CH642368A5 - PYRIDO (1,2-A) PYRIMIDINE AND METHOD FOR THE PRODUCTION THEREOF. - Google Patents

Description

The invention relates to new pyrido [1,2-a] pyrimidines, their salts and quaternary salts and a process for their preparation.

It has previously been unsuccessfully attempted to produce the [(5-ethoxycarbonyl-2-pyridyl) amino-methylene] -malonic acid diethyl ester from 2-aminopyridine-5-carboxylic acid ethyl ester and ethoxymethylene malonic acid diethyl ester (J. Am.

Chem. Soc. 70,3348,1948). Of the pyrido [1,2-a] pyrimidines bearing a free or esterified carboxyl group on the pyridine ring, only 2-methyl-4-oxo-4H-pyrido [1,2a] pyrimidine-9-carboxylic acid, its methyl and Ethyl esters and the 6,7,8,9-tetrahydro derivatives of the esters were prepared [J. Het. Chem. 13,797 (1976)].

The invention now relates to new pyrido [1,2-a] pyrimidines of the general formula I.

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R1

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wherein

R represents hydrogen or alkyl group with 1-4 carbon atoms and

R1 in the event that the broken line between the atoms N and C9a means a valence bond, i.e. there is a double bond between Ni and C? a, stands for a lone pair of electrons, for hydrogen atom or for alkyl group with 1-4 carbon atoms and in the latter case salt formation occurs on the positively charged nitrogen atom, and R1 for the case that there is a between Ni and C9a Single bond is present, represents hydrogen or alkyl group with 1-4 carbon atoms,

R2 is hydrogen, alkyl group with 1-4 carbon atoms or phenyl group and

R3 represents hydrogen, halogen, alkyl group with 1-4 carbon atoms, phenyl group, aralkyl group with 7-12 carbon atoms, for carboxylic acid group or its derivative, for a group of the general formula (CH2) n-COOR4 (in which n = 1, 2 or 3 and R4 is hydrogen or alkyl group with 1-4 carbon atoms), R3 furthermore stands for nitro, amino, benzoyl or alkanoyl group with 1-4 carbon atoms, and the broken lines stand for any valence bonds present, with the condition that under the condition that R2 and R3 cannot simultaneously represent alkyl groups with 1-4 carbon atoms and in the event that R3 represents hydrogen and R2 represents methyl group, the group -COOR has a different meaning than 9-carboxyl-, 9-methoxycarbonyl - or 9-ethoxycarbonyl group.

The connections which do not meet the first condition fall within the scope of protection of the Swiss patent 637 541 -8, while the second condition the connections described in the above-mentioned article by J. Het. Chem. Have been described.

Particular preference is given to those compounds of the general formula I in which R represents hydrogen, methyl or ethyl group, the molecule contains a double bond between the atoms Ni and C «a, R1 for a lone pair of electrons and R2 for hydrogen or alkyl group

1-4 carbon atoms, while R3 is hydrogen, alkyl group with 1-4 carbon atoms, phenyl group, carboxyl group, alkoxycarbonyl group with 1-4 carbon atoms, nitrile group or alkanoyl group with 1-4 carbon atoms.

According to the invention, certain compounds of the general formula I are prepared by the processes defined in claims 4 or 11, 12 and 14.

The starting compounds of the general formula III are preferably propionylacetic acid, acetoacetic acid, benzoylacetic acid, ethoxymethylene malonic acid, ethoxymethyl-lenacetoacetic acid, ethoxymethylene benzoylacetic acid, ethoxymethylene cyanoacetic acid, 2-formylsuccinic acid,

2-formylglutaric acid, 2-formylpropionic acid, 2-formylphenylacetic acid, and also the esters or acid halides of these acids. Of the esters, the methyl, ethyl and isopropyl esters are particularly preferred.

In some cases, the compounds of the general formula III can also be formed in situ by reacting the corresponding β-keto ester with trialkyl orthoformate in the presence of a Lewis acid. For example, aluminum chloride, zinc chloride, etc. can be used as the Lewis acid.

The cyclization is conveniently carried out in the presence of an inert solvent or an acidic condensing agent at 25-400 ° C. Diphyl (the eutectic mixture of diphenyl and diphenyl oxide), trichlorobenzene, paraffin oil or mineral oil fractions are suitable as inert solvents. Phosphorus oxyhalides, for example phosphorus oxychloride, phosphorus trihalides, for example phosphorus trichloride, thionyl chloride, hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, polyphosphoric acid ethyl ester or mixtures of the listed compounds are preferably used as acidic condensing agents.

If the ring closure is carried out in an inert solvent, the compound of the general formula Ia generally precipitates after cooling and dilution of the mixture with petroleum ether or gasoline and can be filtered off. If the product does not separate from the diluted mixture, it can be shaken out with dilute hydrochloric acid and isolated from the acidic solution after its neutralization using known methods.

If the ring closure is carried out in the presence of acidic condensing agents, the reaction mixture is treated with absolute alcohol after the reaction has ended. The compound of general formula Ia or its salt crystallizes out of the reaction mixture. In some cases, a further fraction of the compound of the general formula Ia can be obtained by working up the mother liquor.

If appropriate, the compounds of general formula Ia obtained are hydrogenated in the presence of a catalyst or reduced with complex metal hydrides. The usual hydrogenation catalysts, primarily palladium, rhodium, Raney nickel or platinum oxide, are used in the catalytic hydrogenation. In particular, the alkali borohydrides (for example sodium borohydride, sodium cyanoborohydride) and the sodium bis (2-methoxyethoxy) aluminum hydride are suitable as complex metal hydrides.

The catalytic hydrogenation is preferably carried out at 0-100 ° C and a pressure of 1-15 atm.

The substituent R can be transformed in a manner known from the literature. For example, when R is hydrogen, the carboxylic acid can be esterified with an alcohol having 1-4 carbon atoms, optionally in the presence of a catalyst. Diazomethane or diazoethane can also be used to prepare the methyl or ethyl ester. If R stands for alkyl group with 1-4 carbon atoms, the ester group can be hydrolyzed to the carboxylic acid group by acidic or alkaline hydrolysis.

Group R3 is also transformed using methods known from the literature. If R3 stands for hydrogen, for example, treatment with chemicals suitable for introducing a nitro group (preferably nitric acid and sulfuric acid in a mixture) can give the corresponding compound of the general formula I which contains a nitro group as R3. If desired, the nitro group can be reduced to the amino group, using palladium as the catalyst.

As substituents R3, hydrogen-containing compounds of the general formula I can also be used for Ein4

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bring halogen suitable agents (preferably elemental halogen, halogen complex compounds, halogen-donating compounds, for example N-bromosuccinimide) are treated, resulting in compounds of general formula I which contain halogen as substituents R3.

As substituents R3, an alkoxycarbonyl group-containing compound of the general formula I can be hydrolyzed to the carboxylic acid under acidic or alkaline conditions. The compound of the general formula I now containing a carboxyl group as R3 can optionally be decarboxylated by heating in a solvent (for example phosphoric acid, high-boiling hydrocarbons, quinoline, etc.); the compound of general formula I obtained contains hydrogen as substituent R3. If R3 stands for alkoxycarbonyl groups with 1-4 carbon atoms, this ester group can be converted with ammonia to the carboxyamide group, with hydrazine hydrate to the carbohydrazide group. A carboxyl group present as R3 can, if appropriate in the presence of a catalyst, be esterified with a lower alcohol to form an alkoxycarbonyl group having 1-4 carbon atoms. The methyl or ethyl ester can also be prepared in another way, for example by using diazomethane or diazoethane.

If desired, the salts of the compounds of the general formula I can be prepared by treatment with acids and the quaternary salts by treatment with quaternizing agents. The base can be released from the salts and, if desired, converted to another salt. In this way, for example, the salts formed with hydrochloric acid, sulfuric acid, phosphoric acid, perchloric acid, formic acid, acetic acid, citric acid, malic acid, maleic acid, salicylic acid or the quaternary alkyl halides (for example methoiodides), alkyl sulfates (for example methosulfates), p-toluenesulfonate , Benzenesulfonates, etc. can be produced.

Compounds of the general formula I in which there is a single bond between Ni and Ota and R1 is hydrogen can be converted into compounds of the general formula I by reaction with an alkylating agent suitable for the alkylation of the nitrogen atom - if appropriate in the presence of an acid acceptor, in which R1 stands for alkyl group with 1-4 carbon atoms. Suitable alkylating agents are alkyl iodides (for example methyl iodide), furthermore ethyl bromide, propyl chloride, etc., dialkyl sulfates, trialkyl phosphates, alkyl benzosulfonates and the like. in question.

The term “carboxylic acid derivative” used in the description means alkoxycarbonyl groups with 1-4 carbon atoms, aminocarbonyl, carbohydrazide, nitrite and halocarbonyl groups.

The term "leaving group" used in the description for K is to be understood as meaning the easily leaving groups customary in condensation reactions. For example, K preferably represents halogen, hydroxyl group, alkoxy group, acyloxy, tosyloxy group and optionally mono- or polysubstituted amino group.

The compounds of general formulas II and III used as starting materials are known from the literature and for the most part are commercially available.

The compounds of the general formula I, their salts and quaternary salts can either be used as medicaments or as starting materials for the preparation of compounds which have favorable biological effects. For example, by halogenating in the 9-position and reacting with optionally substituted amines or hydrazines, homopyrimidazole derivatives with antiallergic and antiasthma effects can be obtained. Some representatives of the compounds according to the invention or the derivatives obtained by their further reaction show a favorable anti-inflammatory, antipyretic, anti-atherogenic, anti-asthmatic, anti-allergic effect, furthermore they have a favorable effect on the heart and circulatory system, have antibacterial, antifungal, anti-platelet aggregation activity, one tranquillizing effects and other effects. They can therefore be used as medicines in appropriate doses.

The compounds of general formula I can be used as active ingredients in preparations which still contain inert, non-toxic solid or liquid extenders or carriers. The preparations can be solid (for example tablets, capsules, coated tablets) or liquid (for example solutions, suspensions, emulsions). The substances customary for this purpose (for example talc, calcium carbonate, magnesium stearate, water, polyethylene glycolate, etc.) are used as carriers. If desired, the preparations can also contain the usual auxiliary substances (for example emulsifiers, disintegrants).

The invention is illustrated by the following examples, but is not limited to these examples.

example 1

a) 20 g of 2-aminopyridine-5-carboxylic acid ethyl ester and 28 g of ethoxymethylene malonate are stirred at 120-130 ° C for 30 minutes. Then the reaction mixture is crystallized from ethanol. 31.6 g (78%) of [(5-ethoxycarbonyl-2-pyridyl) aminomethylene] -malonic acid diethyl ester are obtained, which melts at 111-112 ° C.

Analysis: C16H20N2O6:

Calc .: C 57.14%; H 5.99%; N 8.33%

Found: C 57.01%; H 6.11%; N 8.36%.

b) 3.4 g of [(5-ethoxycar-bonyl-2-pyridyl) aminomethylene] malonic acid diethyl ester are introduced into 60 ml of boiling diphyl, and the reaction mixture is stirred at the boiling point for 30 minutes. After cooling to room temperature, the mixture is diluted with 60 ml of petroleum ether. The crystals which have separated out are filtered off. 2.4 g (82.8%) of 4-oxo-4H-pyrido [1,2-a] pyrimidine-3,7-dicarboxylic acid rediethyl ester are obtained, which melts at 110-111 ° C. after recrystallization from ethanol.

Analysis: CMH14N2O5:

Calc .: C 57.93%; H 4.82%; N 9.66%

Found C 57.95%; H 4.86%; N 9.54%.

If [(4-ethoxycarbonyl-2-pyridyl) aminomethylene] malonate is used as the starting compound in the ring closure (mp: 71-72 ° C.), 4-oxo-4H- is obtained in 86% yield. pyrido [l, 2-a] pyrimidine-3,8-dicarboxylic acid diethyl ester, which melts at 134-135 ° C.

Analysis: C14H14N2O5:

Calc .: C 57.93%; H 4.86%; N 9.66%

Found: C 57.94%; H 4.89%; N 9.65%.

Is used as starting material [(3-ethoxycarbonyl-2-pyridyl) -aminomethyienj-malonic acid diethyl ester (mp .: 73-74 ° C)

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used, 4-oxo-4H-pyrido [1,2-a] pyrimidine-3,9-dicarboxylic acid diethyl ester is obtained and melts at 74-76 ° C.

Analysis: C14H14N2O5:

Calc .: C 57.93%; H 4.86%; N 9.66%

Found: C 57.99%; H 4.80%; N 9.67%.

Example 2

6.1 g of 2 - [(6-ethoxycarbonyl-2-pyridyl) aminomethylene] acetoacetic acid ethyl ester (prepared analogously to Example la), mp. Of the cis-trans isomer mixture 148-150 ° C.) are introduced into 100 ml of boiling diphyl . The reaction mixture is stirred at the boiling point for half an hour and then cooled to room temperature. The crystals which have separated out are filtered off. 2.7 g of the starting material 2 - [(6-ethoxycarbonyl-2-pyridyl) aminomethylene] acetoacetic acid ethyl ester are recovered. The filtrate is shaken out three times with 25 ml of 5% hydrochloric acid. The combined hydrochloric acid solutions are neutralized and extracted with chloroform. The organic phase is dried and evaporated, the evaporation residue is recrystallized from ethanol. 1.5 g (52%) of 3-acetyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-6-carboxylic acid ethyl ester are obtained, which melts at 131-133 ° C. after recrystallization from ethanol.

Analysis: C13H12N2O4:

Calc .: C 60.00%; H 4.65%; N 10.76%

Found: C 60.98%; H 4.67%; N 10.78%.

Example 3

The procedure is as described in Example 1, but the starting material used is 2 - [(5-ethoxycarbonyl-2-pyridyl) aminomethylene] acetoacetic acid ethyl ester (melting point of the cis-trans isomer mixture 150-160 ° C.). 3-Acetyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid ethyl ester is obtained in 88% yield and melts at 109-110 ° C.

Analysis: C13H12N2O4:

Calc .: C 60.00%; H 4.65%; N 10.76%

Found: C 59.92%; H 4.68%; N 10.76%.

If 2 - [(4-ethoxycarbonyl-2-pyridyl) aminomethylene] acetoacetic acid ethyl ester (melting point of the isomer mixture 92-93 ° C.) is used as the starting material, the 3- melting at 179-180 ° C. is obtained in 73% yield. AcetyI-4-oxo-4H-pyrido [1,2-a] pyrimidine-8-carboxylic acid ethyl ester.

Analysis: C13H12N2O4:

Calc .: C 60.00%; H 4.65%; N 10.76%

Found: C 59.97%; H 4.60%; N 10.67%.

When using 2 - [(3-ethoxycarbonyl-2-pyridyl) aminomethylene] ethyl acetoacetate (mp. Of the cis-trans isomer mixture 115-116 ° C.) as the starting material, 3-acetyl-4 is obtained in 81% yield -oxo-4H-pyridofl, 2-a] pyrimidine-9-carboxylic acid ethyl ester, which melts at 123-126 ° C.

Analysis: C13H12N2O4:

Calc .: C 60.00%; H 4.65%; N 10.76%

Found: C 59.88%; H 4.67%; N 10.73%.

Example 4

3.4 g of [(6-ethoxycarbonyl-2-pyridyl) aminomethylene] malonic acid diethyl ester (melting point: 110-111 ° C.) are introduced into 60 ml of boiling diphyl. The reaction mixture is stirred for 30 minutes and then cooled to room temperature. The separated crystals are filtered off and washed with petroleum ether. 0.2 g (6.8%) of 4-oxo-1,4-dihydro-l, 8-naphthyridine-3,6-dicarboxylic acid diethyl ester are obtained, which melts at 255-256 ° C.

Analysis: C14H14N2O5:

Calc .: C 57.93%; H 4.86%; N 9.66%

Found: C 58.06%; H 4.78%; N 9.75%.

The diphyl mother liquor is shaken out five times with 35 ml of 5% hydrochloric acid. The combined hydrochloric acid solutions are neutralized, extracted with chloroform, the chloroform extract is dried and evaporated, and the evaporation residue is recrystallized from ethanol. 1.4 g (48%) of 4-oxo-4H-pyrido [1,2-a] pyrimidine-3,6-dicarboxylic acid diethyl ester are obtained, which melts at 108-109 ° C. after recrystallization from ethanol.

Analysis: C14N14N2O5:

Calc .: C 57.93%; H 4.86%; N 9.66%

Found: C 57.96%; H 4.78%; N 9.51%.

Example 5

2.9 g of [(6-ethoxycarbonyl-2-pyridyl) aminomethyl] cyanoacetic acid ethyl ester (mp. Of the cis-trans isomer mixture 141-143 ° C.) are introduced into 300 ml of paraffin oil heated to 300 ° C. The reaction mixture is stirred at the specified temperature for 5 minutes and then cooled to room temperature and diluted with 300 ml of petroleum ether. The separated crystals are filtered off and washed with petroleum ether. 1.6 g of 3-cyano-4-oxo-4H-pyridofl, 2-a] pyrimidine-6-carboxylic acid ethyl ester are obtained, which melts at 215-217 ° C. after recrystallization from ethanol.

If [(5-ethoxycarbonyl-2-pyridyl) aminomethylene] cyanoacetic acid ethyl ester (mp. Of the cis-trans isomer mixture 160-162 ° C.) is used as starting material in the described ring closure reaction, 3 is obtained in 8% yield -Cyano-4-oxo-4H-pyrido [l, 2-a] pyrimidine-7-carbonate, which melts at 150-151 ° C.

Analysis: C12H9N3O3:

Calc .: C 59.26%; H 3.72%; N 17.28%

Found: C 59.18%; H 3.67%; N 17.31%.

If one starts from [(4-ethoxycarbonyl-2-pyridyl) -amino-methylene] -cyanoacetic acid ethyl ester (mp. Of the cis-trans-isomeric mixture 105-106 ° C), one obtains in 24% yield at 180 -181 ° C melting 3-cyano-4-oxo-4H-pyrido [1,2-a] pyrimidine-8-carboxylic acid ethyl ester.

Analysis: C12H9N3O3:

Calc .: C 59.26%; H 3.72%; N 17.28%

Found: C 59.13%; H 3.84%; N 17.20%.

If one starts from [(3-ethoxycarbonyl-2-pyridyl) amine-methylenj-cyanoacetic acid ethyl ester (melting point of the cis-trans isomer mixture 85-87 ° C), then in 57%

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Prey 3-cyano-4-oxo-4H-pyrido [l, 2-a] pyrimidine-9-carbonate, which melts at 165-167 ° C.

Analysis: C17H14N2O3:

Analysis: C12H9N3O3:

Calc .: Found .:

C 69.39%; C 69.49%;

H 4.80%; H 4.88%;

N 9.52% N 9.60%.

Calc .: Found .:

C 59.26%; C 59.25%;

H 3.72%; H 3.73%;

N 17.28% N 17.26%.

Example 6

a) A mixture of 9.6 g of 2-formyl-phenylacetic acid ethyl ester and 8.3 g of 2-aminopyridine-6-carboxylic acid ethyl ester is stirred at 120-130 ° C for 30 minutes. The reaction analysis: C12H12N2O3: mixture is crystallized from 85 ml of ethanol. 14.6 g (86%) of 2 - [(6-ethoxycarbonyl-2-pyridyl) aminomethylene] phenylacetic acid ethyl ester are obtained in the form of the cis-trans isomer mixture. The product melts at 102-105 ° C.

If one starts from ethyl 2 - [(6-ethoxycarbonyl-2-pyridyl) -amino-methylene] -propionate (mp. Of the cis-trans-isomer mixture 93-94 ° C.), 3-methyl is obtained in 98% yield -4-oxo-4H-pyrido [1,2-a] pyrimidine-6-car-bonic acid ethyl ester, which melts at 117-119 ° C.

Calc .: C 62.00%; Found: C 62.10%;

H 5.00%; H 5.02%;

N 12.00% N 12.06%.

Analysis: C19H20N2O4:

Calc .: C 67.05%; H 5.91%; N 8.23% Found: C 67.15%; H 5.92%; N 8.21%.

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If one starts from 2 - [(5-ethoxycarbonyl-2-pyridyl) -amino-methylene] -propionic acid ethyl ester (mp. Of the cis-trans isomer mixture 158-160 ° C.), 3-methyl is obtained in 80% yield -4-oxo-4H-pyrido [1,2-a] pyrimidine-7-car-bonic acid ethyl ester, which melts at 109-110 ° C.

b) 3.4 g of 2 - [(6-ethoxycarbonyl-2-pyridyl) aminomethylene] - Analysis: C12H12N2O3: ethyl phenylacetate are boiling in 60 ml

Diphyl registered. After a reaction time of 30 minutes, the 25 calc .: C 62.00%; H 5.00%; Mixture cooled to room temperature, with 60 ml of petrol. Found: C 62.01%; H 5.10%; ether diluted, the precipitated crystals are filtered off and washed with petroleum ether. 2.3 g (78%) of 3-phenyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-6-carboxylic acid ethyl ester are obtained, which after recrystallization from ethanol at 30

122-123 ° C melts.

N N

12.00% 12.01%.

Analysis: C17H14N2O3:

When using 2 - [(4-ethoxycarbonyl-2-pyridyl) aminomethylene] propionic acid ethyl ester (mp. Of the cis-trans isomer mixture 99-102 ° C.) as the starting material, 3-methyl-4-oxo is obtained in 75% yield -4H-pyrido [1,2-a] pyrimidine-8-carboxylic acid ethyl ester obtained, which melts at 113-114 ° C.

Calc .: C 69.39%; Found: C 69.35%;

H 4.80%; H 4.78%;

N 9.52% N 9.33%.

35 Analysis: C12H12N2O3:

If 2 - [(5-ethoxycarbonyl-2-pyridyl) aminomethylene] phenylacetic acid ethyl ester (mp of the cis-trans isomer mixture 109-110 ° C.) is used as starting material for the described ring closure reaction as the starting material, 97% strength is obtained Yield 3-phenyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-car-bonic acid ethyl ester, which melts at 122-123 ° C.

Calc .: Found .:

C 62.00%; C 62.11%;

H 5.00%; H 5.12%;

N 12.00% N 12.02%.

40 If the starting material used is 2 - [(3-ethoxycarbonyl-2-pyridyl) aminomethylene] propionic acid ethyl ester (mp. Of the cis-trans isomer mixture 66-68 ° C.), 3-methyl is obtained in 70% yield. 4-oxo-4H-pyrido [1,2-a] pyrimidine-9-carboxylic acid ethyl ester, which melts at 87-89 ° C.

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Analysis: C17H14N2O3:

Analysis: C12H12N2O3:

Calc .: Found .:

C 69.39%; C 69.27%;

H 4.80%; H 4.78%;

N 9.52% N 9.33%.

Calc .: Found .:

C 62.00%; C 62.10%;

H 5.00%; H 5.03%;

N 12.00% N 12.07%.

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If one starts from ethyl 2 - [(4-ethoxycarbonyl-2-pyridyl) -amino-methylene] -phenylacetate (mp. Of the cis-trans-isomer mixture 75-80 ° C), the result is obtained in 92% yield at 180 -181 ° C melting 3-phenyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-8-carboxylic acid ethyl ester.

If 2 - [(5-ethoxycarbonyl-2-pyridyl) -aminomethylene] -succinic acid diethyl ester is used as the starting material (mp. Of the cis-trans isomer mixture 143-144 ° C.), the result is obtained in 22% yield at 98-100 ° C melting 55 7-ethoxycarbonyl-4-oxo-4H-pyrido [l, 2-a] pyrimidine-3-acetic acid, ethyl ester.

Analysis: C17H14N2O33:

Calc .: Found .:

C 69.39%; C 69.30%;

H 4.80%; H 4.75%;

N 9.52% N 9.71%.

Analysis: C15H16N2O5:

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If 2 - [(3-ethoxycarbonyl-2-pyridyl) aminomethylene] phenylacetic acid ethyl ester (mp. Of the cis-trans isomer mixture 78-81 ° C.) is used as the starting material, the yield at 122-124 ° is in 92% yield C melting ethyl 3-phenyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-9-carboxylate obtained.

Calc .: Found .:

C 59.21%; C 59.30%;

H 5.30%; H 5.28%;

N 9.21% N 9.23%.

If one starts from 2 - [(4-ethoxycarbonyl-2-pyridyl) -amino- «s methylene] -succinic acid diethyl ester (mp. Of the cis-trans-isomer mixture 116-119 ° C), 8 is obtained in 8% yield -Athoxycarbonyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-3-acetic acid ethyl ester, which melts at 99-101 ° C.

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Analysis: C15H16N2O5:

Calc .: C 59.21%; H 5.30%; N 9.21%

Found: C 59.25%; H 5.28%; N 9.22%.

Example 7

16.8 g of [(4-ethoxycarbonyl-2-pyridyl) aminomethylene] malonic acid diethyl ester are stirred in a mixture of 31 g of phosphoryl chloride and 7 g of polyphosphoric acid at 120-130 ° C. for one hour. The reaction mixture is treated with 30 ml of ethanol and then diluted to three times the volume with water. The pH of the aqueous reaction mixture is adjusted to 7 with sodium hydrogen carbonate. The crystals which precipitate are filtered off and recrystallized from ethanol. 10.8 g (74%) of 4-oxo-4H-pyrido [1,2-a] pyrimidine-3,8-dicarboxylic acid diethyl ester are obtained, which melts at 134-135 ° C. and with the product prepared according to Example 1 no melting point depression shows.

If 2 - [(4-ethoxycarbonyl-2-pyridyl) aminomethylene] propionic acid ethyl ester is used as the starting material, 3-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine is obtained in a yield of 73%. 8-carboxylic acid ethyl ester, which melts at 118-120 ° C and shows no melting point depression with the product prepared according to Example 6.

If one starts from ethyl 2 - [(4-ethoxycarbonyl-2-pyridyl) -amino-methylenj-phenylacetic acid, then 3-phenyl-4-oxo-4H-pyrido [1,2-a] is obtained in a yield of 7%. pyri-midin-8-carboxylic acid ethyl ester, which melts at 182-183 ° C and shows no melting point depression with the product prepared according to Example 6.

Example 8

6.6 g of 2-aminopyridine-6-carboxylic acid ethyl ester and 5.2 g of ethyl acetoacetate are reacted with one another in a mixture of 24.5 g of phosphoryl chloride and 2.8 g of polyphosphoric acid at 100-120 ° C. for 90 minutes. The reaction mixture is treated with 40 ml of ethanol. The crystals which precipitate after cooling are filtered off and washed with ethanol. 9.5 g (88%) of 2-methyl-6-ethoxycarbonyl-4-oxo-4H-pyrido [1,2-a] pyrimidine hydrochloride are obtained, which melts at 210-214 ° C.

Analysis: C12H13N2O3CI:

Calc .: C 53.64%; H 4.88%; N 10.42%; Cl 13.19% Found: C 53.60%; H 4.81%; N 10.39%; Cl 13.22%.

The 9.5 g of hydrochloride are dissolved in 50 ml of water. The pH of the aqueous solution is adjusted to 7 with sodium hydrogen carbonate. Then the aqueous solution is shaken out with chloroform, the organic phase is dried over sodium sulfate, filtered and evaporated. The residue is recrystallized from ethanol. 5.0 g (54%) of 2-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-6-carboxylic acid ethyl ester are obtained, which melts at 93-94 ° C.

Analysis: C12H12N2O3:

Calc .: C 62.00%; H 5.00%; N 12.00%

Found: C 61.98%; H 5.01%; N 12.01%.

If 2-aminopyridine-5-carbonic acid ethyl ester is used as the starting material, the 2-methyl-4-oxo-4H-pyrido- [l, 2-a] pyrimidine which melts at 127-128 ° C. is obtained in 33% yield -7-carboxylic acid ethyl ester.

Analysis: C12H12N2O3:

Calc .: C 62.00%; H 5.00%; N 12.00%

Found: C 61.81%; H 5.12%; N 12.10%.

If one starts from ethyl 2-aminopyridine-4-carboxylate, 2-methyl-4-oxo-4H-pyrido [1,2-alpyrimidine-8-carboxylic acid ethyl ester, which melts at 135-137 ° C., is obtained in 69% yield .

Analysis: C12H12N2O3:

Calc .: C 62.00%; H 5.00%; N 12.00%

Found: C 62.12%; H 5.21%; N 12.04%.

Using 2-amino-pyridine-3-carboxylic acid ethyl ester, the 2-methyl-4-oxo-4H-pyrido [l, 2-a] pyrimidine-9 melting at 222-223 ° C. is obtained with a yield of 5% -Carboxylic acid obtained.

Analysis on the formula C10H8N2Q3:

Calc .: C 58.72%; H 3.95%; N 13.72%

Found: C 58.84%; H 3.68%; N 13.51%.

Example 9

1.66 g of 2-aminopyridine-5-carboxylic acid ethyl ester and 2.5 ml of benzoylacetic acid ethyl ester are stirred in 10 g of polyphosphoric acid at 100-110 ° C. for three hours. The reaction mixture is cooled to room temperature and diluted with 20 ml of water. The solution is neutralized with 5% aqueous sodium hydroxide solution and then shaken out with chloroform. The organic phase is dried over sodium sulfate, filtered and evaporated. 1.1 g (37%) of 2-phenyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid ethyl ester are obtained, which melts at 136-137 ° C. after recrystallization from ethanol.

Analysis: C17H14N2O3:

Calc .: C 69.39%; H 4.80%; N 9.52%

Found: C 69.51%; H 4.79%; N 9.48%.

Example 10

0.98 g of 3-phenyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carbonic acid ethyl ester are dissolved in 10 ml of acetic acid and in the presence of 0.4 g of 10% palladium activated carbon at room temperature and hydrogenated under atmospheric pressure. After the calculated 2 moles of hydrogen have been taken up, the catalyst is filtered off and the filtrate is evaporated under reduced pressure. 0.8 g (80%) of 3-phenyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid, ethyl acetate, are not in the form of a pale yellow receive critical oils.

Analysis: C17H18N2O3:

Calcd .: C 68.44%; H 6.08%; N 9.39%

Found: C 68.03%; H 6.15%; N 9.45%.

Example 11

14.5 g of 4-oxo-4H-pyrido [1,2-a] pyrimidine-3,8-dicarboxylic acid rediethyl ester are hydrogenated in 200 ml of acetic acid in the presence of 5 g of 10% palladium-activated carbon catalyst. After 3 moles of hydrogen have been taken up, the catalyst is filtered off and the filtrate is evaporated under reduced pressure. 12 g (81%) of 4-oxo-1,6,7,8,9,9a-hexahydro-4H-pyrido [1,2-a] -pyrimidine-3,8-dicarboxylic acid diethyl ester are obtained,

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which melts at 227-228 ° C after recrystallization from ethanol.

Analysis: C14H18N2O5:

Calc .: C 56.75%; H 6.80%; N 9.45%

Found: C 57.01%; H 6.82%; N 9.35%.

Example 12

2.98 g of 3-phenyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-9-carbonic acid ethyl ester are dissolved in 1300 ml of ethanol and in the presence of 0.5 g of a 10% palladium-activated carbon catalyst at atmospheric pressure and hydrogenated at room temperature. After the calculated amount (2 mol) of hydrogen has been taken up, the catalyst is filtered off and the solution is evaporated under reduced pressure. 2.76 g (90%) of 3-phenyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] -pyrimidine-9-carboxylic acid ethyl ester, m.p. 119-123 ° C after recrystallization from ethanol.

Analysis: C17H18N2O3:

Calcd .: C 68.44%; H 6.08%; N 9.39%

Found: C 68.20%; H 6.07%; N 9.41%.

If the starting material is replaced by 3-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-9-carboxylic acid ethyl ester in the same process, 3-methyl-4-oxo-6,7,8 is obtained , 9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-9-carboxylic acid, ethyl ester; M.p. 147-149 ° C (78%).

Analysis: C12H16N2O3:

Calc .: C 61.00%; H 6.82%; N 11.85%

Found: C 61.14%; H 6.90%; N 11.76%.

If 4-oxo-4H-pyrido [1,2-a] pyrimidine-3,9-dicarboxylic acid diethyl ester is used as the starting material, 4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2- a] Pyrimidine-3,9-dicarboxylic acid diethyl ester, mp. 156-158 ° C (83%).

Analysis: C14H18N2O5:

Calc .: C 57.13%; H 6.16%; N 9.52%

Found: C 57.04%; H 6.21%; N 9.55%.

Example 13

4.35 g of 4-oxo-4H-pyrido [1,2-a] pyrimidine-3,7-dicarboxylic acid rediethyl ester are dissolved in 1500 ml of ethanol and in the presence of 0.5 g of a 10% palladium-activated carbon catalyst under atmospheric pressure at room temperature hydrated. After the calculated amount (2 mol) of hydrogen has been taken up, the catalyst is filtered off and the solution is evaporated under reduced pressure. 3 g (68%) of 4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3,7-dicarboxylic acid diethyl ester are obtained in the form of a pale yellow oil.

Analysis: CmHisNjOs:

Calc .: C 57.13%; H 6.16%; N 9.52%

Found: C 57.25%; H 6.07%; N 9.83%.

If 4-oxo-4H-pyrido [1,2-a] pyrimidine-3,6-dicarboxylic acid diethyl ester is used as the starting material, 4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1 , 2-a] pyrimidine-3,6-dicarboxylic acid diethyl ester as a pale yellow oil (yield 90%).

Analysis: C14H18N2O5:

Calc .: C 57.13%; H 6.16%; N 9.52%

Found: C 56.95%; H 6.20%; N 9.34%.

Example 14

The procedure is as described in Example 6, but the starting material used is 2 - [(3-ethoxycarbonyl-2-pyridyl) aminomethylene] succinic acid ethyl ester (melting point of the cis-trans isomer mixture 41-58 ° C.). In 34% yield, 9-ethoxycarbonyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-3-acetic acid ethyl ester is obtained, which melts at 134-136 ° C.

Analysis: C15H16N2O5:

Calc .: C 59.21%; H 5.30%; N 9.21%

Found: C 59.35%; H 5.27%; N 9.20%.

Example 15

The procedure is as described in Example 12, but the starting material used is 6-ethoxycarbonyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-3-acetic acid ethyl ester. 9-Ethoxycarbonyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-acetic acid ethyl ester is obtained in 80% yield. The compound obtained is a white-yellow oil.

Analysis: C15H20N2O5:

Calc .: C 58.43%; H 6.54%; N 9.09%

Found: C 58.25%; H 6.66%; N 9.40%.

Example 16

The procedure is as described in Example 12, but the starting material used is 9-ethoxycarbonyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-3-carbonitrile. In a 75% yield, 9-ethoxycarbonyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-3-carbonitrile is obtained, which after recrystallization from ethanol at 197-200 ° C melts.

Analysis: C12H13N3O3:

Calc .: C 58.29%; H 5.30%; N 17.00%

Found: C 58.15%; H 5.28%; N 16.91%.

Example 17

The procedure is as described in Example 12, but the starting material used is 4-oxo-4H-pyrido [1,2-a] pyrimidine-3,8-dicarboxylic acid diethyl ester. In 71% yield, 6,7,8,9-tetrahydro-4-oxo-4H-pyrido [1,2-a] pyrimidine-3,8-dicarboxylic acid, diethyl ester is obtained, which after recrystallization from ethanol at 136-137 ° C melts.

Analysis: C14H18N2O5:

Calc .: C 57.13%; H 6.16%; N 9.52%

Found: C 57.05%; H 6.21%; N 9.65%.

Example 18

The procedure is as described in Example 12, but the starting material used is 3-acetyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-9-carboxylic acid ethyl ester. 3-Acetyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine-9-carboxylic acid ethyl ester is obtained in 82% yield, which after recrystallization from ethanol at 200-202 ° C melts.

Analysis: C13H16N2O4:

Calc .: C 59.08%; H 6.10%; N 10.60%

Found: C 59.05%; H 6.12%; N 10.50%.

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Claims (12)

642368 2-Methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-6-carboxylic acid, as compounds according to claim 1. 2-methyl-8-ethoxycarbonyl-4-oxo-4H-pyrido- [l, 2-a] pyrimidine, 2-methyl-7-ethoxycarbonyl-4-oxo-4H-pyrido- [l, 2-a] pyrimidine, 2-methyl-6-ethoxycarbonyl-4-oxo-4H-pyrido- [l, 2-a] pyrimidine, 2. Compounds according to claim 1, in which R represents hydrogen, a methyl or ethyl group, there is a double bond between the atoms N i and C9a, R1 represents a lone pair of electrons, R2 represents hydrogen or an alkyl group with 1-4 carbon atoms, in particular is a methyl group and R3 is hydrogen, an alkyl group with 1-4 carbon atoms, a phenyl group, alkoxycarbonyl group with 1-4 carbon atoms, nitrile group or alkanoyl group with 1-4 carbon atoms. 2nd PATENT CLAIMS 1. Compounds of general formula I R1 l ROOC 0 wherein R represents hydrogen or an alkyl group with 1-4 carbon atoms and R1 in the event that the broken line between the atoms N i and Oa means a valence bond, i.e. there is a double bond between N 1 and C? a, stands for a lone pair of electrons, for hydrogen atom or for alkyl group with 1-4 carbon atoms and salt formation occurs on the positively charged nitrogen atom, and R 'in the event that there is a single bond between Ni and Csa is hydrogen or alkyl group with 1-4 carbon atoms, R2 represents hydrogen, an alkyl group with 1-4 carbon atoms or phenyl group and R3 for hydrogen, halogen, an alkyl group with 1-4 carbon atoms, a phenyl group, an aralkyl group with 7-12 carbon atoms, for a carboxylic acid group, an alkoxycarbonyl group with 1-4 carbon atoms, an aminocarbonyl, carbohydrazide, nitrii- or halocarbonyl group , represents a group of the general formula - (CH2) n-COOR4, where n = 1, 2 or 3 and R4 denotes hydrogen or an alkyl group with 1-4 carbon atoms, R3 furthermore denotes a nitro, amino, benzoyl or an alkanoyl group with 1-4 carbon atoms, and the broken lines mean any valence bonds present, provided that R2 and R3 cannot simultaneously represent alkyl groups with 1-4 carbon atoms and in the event that R3 is hydrogen and R2 is Is methyl group, the group -COOR has a different meaning than 9-carboxyl, 9-methoxycarbonyl or 9-ethoxycarbonyl group, and the salts and quaternary salts of these compounds. 3-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-9-carboxylic acid, ethyl ester, 3-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-8-carboxylic acid, ethyl ester, 3-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid, ethyl ester, Ethyl 3-methyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-6-carboxylate, 3-phenyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-9-carboxylic acid, ethyl ester, 3-phenyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-8-carboxylic acid, ethyl ester, 3-phenyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylic acid, ethyl ester, 3-phenyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-6-carboxylic acid, ethyl ester, Ethyl 3-cyano-4-oxo-4H-pyrido [1,2-a] pyrimidine-9-carboxylate, 3-cyano-4-oxo-4H-pyrido [1,2-a] pyrimidine-8-carboxylic acid, ethyl ester, Ethyl 3-cyano-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylate, Ethyl 3-cyano-4-oxo-4H-pyrido [1,2-a] pyrimidine-6-carboxylate, 3-acetyl-4-oxo-4H-py rido [1,2-a] py rimidin-9-carboxylic acid, ethyl ester, 3-acetyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-8-carboxylic acid, ethyl ester, Ethyl 3-acetyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-7-carboxylate, 3-acetyl-4-oxo-4H-pyrido [1,2-a] pyrimidine-6-carboxylic acid ethyl ester, 3. 4-oxo-4H-pyrido [1,2-a] pyrimidine-3,7-dicarboxylic acid, diethyl ester, 4. Process for the preparation of the compounds of general formula Ia ROOC O wherein R and R2 have the meaning given in claim 1 and R5 for hydrogen, an alkyl group with 1-4 carbon atoms, a phenyl group, an aralkyl group with 7-12 carbon atoms, a carboxylic acid group, an alkoxycarbonyl group with 1-4 carbon atoms, or a nitrile group, for a group of the general formula - (CH2) n - COOR4 wherein the meaning of n and R4 is the same as in claim 1, represents an alkanoyl group with 1-4 carbon atoms or a benzoyl group, R6 has the meaning carboxylic acid group or alkoxycarbonyl group and K stands for a leaving group, is implemented and the condensation product of the general formula IV obtained aooc I 1 R1 ^ ^ nkSs-nh-C = C ' sr " Diethyl 4-oxo-4H-pyrido [1,2-a] pyrimidine-3,6-dicarboxylic acid, Diethyl 4-oxo-4H-pyrido [1,2-a] pyrimidine-3,8-dicarboxylic acid, Diethyl 4-oxo-4H-pyrido [1,2-a] pyrimidine-3,9-dicarboxylic acid, 5. The method according to claim 4, characterized in that as the starting compound of general formula III acetoacetic acid, benzoylacetic acid, Äthoxymethylenma-lonic acid, Äthoxymethylenacetacetic acid, Äthoxymethylen- ROOC 0 Ib in which the meaning of R and R2 is the same as in claim 1 and R5 has the meaning given in claim 4, characterized in that a compound of the general formula Ia is prepared according to the process according to claim 4 and the compound obtained is catalytic hydrated. 13. The method according to claim 12, characterized in that palladium, platinum, rhodium or Raney nickel is used as the catalyst in the hydrogenation. 14. Process for the preparation of quaternary ammonium salts of the compounds of the general formula Ia, wherein the meaning of R and R2 is the same as in claim 1 and R5 has the meaning given in claim 4, characterized in that a compound of the general formula Ia is prepared according to the process according to claim 4 and a quaternary salt is obtained from the compound obtained forms. 15. Pharmaceutical preparation, characterized in that, together with solid or liquid carriers as active ingredient, compounds of the general formula I in which the meaning of R, R1, R2 and R3 and the dashed line 642 368 benzoylacetic acid, ethoxymethylene cyanoacetic acid, 2-formylpropionic acid, 2-formylphenylacetic acid, 2-formylsuccinic acid or the lower alkyl esters of these acids. 5 6. The method according to claim 4 or 5, characterized in that one carries out the cyclization by heating, preferably not above 400 ° C. 7. The method according to any one of claims 4-6, characterized in that one carries out the ring closure in the presence of an inert solvent. 8. The method according to any one of claims 4-7, characterized in that diphyl, trichlorobenzene, paraffin oil or petroleum fractions are used as the inert solvent. 9. The method according to claim 4 or 5, characterized in that one carries out the ring closure in the presence of an acidic condensing agent. 10. The method according to claim 9, characterized in that the acidic condensing agent used is phosphorus oxychloride, phosphorus oxybromide, phosphorus trichloride, thionyl chloride, hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, polyphosphoric acid ethyl ester or mixtures of the listed compounds. 10th .15 20th 25th 30th 35 40 45 50 55 60 65 wherein the meaning of R, R2, R5 and R6 is the same as above, cyclizes under the condition that R2 and R3 cannot simultaneously represent alkyl groups with 1-4 carbon atoms and in the event that R5 is hydrogen and R2 is methyl group stands, the group -COOR has a different meaning than 9-carboxyl, 9-methoxycarbonyl or 9-ethoxycarbonyl group, and the salts of these compounds, characterized in that 2-aminopyridine derivatives of the general formula II NH or their acid addition salts with compounds of the general formula III R2 c = c m K R " wherein the meaning of R in formula II and of R2 and R5 in formula III is the same as above, and optionally forms a salt from the compound of general formula I obtained or releases the compound from its salt. 11. A process for the preparation of the compounds of the general formula Ia, in which the meaning of R and R2 is the same as in claim 1 and R5 has the meaning given in claim 4, characterized in that a compound of the formula III given in claim 4 forms by reaction of the corresponding β-keto ester and trialkyl orthoformate, the compound obtained is reacted in situ with a pyridine derivative of the formula II given in claim 4 and the resulting condensation product of formula IV given in claim 4 is cyclized. 12. Process for the preparation of the compounds of the general formula Ib or Ic ROOC O Ic Lines is the same as in claim 1, or contains salts thereof.