DK152497B - METHOD FOR PREPARING 8-SUBSTITUTED 2-AMINO-5-OXO-5,8-DIHYDROPYRIDOOE2,3-DAAPYRIMIDINE-6-CARBOXYL ACID - Google Patents

Description

in

DK 152497 B

The present invention relates to a particular process for the preparation of 8-substituted 2-amino-5-oxocr5,8-dihydropyrido [2,3-d] pyrimidine-6-carboxylic acids of the general formula

^ rV00H

Æ. I II I (Ilia) '"R" lo R "5 which are remarkable antibacterial agents.

In this formula, R is an alkyl group having 1-5 carbon atoms, preferably 1-2 carbon atoms, a phenyl group or benzyl group, R and R 'which may be the same or different, each being hydrogen atoms or alkyl groups having 1-5 carbon atoms. or together with the nitrogen atom to which they are attached form a piperazinyl group, methyl-4-piperazinyl group, formyl-4-piperazinyl group, (4- (3-hydroxyethyl) -piperazinyl group or pyrrolidino group).

the process is characterized by employing an 8-substituted 2-alkylsulfonyl-6-carbalkoxy-5-oxo-5,8-dihydropyrido [2,3-d] pyrimidine of formula I

0 - J1 / COOE3 * - ΐ-χχΥ 12 3 wherein R, R and R, which may be the same or different, are alkyl groups having 1-5 carbon atoms, preferably 1-2 carbon atoms, and R may also be a phenyl group or benzyl group, with an amine of formula 'v 2

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wherein R and R 'have the above meaning, after which an 8-substituted 2-amino-6-carbalkoxy-5-oxo-5,8-dihydropyrido [2,3-d] pyrimidine of formula III is formed

il 3

[IN OOOR

/ 'E \ iTAlj (iii)' R '2

R

Wherein R, R ', R and R are as defined above, hydrolyzed.

The starting products, the 8-substituted 2-alkylsulfonyl-6-carbalkoxy-5-oxo-5,8-dihydropyrido [2,3-d] pyrimidines of formula I, are distinguished by their high reactivity, 10 due to the attraction effect of the alkylsulfonyl group.

For this reason, they can be involved in numerous nucleophilic reactions. In particular, they react with ammonia and primary and secondary fatty amines or heterocyclic amines and in very good yields yield 8-substituted 2-amino-6-carbalkoxy-5,8-dihydropyrido [2,3-d] pyrimidines and their 2 -monoalkylamino or 2-dialkylamino derivatives (III) according to the reaction scheme: (OC

'~ R' * -R * I

R2 In2 (I) R (III) 12 3 In these formulas, R, R, R, R and R * have the meanings given above.

20 Hydrolysis of esters (III) yields similar acids (IIa), some of which are valuable antibacterial agents for the treatment of Gram-negative bacteria diseases already described in French Patent No. 2,194,420.

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3

In spite of the high reactivity of the alkyl sulfonyl derivative, the process is preferably carried out in that the reaction between the alkyl sulfonyl derivative (I) and the amine is carried out at a temperature between 60 and 120 ° C, thereby obtaining a better reaction rate.

It is noteworthy that the reactivity of the methylsulfonyl group is such that one can easily work in polar solvents. Therefore, according to the invention, the reaction is preferably carried out in a solvent which allows 10 complete dissolution of. the reaction moieties, especially an alkyl alcohol having 1-5 carbon atoms.

The reaction is carried out using the amine in excess of the sulfone, e.g. 2 moles of amine per ml. mole of sulfone. Equimolecular amounts of the two reaction participants may also be used in the presence of at least one mole of a basic agent, e.g. a tertiary amine such as triethylamine per mole of sulfone.

The amount of solvent used is such that the reaction participants are present therein at a concentration between 10 and 25%.

In general, the reaction is completed after a duration of heating between 1 and 5 hours. The aminated derivatives 20 (III) are isolated according to their solubility properties using ordinary methods described in the following examples.

In the case of reacting ammonia or amines with boiling point lower than the temperature required for the reaction to react, one can work in autoclave with an excess of amine. However, it is possible and particularly interesting to carry out this operation at usual pressure by bubbling a stream of gaseous ammonia or amine through the solution of the sulfone in the selected solvent which is kept under reflux.

A particularly interesting application of the process lies in the direct preparation of 6-carbethoxy-8-ethyl-5-oxo-2-pipe.

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4 reaction of 6-carbethoxy-8-ethyl-2-tertylisulfonyl-5-oxo-5,8-dihydropyrido [2,3-d] pyrimidine (V) with piperazine used in the form of hexahydrate:

° P

O ™ + - »» 3 XXX

i

C, H, C2H5 (V) 25 (IV) The ester (IV) is then hydrolyzed to the corresponding acid, which has excellent antibacterial properties.

It is well known that the ester (IV) cannot be obtained directly by the action of 6-carbethoxy-2-chloro-8-ethyl-5-oxo-5,8-di-hydropyrido [2,3-d] pyrimidine on piperazine. under normal conditions. Therefore, the high reactivity of the halogen atom does not, in fact, allow for a sufficiently selective reaction, and the main product of the reaction is the Ν, Ν'-disubstituted derivative of piperazine (IVbis). Therefore, preparation 15 of the ester (IV) necessitates passing the N-formylated derivative of piperazine, as described in Application No. 4229/73.

Hs ^ OCO. 'yeah. COOC2H5 / γγ

ί N A, NXj J

C „H [- (IVbis) C₂H5

Z D

In contrast, it is possible to obtain the ester (IV) with excellent yields directly by the action of the methyl sulfone (V) on piperazine hexahydrate.

Preferably, an excess (1.5-2 moles) of piperazine is employed relative to the sulfone (1 mole) and in the presence of an excess (2-5 moles) of an aliphatic tertiary base such as triethyl-5

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amine. The piperazine and the tertiary base in solution (concentration of the reaction participants 10-20%) in an alkyl alcohol, e.g. . ethanol, stirred and heated at reflux. Drops are added over approx. 1 hour a solution of the sulfone (V) (.1 mo]) in 3-5 volumes of a suitable solvent, e.g. dimethylformamide (DMF). After addition is complete, the reaction is terminated by continuing to reflux for 30 minutes to 1 hour. The solvents are evaporated in vacuo. The residue is dissolved in a dilute solution of a mineral acid or strong organic acid (e.g., methanesulfonic acid). A small amount of undissolved substance is separated by filtration. The solution is made alkaline by the addition of an alkali metal carbonate and the reaction product is extracted with a suitable solvent, e.g. chloroform. Evaporation of the solvent leaves as the residue ester (IV). Purified by recrystallization in benzene it is obtained with a yield of approx. 80%.

It is known that 2-position amination reactions in the nucleus of the pyrido [2,3-d] pyrimidine derivatives can be performed by the action of the amines on the 2-methylmercapto derivatives or on the 2-chloro derivatives.

The use of alkylsulfonylated derivatives of the invention is a considerable technical advance. In fact, the alkylsulfonylated groups have a reactivity which lies between the reactivity of the alkyl mercapto groups (the least reactive) and the halogen derivatives (the most reactive).

Compared to the 2-alkyl mercapto derivatives, the alkyl-sulfonyl derivatives enable the amination reactions to be carried out at lower temperatures and to avoid working under pressure. Des-30 without causing reactions with the former development of toxic mercaptans and unpleasant odors. The reactions of the latter are odorless, which is another advantage from a pollution point of view. 1 relative to 2-halogenated derivatives allows the smaller 6

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mobility of the sulfonyl group to work with several different solvents and, in particular, as the example of piperazine shows, to achieve a greater selectivity in the case of complex reactions.

The starting products are novel compounds of the following general formula (I) 0 3

11 COOR

Wherein R, R, and R, which may be the same or different, are alkyl groups having 1-5 carbon atoms, preferably 1-2 carbon atoms, and R 1 otherwise may be a phenyl group or benzyl group.

These products can be obtained from an 8-substituted 2-alkyl mercapto-6-carbalkoxy-5-oxo-5,8-dihydropyrido [2,3-d] pyrimidine of formula (II) 9 ·,

11 COOR

»V / 15 H1 - s - (II) 12 in particular a 2-alkyl mercapto-β-earbethoxy-8-ethyl-5-oxo-5,8 dihydropyrido [2,3-d] pyrimidine (IIa), upon oxidation with a mild oxidizing agent commonly used for this purpose such as potassium permanganate, potassium bi-chromate or oxygen. However, it is most convenient to use a halogen, especially chlorine, in aqueous medium. In the latter case, the reaction can be schematized as follows: 0 ° 7

DK 152497B

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N ιΓιι f II i R1-S — L Ji jJ + 2C1_ + 2H00- ^ R1-S0 „-k * X J„ 2 2 2 N + 2 HC1 I | (IIa) C 2 H 5

The reaction is carried out by passing a stream of gaseous chlorine at a temperature between 0 and 25 ° C into a vigorously stirred aqueous suspension of the 2-alkyl mercapto derivative (II), 5 until the weight increase of the reaction mixture corresponds to 90-105% of the theoretical halogen mass. , which can be calculated from the previous equation, or 2 moles of halogen to 1 mole of alkylmercapode derivative (II).

When this weight gain is achieved, the halogen supply is stopped and the reaction is allowed to proceed with stirring at a temperature between 0 and 25 ° C until complete conversion of the starting material, which, depending on the conditions, requires 10 minutes. 1 hour.

After any dilution by adding water, the solid reaction product is air dried, washed and recrystallized in a suitable solvent.

During this oxidation, it is necessary to avoid the use of a large excess of halogen, which favors the formation of by-products, and which gives the risk of reducing the overall yield between 80 and 90%.

The course of the reaction depends on the nature of the medium: In water, the reaction is slow, probably due to the very poor solubility of the alkyl mercapto derivatives (II). Therefore, it is most convenient to use aqueous solutions diluted with water-soluble organic solvents, such as lower alcohols and especially methanol, or acetic acid.

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8

These solubilizing additives can be used at concentrations between 5 and 50%.

With concentrations of additives above 20%, a transient or definitive solution of the alkyl mercapto derivative used can be observed during the oxidation reaction. At weaker concentrations (5-10%), the course of the reaction is expressed in a modification of the properties of the solid in suspension, which can be evaluated on samples of the latter by determining an appropriate physical constant, e.g. the melting point.

Instead of chlorine gas, any other method which allows the release of halogen in the native state in the reaction medium, e.g. alkali metal hypchlorites or oxygenerated water acting on one suspension of the compounds (II) in hydrochloric acid in the presence of soluble additives.

The following examples are given to illustrate the process of the invention, with Example 1 illustrating the preparation of the starting material used.

The products of Examples 2-5 and Example 7 have already been described in the aforementioned French patent, as are the acids 20 obtained by their hydrolysis.

Example 1 6-Carbethoxy-8-ethyl-2-methylsulfonyl-5-oxo-5,8-dihydropyrido [2,3-d] pyrimidine.

(formula I, R1 = CH3, R2 = C3).

In a 500 cm glass flask equipped with mechanical stirrer and thermometer and placed in an ice bath, vigorously stir 29.3 g (0.1 mole) of 6-carbethoxy-8-ethyl-2-methylmercapto-5-oxo-5.8 dihydro-3-dropyrido [2,3-d] pyrimidine in a solution of 15 cm acetic acid in 285 cm water, and a stream of chlorine is allowed at a rate such that the temperature remains between 10 and 15 ° C. .The flask with contents weighed before the introduction of the gas. veins at a regular intervals.

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When the weight gain is 13 g (theoretical for 2 moles of chlorine: 14.2 g), duration approx. 1 hour, the gas stream is stopped and the mixture is stirred for another 30 minutes at 10 ° C.

3

After adding 100 cm of water. The precipitate is air dried, washed with water, then with ethanol (2 x 35 cm) and dried in vacuo. 26.6 g (yield 81.8%) of 6-carbethoxy-8-ethyl-2-methylsulfonyl-5-oxo-5,8-dihydropyrido [2,3-d] pyrimidine are obtained, m.p. 176 ° C. A sample recrystallized from isopropanol maintains the same melting point.

Analysis for C ^ HH-jNgO₂S (325.27)

Calculated% C 48.00 H 4.65 N 12.92 S 9.82 Found% C 47.83 H 4.74 N 13.20 S 9.65 In the following Examples 2-7, the product of this Example 1 is used as intermediate for the preparation of the 8-substituted 2-amino-5-oxo-5,8-dihydropyrido [2,3-d] pyrimidine-6-carboxylic acids, the antibacterial action of which is known.

Example 2

A solution of piperazine hexahydrate (3.9 g, 0.02 mol) and 3 triethylamine (2.02 g, Q, Q2 mol) in 50 cm of ethanol is heated to reflux. M: an added 3.25 g (0.02 mole) of 6-carbethoxy-8-ethyl-2-methylsulfonyl-5- OXO-5,8-dihydropyrido [2,3-d] pyrimidine dropwise over 1 hour. from Example 1 in solution in 15 cm DMF.

The solvents are evaporated in vacuo and the residue is taken up in 20 cm 1.5 N HCl. Slightly insoluble matter is removed by chloroform extraction. The aqueous solution is made alkaline by the addition of Na 2 O 4 and the reaction product is extracted with chloroform (5 x 10 cm). The organic extracts are combined and the solution is decolorized by stirring with animal charcoal and filtered. Evaporation gives 2.65 g (yield 80%) of 6-carbethoxy-8-ethyl-2-piperazinyl-5-oxo-5,8-dihydropyrido

DK 152497B

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[2,3-d] pyrimidine, mp 156 ° C

Analysis for ci6H2iN5 ° 3 (331.37)

Calculated% C 57.99 H 6.39 N 21.14 Found% C 57.98 H 6.23 N 21.39 5 The hydrolysis of this ester gives the corresponding acid. To 3.65 g of the ester in suspension in 30 cm 75% ethanol is added 3 22 cm 1 IN sodium carbonate and the mixture is stirred for 2 hours and 30 minutes at ambient temperature. The solution is acidified 3 with 1.26 cm of concentrated acetic acid. After standing in a refrigerator, the precipitate is air dried, washed with alcohol and then dried in vacuo. There is obtained 2.29 g of 8-ethyl-2-piperazinyl-5-oxo-5,8-dihydropyrido [2,3-d] pyrimidine-6-carboxylic acid, m.p. 260-262 ° C (Kofler block) under decomposition.

Analysis for C 14 H 7 N 5 ° 3 (303.32) Calculated% C 55.43 H 5.65 N 23.09 Found% C 55.68 H5.67 N 23.25

Example 3 1.6 g of 6-carbethoxy-8-ethyl-2-methylsulfonyl-5-oxo-5,8-dihydropyrido [2,3-d] pyrimidine from Example 1 and 1 g of 1-methylpiperazine in 20 cm of isopropanol is heated at reflux for 1 hour. The solvent is evaporated in vacuo, the residue is taken up in 40 cm of a saturated solution of Na 2 CO, and the mixture is extracted with 4 x 10 6 ciri chloroform. The combined organic phases are evaporated. The residue was recrystallized from a mixture of isopropyloxide (1 volume) and benzene (1 volume) to give 1.36 g (yield 79%) of 6-carbethoxy-8-ethyl-5-oxo-2- (41-methylpiperazinyl) -5 8-dihydropyrido [2,3-d] pyrimidine, which melts in two temps. Melting point 146 ° C, then solidification and then melting point 158 ° C.

11 DK 152497 B

Analysis for c17 H23 N5 ° 3 (345.39)

Calculated S C 59.11 H 6.71 N 20.20

Found% C 59.23 H 6.68 N 20.42

Hydrolysis of this ester by adding a solution of 5N NaOH, stirring at 50-60 ° C for 2 hours at ambient temperature and acidifying to pH 6 with acetic acid gives 2- (4'-methyl-piperazinyl) -8-ethyl 5-oxo-5,8-dihydropyridc [2,3-d] pyrimidine-6-carboxylic acid, m.p. 227 ° C.

in Island

Analysis for ci 5 H] 9 N 5 ° 3 (317.34)

Calculated% C 56.77 H 6.04 N 22.07

Found% C 56.69 H 6.23 N 22.35

Example 4 10.7 g of 6-carbethoxy-8-ethyl-2-methylsulfonyl-5-oxo-5,8-dihydropyrido [2,3-d] pyrimidine (0.03 mol) described in Examples 1, 7 , 8 20 2 g of β-hydroxyethylpiperazine (0.06 mol) and 100 cm of isopropanol are heated under reflux for 2 hours. After cooling, the mixture is added 50 cm of isopropyloxy. The precipitate is air dried, washed with 50 cm of a mixture of 30 volumes of isopropanol and 70 volumes of isopropyloxide. 10.2 g (yield 91%) of 6-carbethoxy-8-ethyl-5-oxo-2- (4-p-hydroxyethyl) -piperazinyl-5,8-dihydropyrido [2,3-d] are obtained. pyrimidine, m.p. 172 ° C.

Analysis for cigH25N5 ° 4 (375.42) 30

Calculated% C 57.58 H 6.71 N 18.60 Found% C 57.53 H 6.57 N 18.80

The saponification of this ester gives the corresponding acid. 10.2 g of 3 of the ester and 40 cm of ethanolic sodium carbonate are stirred for 2 hours at ambient temperature. The solution is neutralized with 2 cm of concentrated acetic acid. The precipitate is air dried, washed with water and recrystallized from ethanol. 8.6 g of 8-ethyl-5-oxo-2- (4-β-hydroxyethyl) -piperazinyl-5,8-dihydropylamide are obtained.

12 DK 152497 B

Analysis for ci6H2iN5 ° 4 (347.37)

Calculated% C 55.32 H 6.09 N 20.16

Pound% C 54.96 H 6.04 N 19.92 5

Example 5 In a glass flask equipped with reflux condenser and ammonia supply tubes, a reflux of 6.5 g (0.02 mol) of 6-carbethoxy-8-ethyl-2-methylsulfonyl-5-oxo-3,8,8-dihydropyrido is heated under reflux. 2,3-d] pyrimidine of Example 1 in 40 cm of ethanol under a rapid flow of NH The process is continued until the melting point of the solid (originally 176 ° C) becomes 265 C, which requires approx. 4 hours.

15 3

The mixture is cooled and 100 cm of water is added. The precipitate is air dried, washed with water and dried. There are obtained 3.04 g (57.5%) of 2-amino-6-carbethoxy-8-ethyl-5-oxo-5,8-dihydropyri-2Qdo [2,3-d] pyrimidine which is purified by recrystallization from ethanol. Melting point 266 ° C

Analysis for C12 H14 N4 ° 3 (262/26) Calculated% C 54.95 H 5.38 N 21.37

Found% C 55.35 H 5.58 N 21.17

Hydrolysis of this ester gives 2-amino-8-ethyl-5-oxo-5,8-dihydropyrido [2,3-d] pyrimidine-6-carboxylic acid, m.p. 292 ° C.

30

Example 6 1.6 g of 6-carbethoxy-8-ethyl-2-methylsulfonyl-5-oxo-5,8-dihydropyrido [2,3-d] pyrimidine and 1.6 g of pyrrolidine in 2Q cm of isopropanol are stirred. and heated at reflux. After dissolving the sulfone, the reaction product precipitates rapidly. The heating is continued for 1 hour, the mixture is cooled and the

Claims (6)

A process for the preparation of 8-substituted 2-amino-5-oxo-5,8-dihydropyrido [2,3-d] pyrimidine-6-carboxylic acids of the general formula Wherein is an alkyl group having 1-5 carbon atoms, preferably 1-2 carbon atoms, a phenyl group or benzyl group, R and R 1, which may be the same or different, each are hydrogen atoms or alkyl groups having 1-5 carbon atoms or together with the nitrogen atom to which they are attached form a piperazinyl group, methyl 4-piperazinyl group, formyl-4-piperazinyl group, (4- | 3-hydroxyethyl) - piperazinyl group or pyrrolidino group, characterized by reacting an 8-substituted 2-alkylsulfonyl-6-carbalkoxy-5-oxo-5,8-dihydropyrido [2,3-d] pyrimidine of the formula Rl_! fTj «χ» R I ^ nA n X 35. I 0 R2 Wherein R, R and R, which may be the same or different, are alkyl groups having 1 to 5 carbon atoms, preferably 1-2 carbon atoms, and R may additionally be a phenyl group or benzyl group having a amine of the formula 5 / "X 1> NH wherein R and R 'have the above meaning and then an 8-substituted 2-amino-6-carbalkoxy-5-oxo-5,8-dihydropyrido [2,3- d) pyrimidine of the formula III 0, 5, N COOR 3 Process according to claim 1, characterized in that the reaction between the alkylsulfonyl derivative (I) and the amine is carried out at a temperature between 60 and 120 ° C. Process according to claim 1, characterized in that the reaction is carried out in a solvent which allows complete dissolution of the reaction participants, especially an alkali carbon: down from 1 to 5 carbon atoms. 3 DK 152497B tea substance is air dried and washed with 2 x 5 cm ethanol. 1.38 g (yield 92%) of 6-carbethoxy-8-ethyl-5-oxo-2-pyrrolidino-5,8-dihydropyrido [2,3-d] pyrimidine, m.p. 202 ° C. this ester gives 8-ethyl-5-oxo-2-pyrrolidino-5,8-dihydropyrido [2,3-d] pyrimidine-6-carboxylic acid, mp 314 ° C. 1 o Process according to claim 1, characterized in that the reaction is carried out using an excess of amine of 1.5-2 moles per ml. moles of alkylsulfonyl derivative. Process according to claim 1, characterized in that the reaction is carried out in the presence of a basic agent, step by step, tertiary. alkylamine V - especially. triethylamine. DK 152497B Process according to claim 1, characterized in that 6-carbethoxy-8-ethyl-2-methylsulfonyl-5-oxo-5,8-dihydropyrido [2,3-d] pyrimidine is reacted with piperazine in the form of hexahydrate; to give 6-carbethoxy-8-ethyl-5-oxo-2-piperazinyl-5,8-dihydropyrido [2,3-d] pyrimidine which is hydrolyzed to give the corresponding acid. 10 20 25 30 35