HRP930084A2 - Production of 8-chloroquinoline derivative - Google Patents

Description

Field of invention

The invention relates to a process for the preparation of an 8-chloroquinolone derivative, which has potential antimicrobial activity and high safety, and which holds great promise as a synthetic antimicrobial agent.

Background of the invention

It is believed that the 7-substituted 8-chloro-1-(2-fluorocyclopropyl)-4-quinolone derivatives represented by formula (II) or (III) described below are useful as effective antimicrobial agents, as described in EP-A -0 341493 and JP-A-Hei-2-231475 (the term "JP-A", as used herein, means "unexamined published Japanese patent application").

These compounds were prepared from 3-chloro-2,4,5-trifluorobenzoic acid. As 3-chloro-2,4,5-trifluorobenzoic acid with high purity is relatively difficult to obtain due to the commensurate difficulties involved in its synthesis, it is considered that the process resulting from this compound is economically unsuitable.

Main properties of the invention

The purpose of the presented invention is to provide a process for the preparation of 8-chloroquinolone derivatives with simple and easy operations and with high economic efficiency.

As a result of extensive tests, the inventors have developed a process by which they can obtain 8-chloroquinolone derivatives simply and easily, achieving satisfactory yields and purity.

The presented invention provides a process for the preparation of the 8-chloroquinoline derivative indicated by formula (II)

[image]

where X represents a halogen atom, R1 represents a hydrogen atom, an alkyl group with 1 to 6 carbon atoms or a phenylalkyl group which may contain on the phenyl part a nitro group, a chlorine atom or an alkyl group, and R2 represents a 4- to 8-membered saturated heterocyclic group which contains as a ring member one or two nitrogen atoms, where this heterocyclic group may further contain as a ring member an oxygen atom or a sulfur atom and may have one or more substituents, selected from the group consisting of an amino group, a mono- or dialkylamino group with 1 to 6 carbon atoms in its alkyl part, alkylcarbonylamino groups with 2 to 7 carbon atoms, alkyloxycarbonylamino groups with 2 to 7 carbon atoms, haloalkylcarbonyl groups with 2 to 7 carbon atoms, haloalkyloxycarbonylamino groups with 2 to 7 carbon atoms, phenylalkyloxycarbonylamino groups which can have on the phenyl part a nitro group or a chlorine atom, an alkyl group with 1 to 6 carbon atoms, an alkylene a group with 2 to 6 carbon atoms, which together with the carbon atom that makes up the heterocyclic group can form a spiro ring, a halogen atom and an alkoxy group with 1 to 6 carbon atoms, which is indicated by dividing the quinolone compound represented by formula (I)

[image]

where X, R 1 and R 2 are the same as above, with a chlorinating agent.

The presented invention further provides a process for the preparation of the 8-chloroquinolone derivative represented by formula (III)

[image]

where X represents a halogen atom, R3 represents a 4- to 8-membered saturated heterocyclic group containing as a ring member one or two nitrogen atoms, where this heterocyclic group may further contain an oxygen atom or a sulfur atom as a ring member and may have one or more substituents selected from the group consisting of an amino group, a mono- or dialkylamino group with 1 to 6 carbon atoms in its alkyl part, an alkyl group with 1 to 6 carbon atoms, an alkylene group with 2 to 6 carbon atoms, which together with the carbon atom that composes a heterocyclic group, forms a spiro ring, a halogen atom and an alkoxy group with 1 to 6 carbon atoms, which is indicated by removing the protective group and/or hydrolyzing the ester group from the compound represented by formula (II).

Detailed description of the invention

As a result of extensive tests, the inventors managed to develop a procedure for preparing the compound of formula (II) with chlorination of the compound of formula (I).

Chlorinating agents that can be used in the present invention include sulfuryl chloride, sodium hypochlorite, N-chlorosuccinimide, chlorine and hypochlorous acid ester represented by formula (IV).

R4OCl (IV),

where R4 represents an alkyl group with 1 to 6 carbon atoms, a phenylalkyl group or a chlorophenylalkyl group.

Among the chlorinating agents presented above, hypochlorous acid ester is advantageous for the reasons described below.

Chlorination of the compound of formula (I), which has an amino group on its heterocyclic group R2, has the tendency to prepare it with external reactions, which result in a decrease in the yield and purity of the product, if the amino group is not protected. If we use the compound (I) with a protected amino group, two additional steps are required - the introduction of the protected group and the removal of the protected group. In addition to increasing the number of steps, the introduction and removal of the protected group has a tendency to cause unpleasant external reactions, which lead to further reductions in yield and purity.

In the course of studying the economic and simple synthesis of 8-chloroquinolone derivatives, we have now established that we can solve such a problem by using hypochlorous acid ester of formula (IV) as a chlorinating agent. That is, the use of the hypochlorous acid ester of formula (I) as a chlorinating agent enables the chlorinating agent of the compound of formula (I), which has an amino group on its heterocyclic group R 2 , to obtain the chlorinated compound of formula (II) with high yield and high purity. regardless of whether the amino group is protected or not.

The hypochlorous acid ester of formula (IV) includes alkyl esters, e.g., propyl esters (e.g., n-propyl hypochlorite and isopropyl hypochlorite), butyl esters (e.g., n-butyl hypochlorite, isobutyl hypochlorite, sec-butyl hypochlorite, and t-butyl hypochlorite ) and benzyl ester, where t-butyl hypochlorite is advantageous.

These hypochlorites are synthesized in the usual way, by partitioning alcohol from the salt of hypochlorous acid or by partitioning a mixture of alcohol and alkaline hydroxide (eg sodium hydroxide) with chlorine.

In the example, when the substituent R2 is further substituted with an amino group, we can protect that amino group with a protected group. Protecting groups that can be used for the amino group on R2 include alkylcarbonyl, alkoxycarbonyl, haloalkylcarbonyl, haloalkyloxycarbonyl, phenylalkyloxycarbonyl, and nitro- or chlorophenylalkyloxycarbonyl. Specific examples of protected groups are acetyl, chloroacetyl, 2,2,2-trichloroethyloxycarbonyl, p-nitrobenzyloxycarbonyl and p-chlorobenzyloxycarbonyl groups.

In formulas (I), (II) and (III), the heterocyclic group is derived from a cyclic amine, when R2 or R3 is a cyclic amino group.

A cyclic amine is a compound derived from an alicyclic compound with a carbon atom replacement, which forms a ring with a nitrogen atom. The cyclic amino group R2 is preferably a 4- to 7-membered ring and even more preferably a 5- or 6-membered ring, and may further contain an oxygen atom, a sulfur atom and/or a further nitrogen atom in its ring. Examples of such cyclic amino groups include oxazolidine, morpholine, thiazolidine, thiamorpholine, imidazolidine, pyrazolidine and piperazine, with pyrrolidine and piperazine being particularly preferred.

As we stated above, the cyclic amino group can contain substituent(s), such as polar groups (e.g. substituted or unsubstituted amino group, substituted or unsubstituted aminoalkyl group, 5-substituted 2-oxo-1,3-dioxlo-4-ylmethyl group and a hydroxyl group) and an unbranched, branched or cyclic alkyl group with 1 to 6 carbon atoms. Between these substituents there can be a polar group connected via an alkyl chain with up to 6 carbon atoms.

Preferred substituents of the above amino group include an alkyl group, an acyl group, and an alkyloxycarbonyl group. Polar groups include preferably an unsubstituted amino group, an aminomethyl group, a 1-aminoethyl group, and a hydroxyl group. The alkyl group as a substituent on the cyclic amino group preferably includes a methyl, ethyl, propyl, gem-dimethyl group. It is also advantageous that such an alkyl substituent forms a cyclopropane ring or a cyclobutane ring, so that it forms a spiro ring in combination with a cyclic amino group. Furthermore, there can be a 4- to 7-membered cyclic amino group cross-linked to the cyclic amino group so as to form a bicyclic amino group.

Favorable examples of these cyclic amino groups, especially with amino substituted cyclic amino groups, are shown below:

[image]

where the mentioned R5, R6, R7, R8, R9, R10, R11, R12, R13, R14 and R15 are each a hydrogen atom or an alkyl group with 1 to 6 carbon atoms and that R14 and R15 can be connected to each other and form a methylene chain, and to form a 3- to 6-membered ring, so that it represents a spirocyclic ring structure.

Specific examples of these nitrogen-containing heterocyclic groups are 3-aminopyrrolidinyl,

3-methylaminopyrrolidinyl, 3-dimethylaminopyrrolidinyl, 3-ethylaminopyrrolidinyl, 3-propylamino-pyrrolidinyl,

3-isopropylaminopyrrolidinyl, 3-amino-4-methylpyrrolidinyl, 4-amino-2-methylpyrrolidinyl, 4-amino-2,3-

dimethylpyrrolidinyl, 3-methylamino-4-methylpyrrolidinyl, 4-methylamino-2-methylpyrrolidinyl, 4-methylamino-2,3-

dimethylpyrrolidinyl, 3-dimethylamino-4-methylpyrrolidinyl, 4-dimethylamino-2-methylpyrrolidinyl, 4-dimethylamino-

2,3-dimethylpyrrolidinyl, 3-methylpiperazinyl, 4-methylpiperazinyl, 3,4-dimethylpiperazinyl,

3,5-dimethylpiperazinyl, 3,4,5-trimethylpiperazinyl, 4-ethyl-3,5-dimethylpiperazinyl, 4-isopropyl-3,5-

dimethylpiperazinyl, 3-aminomethylpyrrolidinyl, 3-methylaminomethyl-pyrrolidinyl, 3-(1-amino)ethylpyrrolidinyl,

3-(1-methylamino)ethylpyrrolidinyl, 3-(1-ethylamino)ethylpyrrolidinyl, 3-(1-amino)propylpyrrolidinyl,

3-(1-methylamino)propylpyrrolidinyl, 3-aminopyrrolidinyl, 4-amino-3,3-dimethylpyrrolidinyl, 7-amino-5-azaspiro [2,4]heptan-5-yl, 8-amino-6-azaspiro [3,4]octan-6-yl group, 1,4-diazabicyclo[3.2.1]octan-4-yl,

3,8-diazabicyclo[3.2.1]octan-3-yl, 8-methyl-3,8-diazabicyclo[3.2.1]octan-3yl and 8-ethyl-3,8-diazabicyclo[3.2.1] octan- 3-yl group.

Chlorination of the compound represented by formula (I) can be carried out in the usual way by dissolving compound (I) in a solvent and adding a chlorinating agent to the solution between cooling.

Solvents that we use for chlorination are not particularly limited and are capable of dissolving the starting compounds and are inactive towards the chlorinating agent. Such solvents include halogenated hydrocarbons, eg methylene chloride, chloroform, carbon tetrachloride and 1,2-dichloroethane, alkylcarboxylic acids, eg acetic acid and formic acid.

In addition, chlorosulfonic acid, alcohols (eg methanol, ethanol and propanol), acetonitrile, N,N-dimethylformamide and ethyl acetate are also usable. Formic acid and acetic acid are favorable from the point of view of dissolving ability and reaction acceleration effect.

Chlorination of the compound of formula (I) is carried out either in solution or suspension of compound (I) in a solvent, preferably in solution. The reaction is carried out at a temperature up to the reflux temperature of the solvent used, usually with cooling with ice or at room temperature (that is, at 0°C to 30°C).

The chlorinating agent is usually added in an amount of 1 to 2 molar equivalents in relation to the starting compound (I). If we use chlorine as a chlorinating agent, we can usually use it in excess.

The chlorination reaction in accordance with the present invention proceeds rapidly and is completed in about 5 minutes to about 10 hours and typically in about 5 minutes to about 2 hours with ice cooling.

The 8-chloroquinolone derivative of formula (III) can be obtained by hydrolyzing the resulting chlorinated compound of formula (II), where R1 is an alkyl group, in the usual way, for example with acid or alkaline hydrolysis. If R1 in formula (II) is a phenylmethyl group that can be substituted on its phenyl part with an alkoxy group (groups) with 1 to 6 carbon atoms, a nitro group or a chlorine atom, we can remove such an ester group in a known manner, also with the above-described hydrolysis or hydrogenolysis.

If R2 in the chlorinated compound of formula (II) has a protected amino group, we can remove the protected group with known procedures, such as catalytic reduction or acid or alkaline hydrolysis.

The desired 8-chloroquinoline derivative of formula (III) can be isolated from the reaction mixture by the usual chemical methods such as extraction, washing of the extract, separation with chromatography on a silica gel column, recrystallization and reprecipitation.

We will now explain the presented invention in more detail with reference examples and examples, of course it is understood that it should not be considered that the presented invention is thereby limited. All percentages are by mass, unless otherwise stated.

Reference example 1

7-(S)-amino-5-azaspiro[2,4]heptane dihydrochloride

A mixture of 6.07 g of 7-(S)-amino-5-benzyl-5-azaspiro[2,4]heptane, 7.5 ml of concentrated hydrochloric acid and 2.4 g of 5% palladium on charcoal (50% wet) in 200 ml of methanol was shaken under atmospheric hydrogen pressure for 20 hours. The catalyst was removed by filtration and the filtrate was concentrated to dryness under reduced pressure to obtain 5.13 g of the title compound in powder form. Melting point: 222 to 238°C (decomposition)

[α]D: -43.27° (c=0.537, H2O)

Elemental analysis of C6H12N2. 2HCl:

Calculated (%): C 38.93; H 7.62; N 15.13

Found (%): C 38.83; H 7.88; N 14.67

1H-NMR (D2O)δ: 0.9-1.3 (4H, m), 3.25 and 3.72 (1H, d, J=12.2 Hz, all), 3.68 and 3.82 (1H, dd, J=12.2, 2.9 Hz, all), 4.10 (1H, dd, J=7.3, 6.4 Hz).

Reference example 2

7-[7-(S)-amino-5-azaspiro[2,4]heptan-5-yl]-6-fluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1 monohydrochloride ,4-

dihydro-4-oxoquinoline-3-carboxylic acids

In 85 ml of acetonitrile we added 4.25 g of 6,7-difluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 3.33 g of 7- (S)-amino-5-azaspiro[2,4]heptane dihydrochloride and 10.5 ml of triethylamine and the mixture was heated at reflux for 2.5 hours. After cooling, the resulting precipitate was collected by filtration and suspended in 30 ml of water. We added 2.5 ml of concentrated hydrochloric acid to the suspension and stirred the mixture at room temperature for 1 hour. The crystalline substance in the suspension was collected by filtration, washed with water and dried, and we obtained 5.81 g of the title compound.

Melting point: 228 to 233°C (decomposition)

[α]D: -23.93° (c=0.449, 1N NaOH)

Elemental analysis of C19H19N3F2O3. HCl. 1/2H2O:

Calculated (%): C 54.22; H 5.03; N 9.98

Found (%): C 53.88; H 5.24; N 9.64

1H-NMR (NaOD)δ: 0.4-0.8 (4H, m), 1.4-1.7 (2H, m), 2.97 (1H, br s), 3.10 and 3.53 (1H, d, J=10.3 Hz, all), 3.15-3.3 (2H, m), 3.71 (1H), 5.05 (1H, br d, J=64.0 Hz), 6.40 (1H, d, J=7.3 Hz), 7.51 (1H, d J=15.1 Hz), 8.28 (1H, s).

Example 1

7-[7-(S)-t-butoxycarbonylamino-5-azaspiro[2,4]heptan-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluoro-1 -cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

[image]

We dissolved 120 mg of 7-[7-(S)-t-butoxycarbonylamino-5-azaspiro[2,4]heptan-5-yl]-6-fluoro-1-[(1R,2S)-2 in 20 ml of dichloromethane. -fluoro-1-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and added a solution of 40 mg of sulfuryl chloride in 5 ml of dichloromethane in drops over 5 minutes with stirring and cooling with ice. After the addition in drops, we continued mixing for another 10 minutes. Then, when we confirmed with thin-layer crocatography that the starting material had disappeared, the reaction mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate and water and dried over anhydrous sodium sulfate. Dichloromethane was removed from the mixture under reduced pressure. The residue was purified over a column filled with 10 g of silica gel, where we used a 9:1 mixture of chloroform and methanol as eluent (by volume), to obtain 101 mg of the title compound.

Melting point: 223 to 226°C

[α]D: -211.15° (c=0.771, chloroform)

Elemental analysis of C24H26ClF2N3O5:

Calculated (%): C 56.53; H 5.14; N 8.24

Found (%): C 56.67; H 4.95; N 8.14

The 1H-NMR spectrum of the product is identical to the published data.

Example 2

7-[7-(S)-amino-5-azaspiro[2,4]heptan-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl ]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

[image]

Between mixing and cooling with ice, 120 mg of 7-[7-(S)-t-butoxycarbonylamino-5-azaspiro[2,4]heptan-5-yl]-6-fluoro-1-[(1R, 2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and added the following amount of iodine. We introduced gaseous chlorine into the solution for 10 minutes and stirred the mixture for 1 hour. The reaction mixture was poured onto ice and water. The mixture was made alkaline once with a 1N aqueous sodium hydroxide solution and then adjusted to pH 7 with an aqueous citric acid solution. The mixture was extracted with three portions of 50 ml of chloroform and the extract was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was recrystallized from aqueous ethanol to obtain 45 mg of the title compound.

Melting point: 127.3 to 135.5°C

[α]D: -179° (c=1.12, 1N NaOH)

Elemental analysis of C19H18ClF2N3O3. 3/2H2O:

Calculated (%): C 52.24; H 4.85; N 9.61

Found (%): C 52.16; H 4.70; N 9.53

Example 3

7-[7-(S)-amino-5-azaspiro[2,4]heptan-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl )-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

[image]

We dissolved 3.09 g of 7-[7-(S)-amino-5-azaspiro[2,4]heptan-5-yl]-6-fluoro-1-[(1R,2S)-2 hydrochloride in 15 ml of formic acid. -fluoro-1-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and cooled the mixture so that the temperature of the solution was in the range of 5 to 10°C. We slowly added 1.25 g of t-butyl hypochlorite to the solution at that temperature in drops. After the addition, we stirred the reaction mixture for another 5 minutes and poured it into cold water and neutralized it with a 20% aqueous solution of sodium hydroxide. The precipitated crystals were collected by filtration, washed with water and dried, and we obtained 3.02 g of the title compound as pale yellow crystals.

Melting point: 221 to 226°C (decomposition)

[α]D: -209.7° (c=0.631, 1N NaOH)

Elemental analysis of C19H18ClF2N3O5. 3/2H2O:

Calculated (%): C 52.24; H 4.85; N 9.61

Found (%): C 52.31; H 4.52; N 9.60

The 1H-NMR spectrum of the product is identical to the published data.

Example 4

7-[7-(S)-t-butoxycarbonylamino-5-azaspiro[2,4]heptan-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluoro-1 -cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid

[image]

In 5 ml of methylene chloride we dissolved 238 ml of 7-[7-(S)-t-butoxycarbonylamino-5-azaspiro[2,4]heptan-5-yl]-6-fluoro-1-[(1R,2S)- 2-fluoro-1-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and to this, between cooling with ice, slowly added dropwise 80 ml of t-butyl hypochlorite. After that, we stirred the mixture at that temperature for another 2 hours. The reaction mixture was washed successively with 5% aqueous solution of citric acid and water and the solvent was removed under reduced pressure, and we obtained 217 mg of the title compound as a pale yellow powder.

Melting point: 220 to 224°C (decomposition)

[α]D: -208.31° (c=0.693, chloroform)

Elemental analysis of C24H26ClF2N3O5:

Calculated (%): C 56.53; H 5.14; N 8.24

Found (%): C 56.21; H 5.04; N 8.31

The 1H-NMR spectrum of the product is identical to the published data.

In accordance with the presented invention in which we chlorinate 8-unsubstituted quinolone derivatives, we can obtain 8-chloroquinolone derivatives with a satisfactory yield and high purity with simple and easy operations. Especially if it has a starting derivative in its molecule as a substituent amino group, it enables the use of hypochlorous acid ester as a chlorinating agent, to achieve chlorination of such a compound without the need for a protected amino group, in which case we get a satisfactory yield and purity of the product.

As we have described the invention in detail and with reference to its specific examples, it will be clear to the expert that we can make various changes and modifications to the invention without departing from its meaning and scope.

Claims (17)

1. Preparation procedure of 8-chloroquinolone derivative represented by formula (II) [image] where X represents a halogen atom, R1 represents a hydrogen atom, an alkyl group with 1 to 6 carbon atoms or a phenylalkyl group which may contain on the phenyl part a nitro group, a chlorine atom or an alkyl group, and R2 represents a 4- to 8-membered saturated heterocyclic group which contains as a ring member one or two nitrogen atoms, where this heterocyclic group may further contain as a ring member an oxygen atom or a sulfur atom and may have one or more substituents, selected from the group consisting of an amino group, a mono- or dialkylamino group with 1 to 6 carbon atoms in its alkyl part, alkylcarbonylamino groups with 2 to 7 carbon atoms, alkyloxycarbonylamino groups with 2 to 7 carbon atoms, haloalkylcarbonyl groups with 2 to 7 carbon atoms, haloalkyloxycarbonylamino groups with 2 to 7 carbon atoms, phenylalkyloxycarbonylamino groups which can have a nitro group or a chlorine atom on the phenyl part, an alkyl group with 1 to 6 carbon atoms, an alkylene to a group with 2 to 6 carbon atoms, which together with the carbon atom that makes up the heterocyclic group can form a spiro ring, a halogen atom and an alkoxy group with 1 to 6 carbon atoms, indicated by the fact that we block the quinolone compound represented by formula (I) [image] where X, R 1 and R 2 are the same as above, with a chlorinating agent. 2. Preparation procedure of 8-chloroquinolone derivative represented by formula (III) [image] where X represents a halogen atom, R3 represents a 4- to 8-membered saturated heterocyclic group containing as a ring member one or two nitrogen atoms, where this heterocyclic group may further contain an oxygen atom or a sulfur atom as a ring member and may have one or more substituents selected from the group consisting of an amino group, a mono- or dialkylamino group with 1 to 6 carbon atoms in its alkyl part, an alkyl group with 1 to 6 carbon atoms, an alkylene group with 2 to 6 carbon atoms, which together with the carbon atom that composes a heterocyclic group, forms a spiro ring, a halogen atom and an alkoxy group with 1 to 6 carbon atoms, indicated by the fact that from the compound represented by formula (II), [image] where X represents a halogen atom, R1 represents a hydrogen atom or an alkyl group with 1 to 6 carbon atoms and R2 represents a 4- to 8-membered saturated heterocyclic group containing as a ring member one or two nitrogen atoms, where this heterocyclic group can further contain as ring member an oxygen atom or a sulfur atom and may have one or more substituents selected from the group consisting of an amino group, a mono- or dialkylamino group with 1 to 6 carbon atoms in its alkyl part, an alkylcarbonylamino group with 2 to 7 carbon atoms , alkyloxycarbonylamino groups with 2 to 7 carbon atoms, haloalkylcarbonyl groups with 2 to 7 carbon atoms, haloalkyloxycarbonylamino groups with 2 to 7 carbon atoms, phenylalkyloxycarbonylamino groups which may have a nitro group or a chlorine atom on the phenyl part, an alkyl group with 1 to 6 carbon atoms , an alkylene group with 2 to 6 carbon atoms, which together with the carbon atom composing the heterocyclic group can form with pyro ring, a halogen atom and an alkoxy group with 1 to 6 carbon atoms, remove the protecting group and/or hydrolyze the ester group. 3. The method according to claim 1, characterized in that we choose the chlorinating agent from among furyl chloride, sodium hypochlorite, N-chlorosuccinimide and chlorine. 4. The method according to claim 1, characterized in that the chlorinating agent is hypochlorous acid ester, represented by formula (IV) R4OCl (IV) where R4 represents an alkyl group with 1 to 6 carbon atoms, a phenylalkyl group or a chlorophenylalkyl group. 5. The method according to claim 4, characterized in that R4 is an isopropyl group, a t-butyl group or a benzyl group. 6. The method according to claim 4, characterized in that R4 is a t-butyl group. 7. The method according to claim 1, characterized in that R2 is a 7-amino-5-azaspiro[2,4]heptan-5-yl group, 8-amino-6-azaspiro[3,4]octan-6-yl, 3,3-dimethyl-4-aminopyrrolidinyl or 3-aminopyrrolidinyl group. 8. The method according to claim 2, characterized in that R2 is a 7-amino-5-azaspiro[2,4]heptan-5-yl group, 8-amino-6-azaspiro[3,4]octan-6-yl, 3,3-dimethyl-4-aminopyrrolidinyl or 3-aminopyrrolidinyl group. 9. The method according to claim 1, characterized in that the compound represented by formula (I) is a compound represented by the formula [image] where R1 and X are the same as in claim 1. 10. The method according to claim 1, characterized in that the compound represented by formula (I) is a compound represented by the formula [image] where R1 and X are the same as in claim 1. 11. The method according to claim 1, characterized in that the compound represented by formula (I) is a compound represented by the formula [image] where R1 and X are the same as in claim 1. 12. The method according to claim 1, characterized in that the compound represented by formula (II) is 7-[7-amino-5-azaspiro[2,4]heptan-5-yl]-8-chloro-6-fluoro1 -(1,2-cis-2-fluorocyclopropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or its ester. 13. The method according to claim 1, characterized in that the compound represented by formula (II) is 7-(3-aminopyrrolidinyl)-8-chloro-6-fluoro-1-(1,2-cis-2-fluorocyclopropyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid or its ester. 14. The method according to claim 1, characterized in that the compound represented by formula (II) is 7-[7-(S)-amino-5-azaspiro[2,4]heptan-5-yl]-8-chloro -6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or its ester. 15. The method according to claim 1, characterized in that the compound represented by formula (II) is 7-[3-(S)-aminopyrrolidinyl]-8-chloro-6-fluoro-1-[(1R,2S)- 2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid or its ester. 16. The method according to claim 1, characterized in that the compound represented by formula (I) is 7-[7-amino-5-azaspiro[2,4]heptan-5-yl]-6-fluoro-1-( 1,2-cis-2-fluorocyclopropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or its ester, that the chlorinating agent is t-butyl hypochlorite and that the compound represented by formula (II), 7- [7-amino-5-azaspiro[2,4]heptan-5-yl]-8-chloro-6-fluoro1-(1,2-cis-2-fluorocyclopropyl)-4-oxo-1,4-dihydroquinolin-3- carboxylic acid or its ester. 17. The method according to claim 1, characterized in that the compound represented by formula (I) is 7-[7-(S)-amino-5-azaspiro[2,4]heptan-5-yl]-6-fluoro -1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid or its ester, that the chlorinating agent is t-butyl hypochlorite and that the compound represented by the formula (II ), 7-[7-(S)-amino-5-azaspiro[2,4]heptan-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]- 1,4-dihydro-4-oxoquinoline-3-carboxylic acid or its ester.