl groups wherein the hydroxy group and the free bond are on various carbon atoms such as 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxy-2-methylpropyl, 3-hydroxypropyl. 2-hydroxy-1,1-dimethylethyl, 4-hydroxybutyl, 5-hydroxyamyl and 6-hydroxyhexyl.

For elucidation of PY of formula I wherein PY is 4-, 3- or 25-pyridinyl, optionally having one or two alkyl substituents of 1-6 carbon atoms, may be mentioned: 2-methyl-4-pyridinyl, 2, 6-dimethyl-4-pyridinyl, 3-methyl-4-pyridinyl, 2-methyl-3-pyridinyl, 6-methyl-3-pyridinyl (also called 2-methyl-5-pyridinyl), 4-methyl-2 -pyridinyl, 6-methyl-2-pyridinyl, 2,3-dimethyl-4-pyridinyl, 2,6-dimethyl-4-pyridinyl, 4,6-dimethyl-2-pyridinyl, 2-ethyl-4- pyridinyl, 2-isopropyl-4-pyridinyl, 2-n-butyl-4-pyridin-7

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nyl, 2-n-hexyl-4-pyridinyl, 2,6-diethyl-4-pyridinyl, 2,6-diethyl-3-pyridinyl, 2,6-diisopropyl-4-pyridinyl and 2,6-di-n hexyl-4-pyridinyl.

The term "alkanoyl of 1-6 carbon atoms" encompasses 3 straight and branched groups such as formyl, acetyl, propionyl (n-propanoyl), butyryl (n-butanoyl), isobutylryl (2-methyl-n-propanoyl) and caproyl ( n-hexanoyl).

The term "alkoxycarbonyl having 1-6 carbon atoms in the alkoxy moiety" means alkoxycarbonyl groups wherein the alkoxy moiety may be straight or branched, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, tert-butoxycarbonyl -hexoxycarbonyl.

The preparation of the compounds of the invention 15 as well as their conversion to the therapeutically valuable compounds will be described in the following, so that a person skilled in pharmaceutical chemistry is enabled to perform and use it.

The preparation of 1,2-dihydro-2-oxo-5-PY-nicotinamide 1? Preferably, the reaction of α-PY-β- (R R N) acrolein (II) with malonic acid amide is carried out by mixing the reactants in a suitable solvent in the presence of a basic condensing agent. The reaction is conveniently carried out using a lower alkanol 25 as solvent, preferably methanol or ethanol, and an alkali metal lower alkoxide, preferably sodium methoxide or sodium ethoxide, as the basic condensing agent. In a practical embodiment, the reaction was carried out in refluxing methanol using sodium methoxide. Other basic condensing agents include sodium hydride, lithium diethylamide, lithium diisopropylamide and the like in an aprotic solution 8

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agent, e.g. tetrahydrofuran, acetonitrile, ether, benzene and dioxane.

1 2

The above-mentioned α-PY-P (R R N) acrolein starting compounds (II) are well known in the art and are prepared by conventional methods. For example, II is prepared by reacting an α-ΡΥ-acetic acid with the reaction product of dimethylformamide with a phosphorus oxyhalide, preferably the oxychloride or oxybromide. The reaction of dimethylformamide with the phosphorus oxyhalide is preferably carried out at a temperature below 10 ° C, and the resulting reaction product is heated with the α-PY acetic acid to from about 50 to about 80 ° C to form II. The α-ΡΥ acetic acid intermediates are generally known compounds prepared by conventional methods; for example, they are readily prepared by heating the corresponding acetylpyridine of formula PY-COCH 2 with sulfur and morpholine to form the corresponding PY-thioacetomorpholinamide, which upon refluxing with 12 N hydrochloric acid gives the α-PY acetic acid; 20 e.g. α- (3-ethyl-4-pyridinyl) acetic acid is prepared from 4-acetyl-3-ethylpyridine via 3-ethyl-4-pyridinyl-thioacetomorpholinamide [Jain et al., Indian Journal of Chemistry H), 455 (1972)] . The acetylpyridines, i.e.

PY-COCH 2 are also commonly known compounds which are prepared by conventional procedures, e.g. from the corresponding cyanpyridines, viz. PY-CN [GB Patent No. 920,303; Case et al., J. Am. Chem. Soc., 78, 5842 (1956)]. 1 2

The reaction of α-PY-β- (RRN) acrolein (II) with α-cyano-acetamide to give 1,2-dihydro-2-oxo-5-PY-nicotinonitrile (111) is preferably carried out by mixing the reactants in a suitable solvent in the presence of a basic condensing agent. The reaction is carried out

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9, preferably using a lower alkanol as solvent, preferably methanol or ethanol, and an alkali metal lower alkoxide, preferably sodium methoxide or sodium ethoxide, as the basic condensing agent. In a practical embodiment, the reaction was carried out in refluxing methanol using sodium methoxide. Other basic condensing agents include sodium hydride, lithium diethylamide, lithium diisopropylamide and the like in an aprotic solvent, e.g. tetrahydrofuran, acetonitrile, ether, benzene and dioxane.

The reaction of α-PY-malonaldehyde (II ') with α-cyanacetamide to give 1,2-dihydro-2-oxo-5-PY-nicotinonitrile (III) is carried out by heating the reactants in the presence of a catalytic condensing agent, preferably morpholine or piperidine and / or its acetate. The reaction is conveniently carried out by heating a benzene solution containing the reactants under reflux in the presence of morpholine, piperidine, morpholine acetate, piperidine acetate or mixtures thereof, preferably with a water separator connected to the reaction vessel to collect the water formed by the reaction.

The partial hydrolysis of 1,2-dihydro-2-oxo-5-PY-nicotino-nitrile (III) to give 1,2-dihydro-2-oxo-5-PY-ni-cotinamide (I ') is carried out by heating III with concentrated sulfuric acid. Although the reaction is conveniently and preferably carried out by heating the reactants on a steam bath, the temperature range of the reaction can range from about 25 to about 135 ° C. Alternatively, the conversion of III to 1 'can be accomplished by heating III to from about 100 to about 175 ° C with polyphosphoric acid for from about 1 to about 5 hours.

The conversion of 1,2-dihydro-2-oxo-5-PY-nicotinamide (I1)

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ID

to 3-amino-5-PY- (2 (1H) -pyridinone (Ib)) is carried out by reacting 1 'with a reagent capable of converting carbamyl to amino. This reaction is conveniently carried out by heating an aqueous mixture. 5 containing an alkali metal hypohalogenite, preferably hypobromite such as using bromine and an alkali metal hydroxide, or hypochlorite, and 11 and then acidifying the reaction mixture, preferably with an aqueous mineral acid, for example hydrochloric acid. 25 to about 100 ° C, preferably from about 60 to about 100 ° C.

The reaction of 1,2-dihydro-2-oxo-5-PY-nicotinonitrile (IIIa) or 1,2-dihydro-2-oxo-5-PY-nicotinamide (I1, R = H) with a lower alkylating agent to form of the corresponding 1-R 'compound is usually carried out using a lower-alkyl or lower-hydroxy-alkyl ester of a strong inorganic acid or an organic sulfonic acid, which ester has the formula R'-An, where An is an anion of a strong inorganic acid or an organic sulfonic acid, e.g. chloride, bromide, iodide, sulfate, methanesulfonate, benzenesulfonate and p-toluenesulfonate (or tosylate), and R 'is alkyl of 1-6 carbon atoms or hydroxyalkyl of 2-6 carbon atoms. This alkylation is preferably carried out using a slight excess of the alkylating agent, although equimolar amounts give satisfactory results.

The chloride, bromide, iodide or tosylate is preferred because of the ease of availability of the required lower alkyl halides or tosylates; and the reaction is preferably conducted in the presence of an acid binding agent. The acid binding agent is a basic substance which preferably forms freely water-soluble by-products which are readily separable from the reaction product, e.g. sodium hydroxide, potassium hydroxide, sodium carbonate, potassium 11

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carbonate, sodium alkoxides, potassium alkoxides and sodium amide. The acid-binding agent absorbs the hydrogen halide or tosylate (or HAn) which is decomposed during the course of the reaction. The reaction is preferably carried out in the presence of a suitable solvent which is inert under the reaction conditions, for example a single solvent such as a lower alkanol, acetone, dioxane, dimethylformamide, dimethylsulfoxide and hexamethylphosphoramide, or, a mixture of solvents, e.g. a mixture of water and a lower alkanol.

The reaction is generally carried out at a temperature from about room temperature (20-25 ° C) to about 150 ° C, preferably while heating on a steam bath in a stirred mixture of dimethylformamide and anhydrous potassium carbonate.

The acylation of 1R-3-amino-5-PY-2 (1H) -pyridinone (Ib) to form the corresponding 1R-3-NHAc-5-PY-2 (1H) -pyridinone (Id) is carried out by reacting Ib with a lower alkanoylating agent or a lower alkoxycarbonylating agent, e.g. a lower alkanoyl halide, preferably chloride, a lower alkanoic anhydride and a lower alkyl halogen formate, preferably in the presence of an acid binding agent as illustrated above for the alkylation reaction. The alkoxycarbonylation reaction can be carried out stepwise by first reacting the 1-R-3-amino-5-PY-1-R-2 (1H) pyridinone (Ib) with 1,1'-carbonyldiimidazole in the presence of a suitable solvent, e.g. dimethylformamide, to give N- (1-R1, 2-dihydro-2-oxo-5-PY-3-pyridinyl) -imidazole-1-carboxamide, which is then heated with a lower alkanol to give the corresponding lower-alkyl-N- (1-R1, 2-dihydro-2-oxo-5-PY-3-pyridinyl) carbarnate.

A preferred method of preparing 3-dimethylamino-5-PY-2 (1H) -pyridinone is to heat 3-amino-5-PY-2 (1H) -pyridinone (1b) with a mixture of formaldehyde and formic acid.

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re to produce dimethylation of the primary 3-amino group. This reaction is conveniently carried out by heating the 3-amino-5-PY-2 (1H) -pyridinone (1b) under reflux with an excess of both formaldehyde, preferably an aqueous solution thereof, and formic acid, preferably more than double molar. profits of each.

The conversion of 1R-3-amino-5-PY-2 (1H) -pyridinone (1b) to dialkyl-N- [1,2-dihydro-1R-2-oxo-5-PY-3-pyridinyl] aminomethylene malonate ( 1e) is conveniently carried out by stirring the reactants, 1R-3-amino-5-PY-2 (1H) -pyridinone (1b) and dialkyl-α-alkoxymethylene malonate of formula R ROCH = C (C00R6) 2, at room temperature (20-25 ° C) or under heating to a temperature of from about 80 to about 120 ° C, preferably in a molar ratio of 15: 1: 1 and preferably in the presence of a suitable inert solvent, e.g. a lower alkanol, preferably methanol or ethanol. Other inert solvents which may be used are, for example, acetonitrile, isopropyl alcohol, dimethylformamide and benzene. Alternatively, this reaction can be carried out in the preparation of the reactant di (lower alkyl) -α- (lower alkoxymethylene) malonate in situ without isolation by heating a mixture of equimolar amounts of 1R-3-amino-5-PY-2 (1H) -pyridinone, tri- (lower-alkyl) orthoformate, preferably the triethyl ester, and di- (1a-25-lower-alkyl) malonate using similar reaction conditions as those listed above, although the reactants here are preferably heated in a suitable inert solvent, preferably a lower alcohol, e.g. ethanol, to from about 60 to about 90 ° C.

The following examples illustrate the preparation of the compounds of the invention and their use as intermediates in the preparation of the cardiotonically active end products, Examples 1 and 2 illustrating the preparation of the compounds and Examples 3A-F 35 their use.

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EXAMPLE 1 A. 1,2-Dihydro-2-oxo-5- (4-pyridinyl) nicotinonitrile

A reaction mixture containing 35 g of α- (4-pyridinyl) -β-dimethylaminoacrolein, 21.6 g of sodium methoxide, 500 ml of methanol and 17 g of α-cyanacetamide was heated to reflux under stirring, followed by an exothermic reaction which was sufficient. to reflux the reaction mixture without using external heat. The reaction mixture was then heated under reflux and stirring for a further 30 minutes, after about 5 minutes refluxing a solid precipitated. The reaction mixture was cooled and the precipitate collected, washed with ethyl ether and dried. The solid product was recrystallized from methanol and dried in vacuo at 80 ° C to give 13 g of 1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinonitrile as the sodium salt, m.p. 300 ° C. Subsequent concentrations of mother liquor gave additional fractions of 10 g, 6.5 g and 3 g of the product so that a total of 32.5 g of said sodium salt was obtained.

This was dissolved in water, the aqueous solution was neutralized with 6N hydrochloric acid and the acidic solution cooled. The precipitated solid was collected, washed successively with isopropyl alcohol and ether and dried in vacuo at 80 ° C to give 1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinonitrile, m.p. > 300 ° C.

An alternative method for preparing 1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinonitrile is as follows: A mixture containing 15 g of oi- (4-pyridyl) malonaldehyde, 9.3 g of α-cyanacetamide , 11 g of morpholine, 13 g of acetic acid and 1 liter of benzene were heated at reflux for about 24 hours with a water separator connected to the reaction vessel and then allowed to stand over the weekend. The solid which had precipitated was collected, 14

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recrystallized from dimethylformamide and dried in vacuo at 90 ° C for about 15 hours to give 5 g of 1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinonitrile, m.p. > 300 ° C.

B. 1,2-Dihydro-2-oxo-5- (4-pyridinyl) nicotinamide (optionally referred to as 1,6-dihydro-6-oxo- [3,4'-bipyridine] -5-carboxamide)

A mixture containing 10 g of 1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinonitrile and 100 ml of 90% sulfuric acid was heated in a steam bath for 1 hour and then poured on ice.

The acidic solution was neutralized with 35% aqueous sodium hydroxide solution and then basified with 10% potassium hydrogen carbonate solution. The separated product was collected, washed with water, dried, recrystallized from dimethylformamide, washed successively with ethanol and ethyl ether and dried in vacuo at 80 ° C to give 8.5 g of 1,2-dihydro-2-oxo-2 5- (4-pyridinyl) -nicotinamide, m.p. > 300 ° C.

In another embodiment of the same procedure using 68 µl, 2-dihydro-2-oxo-5- (4-pyridinyl) nicotinonitrile, 700 ml of 90% sulfuric acid, a two-hour heating period in a steam bath, isolation as above, recrystallization from dimethylformamide and washing with methanol and ether followed by drying yielded a quantitative yield of 80 g of the product 1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinamide, mp. > 300 ° C.

EXAMPLE 2 1,2-Dihydro-2-oxo-5- (4-pyridinyl) nicotinamide A reaction mixture containing 17.6 g of α- (4-pyridinyl) - β-dimethylaminoacrolein, 10.0 g of malonamide, 10.8 g sodium 15

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methoxide and 200 ml of methanol were heated under reflux for 30 minutes and allowed to cool. The separated product was collected and dried to obtain "A". The mother liquor was concentrated in vacuo to remove solvent 3 and the remaining material was diluted with water. The mixture was neutralized with acetic acid and the solid was collected, washed with water and dried to give "B". "A" was dissolved in water and the solution was neutralized with acetic acid, and the mixture cooled. The separated solid was collected, washed with water and dried. "A" and "B" were combined and recrystallized from 400 ml of dimethylformamide to give 13 g of 1,2-dihydro-2-oxo-5- (4-pyridinyl) nieotinamide, mp, 3'300 ° C. The product obtained by this procedure was identical to the compound obtained in Example 1B.

Example 3 A. 3-Amino-5- (4-pyridinyl) -2 (1H) -pyridinone

To a solution containing 90 g of sodium hydroxide in 1300 ml of water, kept at 0 ° C, was added dropwise with stirring 23 ml of bromine. To the reaction mixture was then added 80 g of 1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinamide and the resulting reaction mixture was heated on a steam bath for 3 hours. The reaction mixture was cooled to room temperature, slowly acidified with 6N hydrochloric acid, and the resulting mixture was stirred for an additional 30 minutes. The acidic mixture was neutralized with 10% aqueous potassium hydrogen carbonate solution and the mixture cooled. The precipitate was collected, washed with water and dried. The solid product was recrystallized from dimethylformamide, washed successively with methanol and ethyl ether and dried in vacuo at 80 ° C to give 35 g of 3-amino-5- (4-pyridinyl) -2 (1H) pyridinone. mp. 295 - 297 ° C (decomp.). Another 7 g of pro-

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Ιέ The product was obtained by diluting the mother liquor with ethyl ether.

B. N- [1,2-Dihydro-2-oxo-5- (4-pyridinyl) -3-pyridinyl] acetamide A mixture containing 9.4 g of 3-amino-5- (4-pyridinyl) -2 (1 H) -pyridinone, 5.6 g of acetic anhydride and 120 ml of pyridine were heated on a steam bath for 1 hour and then allowed to cool. The separated product was collected, washed with ether and dried and recrystallized twice from dimethylformamide to give 8 µl of 1- [1,2-dihydro-2-oxo-5- (4-pyridinyl) -3-pyridinyl] ] acetamide, m.p. 300 ° C.

C. Methyl N- [1,2-dihydro-2-oxo-5- (4-pyridinyl) -3-pyridinyl] carbamate A mixture containing 10 g of 3-amino-5- (4-pyridinyl) - 2 (1H) -pyridinone, 100 ml of dimethylformamide and 24 g of 1,1'-carbonyldiimidazole were stirred at room temperature for 2 hours and the solvent was then distilled off in vacuo. Cold water was added to the residue and the mixture was stirred until the evolution of carbon dioxide stopped. The solid was collected, washed with water and dried. The solid was then slurried with acetone, collected again and dried. The solid was dissolved in 200 ml of dimethylformamide, the solution was treated with decolorizing coal, and the mixture was filtered. The filtrate was heated in vacuo to remove dimethylformamide.

The remaining material, consisting mainly of N- [1,2-dihydro-2-oxo-5- (4-pyridinyl) -3-pyridinyl] -imidazole-1-carboxamide, was heated with methanol to give 30 a reaction occurred. The reaction mixture was allowed to cool and the separated product was collected and dried to give 3.5 g of methyl N- [1,2-dihydro-2-

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oxo-5- (4-pyridinyl) -3-pyridinyl] carbamate, m.p. > -300 ° C.

D. N- [1,2-Dihydro-2-oxo-5- (4-pyridinyl) -3-pyridinyl] -formamide (also called N- (1,6-dihydro-6-oxo- [3,41- bipyridin-5-yl (formamide)

A reaction mixture containing 28 g of 3-amino-5- (4-pyridinyl) -2- (1H) -pyridinone and 200 ml of 97% formic acid was heated on a steam bath for 3 hours, after which the mixture was cooled and the excess formic acid was distilled off. under reduced pressure. The residue was dissolved in water and the aqueous solution made alkaline with ammonium hydroxide. The precipitated product was collected, washed with water, dried, recrystallized from dimethylformamide, washed with ether and dried to give 26 g of N- [1,2-dihydro-2-oxo-5- (4-pyridinyl) - 3-pyridinyl] -formamide, m.p. 299-300 ° C (decomp.).

E. 3-Dimethylamino-5- (4-pyridinyl) -2 (1H) -pyridinone (also called 5- (dimethylamino) - [3,4-bipyridine] -6 (1H) -one) A mixture containing 36 g 3-Amino-5- (4-pyridinyl) -2 (1H) -pyridinone, 40 g of 30% aqueous formaldehyde solution and 400 ml of formic acid were heated under reflux for 2.5 hours and cooled. The reaction mixture was heated in vacuo to remove the excess formaldehyde and formic acid, and the remaining material was neutralized with 10% potassium hydrogen carbonate solution and allowed to stand at room temperature over the weekend. The aqueous mixture was extracted with three 150 ml portions of methylene dichloride and the combined extracts were dried over anhydrous magnesium sulfate and treated with decolorizing charcoal, filtered, and the filtrate heated in vacuo to remove the methylene dichloride. The residue was recrystallized.

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18, twice washed from acetonitrile, washed with ether and dried in a vacuum oven at 80 ° C to give 11.5 g of 3-dimethylamino-5- (4-pyridinyl) -2 (1H) -pyridinone, m.p. 190 - 194 DC.

F. Diethyl N- [1,2-dihydro-2-oxo-5- (4-pyridinyl) -3-pyridinyl] aminomethylene malonate (also called diethyl- [1,6-dihydro-6-oxo- ( 3,4'-bipyridine) -5-ylaminomethyl-en] propanedioate)

A mixture containing 9.4 g of 3-amino-5- (4-pyridinyl) ~ 10 5 hours. The reaction mixture was filtered through diatomaceous earth and the filtrate was distilled in vacuo to remove the solvent.

The solid residue was recrystallized once from ethanol and then once from methanol using decolorizing coal, washed successively with isopropyl alcohol and ether and then dried to yield 22 g of diethyl-N- [1,2-dihydro-2 -oxo-5- (4-pyridinyl) -3-pyridinylaminomethylene malonate, m.p. 218 - 222 ° C.

Claims (1)

Compound according to claim 1, characterized in that it is 1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinamide.