A method of obtaining a 1-substituted-6-fluoro-4-oxo-7-(1 - piperazinil)-1,4-dihydro-quinoline-3 - carboxylic acid, 1 - substituted-6-fluoro-4-oxo-7-(4-substituted-1-piperazinil)-1,4 - dihydroquinoline-3-carboxylate-boron diacetate and method thereof

 

(57) Abstract:

A method of obtaining a 1-substituted-6-fluoro-4-oxo-7-(1-piperazinil)-1,4-dihydroquinoline-3-carboxylic acid of General formula II

< / BR>
in which R1represents a lower alkyl lower cycloalkyl on which the 1-substituted-6-fluoro-4-oxo-7-(4-substituted-1-piperazinil)-1,4-dihydroquinoline-3-carboxylate-boron diacetate General formula I

< / BR>
in which R2represents a lower alkyl subjected to alkaline hydrolysis. The compound of formula I is used in medicine to treat various inflammatory phenomena. The compound of formula I represents a fundamentally new connection. It is obtained by nucleophilic substitution of the halogen atom in the 7-imposition in connection formula III

< / BR>
when using 1-substituted piperazine

3 S. and 4 C.p. f-crystals.

The present invention relates to the field of organic chemistry and relates to a method of obtaining biologically active compounds 1-substituted-6-fluoro-4-oxo-7-(1-piperazinil)-1,4-dihydroquinoline-3 - carboxylic acid of General formula II

< / BR>
in which R1represents lower alkyl, lower cycloalkyl, a new intermediate product 1-substituted-6-fluoro-4-oxo-7-(4-SUB>1represents lower alkyl, lower cycloalkyl, and R2represents lower alkyl, as well as the method of obtaining this connection.

The compounds of formula II used in medicine for treatment of various inflammatory diseases. Their spectrum of activity is very wide as they have activity against both gram-positive and gram-negative bacteria.

The synthesis of compounds of General formula II are described in several patent publications, such as the substitution of chlorine in the 7-position of 1-substituted-6-fluoro-7-halogen-4-oxo-1,4-dihydroquinoline-3 - carboxylic acid piperazine described in the Japan patent 66686/1979 and 33453/1980 and patents Germany 2840910 and 3308909, and the hydrolysis reaction Olkiluoto ether at the 3-position of 1-alkyl-6-fluoro-7-(1-piperazinil)-4-oxo-1,4-dihydroquinoline-3 - carboxylic acid described in the patent Belgium 890223.

However, a characteristic feature of all these methods is that the reaction successfully substitution takes place only at temperatures above 100oC, which causes a large percentage of the competing reactions in the 6-position.

In ES 9001782 described nucleophilic substitution at the boron chelates, aluminum and silicon, in which the product substitution is not the separation of the Hungary 1505/87 also described nucleophilic substitution of the halogen atom in the 7-position chelate complex of boron, which takes place at temperatures above 100oC. In this case, the resulting product substitutions also do not emit, by hydrolysis directly after synthesis.

The objective of the invention is to develop a new method of obtaining biologically active 1-substituted-6-fluoro-4-oxo-7-(1-piperazinil)- 1,4-dihydroquinoline-3 - carboxylic acid, to reduce the output side of the product, as well as the creation of new intermediate - 1-substituted-6-fluoro-4-oxo-7-(4-substituted-1-piperazinil)- 1,4-dihydroquinoline-3-carboxylate-diacetate and method of its production. This object is achieved by this method lies in the fact that the compound of General formula I

< / BR>
in which R1has the above significance, and R2represents lower alkyl, are subjected to alkaline hydrolysis and, if necessary, the obtained compound of the formula I is converted into pharmaceutically acceptable salt is a product of accession acids, such as hydrochloride or lactate and their hydrates.

Alkaline hydrolysis is carried out in aqueous or aqueous-alcoholic medium, for example, with a solution of alkali metal hydroxide, such as 10% NaOH, at a temperature of from 50oC to temperature phlegmy, predpochtitelnei acid, get a product containing (without further purification) less than 0.5% impurities.

The task is also achieved new intermediate product, namely 1-substituted-6-fluoro-4-oxo-7-(4-substituted-1 - piperazinil)- 1,4-dihydro-quinoline-3-carboxylate-Bor-diacetate General formula I used as starting product in the above method of obtaining biologically active compounds of General formula II, and which is obtained by carrying out nucleophilic substitution of the halogen atom in the 7-position of the 1-substituted-6-fluoro-4-oxo-7-halogen-4-oxo-1,4-dihydroquinoline-3 - carboxylate-boron diacetate General formula III when using 1-substituted piperazine of General formula

< / BR>
in which R2has the above value.

The reaction is carried out in an organic solvent, for example pyridine, dimethylsulfoxide, dimethylformamide, 1-methyl-2-pyrrolidone, preferably 1-methyl-2-pyrrolidone at temperatures from 0 to 45oC, preferably at 25 - 30oC. In the specified temperature range the reaction is complete within 10 - 15 hours (when using 1-methyl-2-pyrrolidone as a solvent), without formation of side products, and hydrolysis of salts of boron not proishodivshem with increasing temperature. The resulting decomposition of the 3-carboxylic acid significantly less reaktsionnosposobnykh as nucleophilic substitution occurs at temperatures above 100oC.

Select the compound obtained of the formula I is very simple, since the deposition of alcohol will have the net connection that does not require additional purification.

The compound of General formula I used as starting material to obtain compounds of General formula II in the selected form or in situ.

All reaction components are either on sale, or obtained by the method described above.

Both are relevant to the invention of the method are illustrated by the following reaction scheme, in which X, R1and R2have the above meaning.

< / BR>
More in detail the invention is illustrated by the following examples, however, their description of the scope of the invention is not limited to.

Example 1. 1-cyclopropyl-6-fluoro-4-oxo-7-(4-carboethoxy-1 - piperazinil)-1,4-dihydroquinoline-3-carboxylate-boron diacetate.

1-cyclopropyl-6-fluoro-4-oxo-7-chloro-1,4-dihydroquinoline-3 - carboxylate-boron diacetate (10 g, 0,0244 moles) and 1-carbomethoxybiphenyl (15,44 g, 0,0977 moles) is suspended vinnova process in the reaction mixture was added absolute ethanol (60 ml) and continue stirring at room temperature for 2 hours. The precipitate is treated on a vacuum filter, washed with ethanol and dried in vacuum at 80oC. the Filtrate is cooled to 0 to 5oC, the precipitate is filtered under slight irritation, suspended in a mixture of 1-methyl-2-pyrrolidone/ethanol (2:1) and soaked for 2 hours, then treated in a vacuum filter and dried. The products obtained are combined. So get chromatographically pure 1-cyclopropyl-6-fluoro-4-oxo-7-(4-carboethoxy-1-piperazinil)-1,4 - dihydroquinoline-3-carboxylate-boron diacetate (10,75 g, 83%) with T. pl. 235-240oC.

Spectroscopic data analysis:

1H-NMR-spectrum (CF3COOH, TMS), shot using 300 merc device:

CH2(cyclopropyl) = 1,29(m, J=8 Hz, 2H), CH3= 1,30(T, J=8 Hz, 3H), CH2(cyclopropyl) = 1,52(m, J=8 Hz, 2H), CH3= 2,03 (s, 6H), CH2(piperazinil) = 3,42 (m, 4H), CH2(piperazinil) = 3,74 (m, 4H), CH(cyclopropyl) = to 3.73(m, J = 8 Hz, 1H), OCH2= 4,2 (q, J = 8 Hz 2H), H8= 7.48 ppm (d, J = 8 Hz, 1H), H5= 8,08 (d, J = 14,3 Hz, 1H), H2= 9.0 ppm (s, 1H).

IR-spectrum:

1700, 1630, 1480, 1370, 1275, 1240, 1060, 960 cm-1.

Example 2. 1-ethyl-6-fluoro-4-oxo-7-(4-carboethoxy-1 - piperazinil)-1,4-dihydroquinoline-3-carboxylate-Bor-diacetoxybiphenyl (of 3.78 g, 0,024 mole) is suspended in 1-methyl-2-pyrrolidone (9,5 ml) and stirred at 30oC for 9 hours. After completion of the reaction process to the reaction mixture add absolute ethanol (19 ml) and continue stirring at room temperature for 2 hours. The resulting product is treated in a vacuum filter, washed with ethanol and dried in vacuum at 80oC. are Thus obtained 1-ethyl-6-fluoro-4-oxo - 7-(4-carboethoxy-1-piperazinil)-1,4-dihydroquinoline-3-carboxylate - boron diacetate (2.7 g, 87%) with T. pl. 235-238oC.

Spectroscopic data analysis:

1H-NMR-spectrum (CF3COOH, TMC), shot using 60 merc device:

CH3= 1,53(t, J=7 Hz, 3H), CH3= 1,97(t, J=7 Hz, 3H), CH3= 2,4(s, 6H), CH2(piperazinil) = 4,0 (m, 8H), NCH2= 4,53 (kV, J=7 Hz, 2H), OCH2= 5,03 (kV, J=7 Hz, 2H), H8= 7.7 (d, J = 6 Hz, 1H), H5= 8,4 (d, J = 12 Hz, 1H), H2= 9.6 ppm (s, 1H).

19F-NMR spectrum (CF3COOH, CFCl3), shot using 60 merc device:

F= -114,0 ppm (DD, J = 12 Hz, 6 Hz).

These IR spectrum:

1777, 1635, 1490, 1375, 1285, 1240, 1060, 970 cm-1.

Example 3. 1-cyclopropyl-6-fluoro-4-oxo-7-(1-piperazinil)-1,4 - dihydroquinoline-carboxylat-boron diacetate (10 g, 0,0188 moles) is suspended in 10% KOH (187 ml) and refluxed for 1.5 hours. Then the reaction mixture is cooled to room temperature with acetic acid, establish a pH level of 7.2 to 7.4. The reaction mixture is stirred for 30 minutes, the precipitate is treated on a vacuum filter, washed with ethanol and dried. Get 1-cyclopropyl-6-fluoro-4-oxo - 7-(1-piperazinil)-1,4 - dihydroquinoline-3-carboxylic acid (5,95 g, 96%) with T. pl. 258-263oC.

Example 4. Hydrochloride.over 1-cyclopropyl-6-fluoro-4-oxo - 7-(1-piperazinil)-1,4-dihydroquinoline-3-carboxylic acid.

1-cyclopropyl-6-fluoro-4-oxo-7-(4-carboethoxy-1-piperazinil)- 1,4-dihydroquinoline-3-carboxylate-boron diacetate (3 g, 0,0056 moles) is suspended in 10% KOH (56 ml) and refluxed for 1.5 hours. After completion of the reaction process, add concentrated HCl (8 ml) and heated at a temperature of 80oC for 30 minutes. After that the reaction mixture is cooled to room temperature, add ethanol (14 ml), continue stirring for another 30 minutes. The resulting residue is treated using a vacuum filter, washed with water and dried to constant weight. Get 1-cyclopropyl-6-fluoro-4-oxo - 7-(1-PIR> Example 5. 1-ethyl-6-fluoro-4-oxo - 7-(1-piperazinil)-1,4 - dihydroquinoline-3-carboxylic acid.

1-ethyl-6-fluoro-4-oxo-7-(4-carboethoxy-1-piperazinil)- 1,4-dihydroquinoline-3-carboxylate-boron diacetate (1.04 g, of 0.002 moles) is suspended in 10% KOH (16 ml) and ethanol (12 ml), after which the mixture is refluxed for 11 hours. The mixture is then end of the reaction process, add concentrated HCl (8 ml) and heated at a temperature of 80oC for 30 minutes. After that the reaction mixture is cooled to room temperature, add ethanol (14 ml), continue stirring for another 30 minutes. The resulting residue is treated using a vacuum filter, washed with water and dried to constant weight. Get 1-cyclopropyl-6-fluoro-4-oxo - 7-(1-piperazinil)-1,4 - dihydroquinoline-3-carbonbearing hydrochloride-monohydrate (1.98 g, 92%) with T. pl. 282-288oC.

Example 5. 1-ethyl-6-fluoro-4-oxo-7-(1-piperazinil)- 1,4-dihydroquinoline-3-carboxylic acid.

1-ethyl-6-fluoro-4-oxo-7-(4-carboethoxy-1-piperazinil)- 1,4-dihydroquinoline-3-carboxylate-boron diacetate (1.04 g, of 0.002 moles) is suspended in 10% KOH (16 ml) and ethanol (12 ml), after which the mixture is refluxed for 11 hours. The mixture is then cooled to 15oC, with the so The precipitate is placed on a vacuum filter, washed with water and dried to constant weight in a vacuum dryer at a temperature of 100oC. Receive 1-ethyl-6-fluoro-4-oxo - 7-(1-piperazinil)-1,4 - dihydroquinoline-3-carboxylic acid (0.6 g, 93%) with T. pl. 218 to 221oC.

1. A method of obtaining a 1-substituted-6-fluoro-4-oxo-7-(1-piperazinil)-1,4-dihydro-quinoline-3-carboxylic acid of General formula II

< / BR>
in which R1represents lower alkyl, lower cycloalkyl or its pharmaceutically acceptable salt is the product of the merger acids, such as hydrochloride or lactate or their hydrates, characterized in that the compound of General formula I

< / BR>
in which R1has the above significance, and R2represents lower alkyl, are subjected to alkaline hydrolysis, and, if necessary, the obtained compound of General formula II is converted into pharmaceutically acceptable salt is a product of accession acids, such as hydrochloride or lactate and their hydrates.

2. 1-Substituted-6-fluoro-4-oxo-7-(4-substituted-1-piperazinil)-1,4-dihydro-quinoline-3-carboxylate-boron diacetate General formula I

< / BR>
in which R1represents lower alkyl, lower cycloalkyl and R2represents the bottom of the Olin-3-carboxylate-boron diacetate General formula I

< / BR>
in which R1represents lower alkyl, lower cycloalkyl and R2represents lower alkyl, wherein the 1-substituted-6-fluoro-7-halogen-4-oxo-1,4-dihydro-quinoline-3-carboxylate-boron diacetate General formula III

< / BR>
in which X represents F or Cl, and R1has the above value, nucleophilic substitution of the halogen atom in the 7-position is carried out using a 1-substituted piperazine of the formula

< / BR>
in which R2has the above values.

4. The way of getting p. 1, wherein the process is carried out in water or atenolo/aquatic environment.

5. A way of getting under item 1, characterized in that the reaction is carried out at temperatures from 50oWith up to temperature phlegmy reaction mixture.

6. The way of getting p. 3, characterized in that the reaction is carried out in an organic solvent, for example pyridine, dimethylsulfoxide, dimethylformamide, 1-methyl-2-pyrrolidone, preferably 1-methyl-2-pyrrolidone.

7. The way of getting p. 3, characterized in that the reaction is carried out in the range of reaction temperatures from 0 to 40oC, preferably from 20 to 30oC.

 

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(I)

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< / BR>
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EFFECT: valuable medicinal properties of compounds.

15 cl, 4 sch, 86 ex

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