HU221195B1 - Process for producing 8-chloroquinolone derivatives - Google Patents

Abstract

The present invention relates to a novel process of formula (II) wherein X is halogen, R1 is hydrogen, alkyl, or phenylalkyl substituted on phenyl with nitro, chloro or alkoxy, and R2 is a 4- to 8-membered saturated ring containing one or two nitrogen atoms. wherein said heterocyclic group may contain, in addition to the above, an oxygen atom or a sulfur atom, and optionally one or more substituents such as an amino group, an amino group substituted with one or two alkyl groups, an alkylcarbonylamino group, an alkoxy group an amino group, a haloalkylcarbonyl group, a haloalkoxycarbonylamino group, a phenylalkoxycarbonylamino group substituted with a phenyl group nitro group or a chlorine atom and an alkylene group together with one of the carbon atoms of the ring of the heterocyclic group, halogen and / or alkoxy for the preparation of 8-chloroquinolone derivatives by chlorinating the corresponding compound of formula (I). ŕ

Description

The present invention relates to a novel process for the preparation of known 8-chloroquinolone derivatives having antimicrobial activity, which is safe and thus may be used as a synthetic antimicrobial agent.

The 8-chloro-7-substituted-1- (2-fluorocyclopropyl) -4-quinolone derivatives of formula II described below can be used as potent antimicrobial agents, as disclosed in European Patent Application EP-A-0341493, and JP-A-Hei-2-231475 ("JP-A" refers to Japanese Unexamined Patent Application).

To date, these compounds have been prepared from 3-chloro-2,4,5-trifluorobenzoic acid. However, due to the difficulty of preparing the 3-chloro-2,4,5-trifluorobenzoic acid in its pure form due to the difficulties of its preparation, the process starting from this compound is not considered economically advantageous.

It is an object of the present invention to provide a process for the preparation of 8-chloroquinolone derivatives which is simple and easy to carry out and is economically efficient.

As a result of our extensive research, we have developed a process by which the 8-chloroquinolone derivatives can be prepared in a simple, easy to carry out operation, in addition to a satisfactory yield and a sufficiently pure form.

The present invention relates to a process of formula (II) wherein:

X is halogen;

R * is hydrogen, (C 1 -C 6) -alkyl, phenyl (C 1 -C 6) -alkyl substituted on the phenyl with nitro, chloro or C 1-6 -alkoxy; and

R ² is a 4- to 8-membered saturated heterocyclic group containing one or two nitrogen atoms in the ring, wherein said heterocyclic group may additionally contain an oxygen or sulfur atom and optionally one or more substituent groups, Thus, an amino group, one or two amino groups substituted with 1 to 6 carbon atoms, an alkylcarbonylamino group containing 2 to 7 carbon atoms, an alkoxycarbonylamino group containing 2 to 7 carbon atoms, a haloalkyl having 2 to 7 carbon atoms a carbonyl group, a C 2 -C 7 haloalkoxycarbonylamino group, a phenyl (C 1 -C 6) alkoxycarbonylamino group substituted on the phenyl group with a nitro group or a chlorine atom, a C 1 -C 6 alkyl group or a 2- It is a spiro ring containing 6 carbon atoms and one carbon atom of the ring of the heterocyclic group a alkylene group, a halogen atom and / or an alkoxy group containing 1 to 6 carbon atoms,

For the preparation of 8-chloroquinolone derivatives by reacting a quinolone derivative of formula (I) wherein X, R ¹ and R ² are as defined above with a chlorinating agent, and optionally, a compound of formula (II) wherein

X is halogen,

R ¹ is as defined above,

R ² is a 4- to 8-membered saturated heterocyclic group containing one or two nitrogen atoms in the ring, wherein said heterocyclic group may additionally contain one oxygen or sulfur atom and one or more amino groups,

For the preparation of the 8-chloroquinolone derivative of the formula (II) thus obtained, wherein X is a halogen atom,

^R1 is as defined above and

R ² represents a 4-8 membered saturated ring containing one or two nitrogen atoms in the ring, attached via the nitrogen atom a heterocyclic group, wherein, moreover, said heterocyclic group may contain an oxygen or sulfur atom, and one or more substituent groups, such as the ring 2 C7-C7-alkylcarbonylamino, C2-C7-alkoxycarbonylamino, C2-C7-haloalkoxycarbonylamino, phenyl-alkoxycarbonyl-amino optionally substituted on the phenyl , the amino group of the compound is deprotected. As a result of their extensive research, the inventors of the process of the present invention have successfully developed a process for the preparation of compounds of formula II by chlorination of compounds of formula I.

Suitable chlorinating agents for use in the process of the present invention include, for example, sulfuryl chloride, sodium hypochlorite, N-chlorosuccinimide, elemental chlorine, or a compound of formula IV wherein

R ⁴ is C 1-6 alkyl, phenylalkyl or chlorophenylalkyl, a hypochlorous acid ester.

Of the above chlorinating agents, hypochlorous acid esters are preferred for the reasons described below.

During chlorination of compounds of formula (I) wherein R ² is amino-substituted heterocycle reproducing side reactions can, and this can lead to a reduction in yield and deterioration of the product purity, unless protected with an amino group. If, on the other hand, the amino group is protected from the compound of formula (I), then two additional reaction steps must be introduced, deprotected and then cleaved. In addition to increasing the number of reaction steps, it is also disadvantageous that unfavorable side reactions may also occur during deprotection and deprotection, thereby further reducing the yield and purity of the desired product.

In our studies of the economical and simple synthesis of 8-chloroquinolone derivatives, it has been found that a hypochlorous acid ester of formula (IV) is used as the chlorinating agent. In other words, through the hipoklórossavészter formula (IV) than the use of chlorinating agent it is possible that the R ² is ami2

The chlorination of the compound of formula (I) containing a heterocyclic group substituted with a 195 Β1 group is carried out in such a way that the chlorinated compound of formula (II) is obtained in high yield and high purity, regardless of whether the amino group is in protected or unprotected form.

An example of a hypochlorous acid ester of formula (IV) is an alkyl ester such as a propyl ester (e.g. n-propyl hypochlorite or isopropyl hypochlorite), a butyl ester (e.g. n-butyl hypochlorite, isobutyl hypochlorite, secondary butyl). hypochlorite or tert-butyl hypochlorite) or a benzyl ester, of which tert-butyl hypochlorite is preferred.

Such hypochlorites are prepared in a conventional manner known per se, for example, by reacting an alcohol with a salt of hypochlorous acid, or by reacting a mixture of an alcohol and an alkali metal hydroxide (e.g., sodium hydroxide) with elemental chlorine.

In the case where the group R ² has an amino group as an additional substituent, this amino group may be protected by a protecting group. Examples of protecting groups that may be used to protect the amino group on R ² include an alkylcarbonyl group, an alkoxycarbonyl group, a haloalkylcarbonyl group, a haloalkoxycarbonyl group, a phenylalkoxycarbonyl group, and the like. or a nitro or chlorophenylalkoxycarbonyl group. Particularly preferred such protecting groups are, for example, the acetyl group, the chloroacetyl group, the 2,2,2-trichloroethoxycarbonyl group, the p-nitrobenzyloxycarbonyl group and the chlorobenzyloxycarbonyl group.

In the compounds of formulas I and II, the heterocyclic group at the R ² position can be derived from a cyclic amine, a so-called cyclic amino group. A ring amine can be derived from an alicyclic compound by replacing one carbon atom of the ring with a nitrogen atom. The cyclic amino group at R ² is preferably one

It may be derived from a 4- to 7-membered ring, and more preferably from a 5 or 6 membered ring, which may additionally contain an additional oxygen atom, a sulfur atom and / or a nitrogen atom. Examples of such cyclic amino groups are those derived from oxazolidine, morpholine, thiazolidine, thiomorpholine, imidazolidine, pyrazolidine and piperazine, with pyrrolidine and piperazine being particularly preferred.

As noted above, the cyclic amino group may contain one or more substituent groups, such as polar groups (e.g., the above substituted or unsubstituted amino group; and linear, branched or cyclic C 1-6 alkyl groups).

Suitable substituents for the aforementioned amino group include, for example, alkyl groups, acyl groups and alkoxycarbonyl groups as defined above. A preferred polar group is, for example, an unsubstituted amino group. Preferred alkyl groups attached to the cyclic amino group as substituents include, for example, methyl, ethyl, propyl, or two methyl groups or two ethyl groups attached to the same carbon atom of the ring. It is also preferred that such alkyl groups form a cyclopropane ring or a cyclobutane ring to form a spiro ring with the cyclic amino group.

Suitable examples of such cyclic amino groups, and in particular the amino substituted cyclic amino groups, are those of formulas (a), (b), and (d), wherein

R 5, R 6, R 7, R 9, R 9, R 10, R 13, R 14 and R 15 are hydrogen or C 1-6 alkyl; and

R ¹⁴ and R ^{15 can be} linked together to form a 3- to 6-membered ring to form a spiro ring structure.

Particularly preferred 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-methyl pyrrolidinyl, 4-dimethylamino-2-methylpyrrolidinyl, 4-dimethylamino-2,3-dimethylpyrrolidinyl, 3-methylpiperazinyl, 4-methylpiperazinyl, 3,4 -dimethyl-piperazinyl, 3,5-dimethyl-piperazinyl, 3,4,5-trimethyl-piperazinyl, 4-ethyl-3,5-dimethyl-piperazinyl, 4-isopropyl-3,5-dimethyl -piperazinyl, 3-aminopyrrolidinyl, 4-amino-3,3-dimethylpyrrolidine nyl, 7-amino-5-azaspiro [2.4] heptan-5-yl, 8-amino-6-azaspiro [3.4] octan-6-yl.

The chlorination of compounds of formula (I) can generally be accomplished by dissolving a compound of formula (I) in a solvent and adding a chlorinating agent to the solution under cooling.

The solvents used for chlorination need not be particularly limited as long as they can dissolve the starting compound and are neutral to the chlorinating agent. Examples of such solvents are halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; alkane carboxylic acids such as acetic acid and formic acid. Additionally, chlorosulfonic acid, alcohols (such as methanol, ethanol or propanes), acetonitrile, Ν, Ν-dimethylformamide and ethyl acetate may also be used. Formic acid and acetic acid are preferred because of their solubility and their ability to accelerate the reaction.

The chlorination of a compound of formula (I) is carried out in a solution or suspension of this compound in a solvent, preferably a solution. The reaction is carried out at temperatures up to the boiling point of the solvent used, usually under ice-cooling or at room temperature (i.e., 0 ° C to 30 ° C).

The chlorinating agent is generally 1 to 2 equivalents molar to the starting compound (I)

It is used in an amount of 195 Β1. If, on the other hand, elemental chlorine is used as the chlorinating agent, it can usually be used in excess.

The chlorination reaction of the present invention proceeds rapidly, is complete within about 5 minutes to about 10 hours, and generally takes about 5 minutes to about 2 hours under ice-cooling.

The 8-chloroquinolone derivatives of the formula (II) containing the hydrogen atom in R ¹ can be prepared by reacting the chlorination compound of the formula (II) wherein

R ¹ is alkyl, the chlorinated compound is hydrolyzed by a conventional method known per se, for example under acidic or basic conditions. If in the formula (II)

R * is phenylmethyl substituted on one or more alkoxy groups, nitro groups and / or chlorine atoms containing 1 to 6 carbon atoms in the phenyl group, such ester group may be removed either by hydrolysis as described above or by hydrogenolysis in a manner known per se.

When R ^{2 in the} chlorinated compound of formula II contains a protected amino group, the protecting group may be removed by methods known per se, for example by catalytic reduction or by hydrolysis under acidic or basic conditions.

The desired 8-chloroquinolone derivative (II) can then be isolated by conventional chemical methods known in the art, such as solvent extraction, washing of the organic solvent, chromatography on a silica gel column, recrystallization, and dissolution and precipitation. .

The present invention is further illustrated by the following non-limiting Examples.

Example 1

7- (S) -amino-5-azaspiro [2.4] heptane dihydrochloride

6.07 g of 7- (S) -amino-5-benzyl-5-azaspiro [2.4] heptane, 7.5 ml of concentrated hydrochloric acid, 2.4 g of 5% palladium on carbon with 50% moisture and 200 ml the methanol mixture was shaken under atmospheric hydrogen for 20 hours. The catalyst was filtered off and the filtrate was evaporated under reduced pressure. This gave 5.13 g of the title compound as a powder, m.p. 222-238 ° C (dec.).

(α) _D = -43.27 ° (c = 0.537, water).

Calcd for C ₆ H ₂ F _I2 .2HC1 O:

Calculated: C, 38.93; H, 7.62; N, 15.13. Found: C, 38.83; H, 7.88; N, 14.67.

1 H NMR (D ₂ O) δ 0.9-1.3 (4H, m),

3.25 and 3.72 (both 1H, d, J = 12.2 Hz), 3.68 and

3.82 (both 1H, dd, J = 12.2, 2.9 Hz), 4.10 (1H, dd, J = 7.3,6.4 Hz).

Example 2

7- (7- (S) -Amino-5-azaspiro [2.4] heptan-5-yl) -6-fluoro-1- (1R, 2S) -2-fluoro-1-cyclopropyl-1,4-dihydro - Oxoquinoline-3-carboxylic acid monohydrochloride To 4.2 ml of 6,7-difluoro-1 - ((1R, 2S) -2-fluoro-1-cyclopropyl) -1,4-dihydro-4-oxo-1 quinoline-3-carboxylic acid, 3.33 g of 7- (S) -amino-5-azaspiro [2.4] heptane dihydrochloride and 10.5 ml of triethylamine and reflux for 2.5 hours. After cooling, the precipitate was filtered off and suspended in water (30 ml). Concentrated hydrochloric acid (2.5 ml) was added to the suspension and the mixture was stirred at room temperature for 1 hour. The crystalline portion of the suspension is filtered off, washed with water and dried. 5.81 g of the title compound are obtained, m.p. 228-233 ° C (dec.). (α) _D = -23.93 ° (c = 0.449, 1 N sodium hydroxide solution).

Analysis calculated for C ₁₉ H ₁₉ F ₂ N ₃ O ₃ .HCl 1.1 / 2H ₂ O: C, 54.22; H, 5.03; N, 9.98. Found: C, 53.88; H, 5 , 24 N: 9.64.

1 H-Nuclear magnetic resonance spectrum (NaOD), δ 0.4-0.8 (4H, m),

1.4-1.7 (2H, m), 2.97 (1H, br s), 3.10 and 3.53 (both 1H, d, J = 10.3 Hz), 3.15-3, 3 (2H, m), 3.71 (1H, br s), 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 3

7- (7- (S) -tert-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 (Scheme A) Dissolve 120 mg of 7- (7- (S) -tert-butoxycarbonylamino-5-azaspiro [2.4] in dichloromethane). ] heptan-5-yl / 6-fluoro-1- (1R, 2S) -2-fluoro-1-cyclopropyl--1,4-dihydro-4-oxoquinoline-3-carboxylic acid and ice-cooling the solution and a solution of 40 mg of sulfuryl chloride in 5 ml of dichloromethane is added dropwise with stirring over 5 minutes. After instillation, stirring was continued for an additional 10 minutes. After confirming the disappearance of the starting material by TLC, the reaction mixture was washed first with saturated aqueous sodium bicarbonate solution, then with water, and dried over anhydrous sodium sulfate. The dichloromethane is then distilled off under reduced pressure and the residue is purified by chromatography on a silica gel column (10 g), eluting with a 9: 1 mixture of chloroform and methanol. 101 mg of the title compound are obtained, m.p. 223-226 ° C. (α) _D = -211.15 ° (c = 0.771, chloroform).

Analysis according to the formula C ₂₄ H ₂₆ C ₁ F ₂ N ₃ O ₅ :

Calculated: C, 56.53; H, 5.14; N, 8.24. Found: C, 56.67; H, 4.95; N, 8.14.

The product has a Ή NMR spectrum as described.

Example 4

7- (7- (S) -Amino-5-azaspiro [2.4] heptan-5-yl) -8-chloro-6-fluoro-1 - ((R, 2S) -2-fluoro-1-cyclopropyl) -1,4 -dihydro-4-oxo-quinoline-3-carboxylic acid (Scheme B)

HU 221 195 Β1

To the chlorosulfonic acid is added 120 mg of 7- [7- (S) -tert-butoxycarbonylamino-5-azaspiro [2.4] heptan-5-yl] -6-fluoro-1 - [(1R, 2S) under ice-cooling and stirring. 2-Fluoro-1-cyclopropyl--1,4-dihydro-4-oxo-quinoline-3-carboxylic acid is added followed by trace amounts of iodine. Chlorine gas is then added to the solution for 10 minutes and the mixture is stirred for 1 hour. The reaction mixture was poured into ice water, basified with 1 N sodium hydroxide solution, and then adjusted to pH 7 with aqueous citric acid. The mixture was partitioned between chloroform (3 x 50 mL), the organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from aqueous ethanol to give 45 mg of the title compound, m.p. 127.3-135.5 ° C.

(α) _D = -179 ° (c = 1.12, 1 N sodium hydroxide solution).

Calcd for C ₁₉ H ₁₈ C1F ₂ N ₃ O ₃ .3 / 2H ₂ O Calcd: C: 52.24 H: 4.85 N: 9.61 Found: C: 52.16 H: 4.70 N, 9.53.

Example 5

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-oxo-quinoline-3-carboxylic acid (Scheme C) Dissolve 3.09 g of 7- (7- (S) -amino-5-azaspiro [2.4] heptan-5-yl) -6- fluoro-1 - ((1R, 2S) -2-fluoro-1-cyclopropyl--1,4-dihydro-4-oxo-quinoline-3-carboxylic acid hydrochloride) and the solution was cooled to an internal temperature of 5-10 ° C. Then 1.25 g of tert-butyl hypochlorite are slowly added dropwise at the same temperature. After the addition, the mixture was stirred for an additional 5 minutes, then poured into cold water and neutralized with 20% aqueous sodium hydroxide solution. The precipitated crystalline material is filtered off, washed with water and dried. This gave 3.02 g of the title compound as a pale yellow crystalline solid, m.p. 221-226 ° C (dec.).

(α) _D = -209.7 ° (c = 0.631, 1 N sodium hydroxide solution).

Calc'd for C ₁₉ H _i8 C1F ₂ N ₅ O ₃ .3 / 2H ₂ O Calcd: C: 52.24 H: 4.85 N: 9.61 Found: C: 52.31 H: 4.52 N: 9.60.

The product had a 1 H-NMR spectrum as described.

Example 6

7- / 7-(S)- tertiary -Butoxycarbonylamino-5-azaspiro[2.4]heptan-5-yl/-8- chloro-6-fluoro-1 /( lR,2S)-2-fluoro- l- cyclopropyl N-1,4-Dihydro-4-oxo-quinoline-3-carboxylic acid (Scheme D) Dissolve 238 mg of 7- [7- (S) -tert-butoxycarbonylamino-5-azaspiro [2.4] in dichloromethane. heptane-5-yl-6-fluoro-1- (1R, 2S) -2-fluoro-1-cyclopropyl--1,4-dihydro-4-oxoquinoline-3-carboxylic acid, and the solution was cooled with ice 80 mg of tert-butyl hypochlorite are added dropwise. After the addition, the mixture was stirred at the same temperature for a further 2 hours. Subsequently, the mixture was washed first with 5% aqueous citric acid solution and then with water, and the solvent was distilled off under reduced pressure. This gives 217 mg of the title compound as a pale yellow powder, m.p. 220-224 ° C.

(α) _D = -208.31 ° (c = 0.693, chloroform).

Analysis according to the formula C ₂₄ H ₂₆ C ₁ F ₂ N ₃ O ₅ :

H, 5.14; N, 8.24. Found: C, 56.21; H, 5.04; N, 8.31.

The product has the same 1 H NMR spectrum as described.

The process of the present invention wherein the unsubstituted quinolone derivatives at the 8-position are chlorinated provides 8-chloroquinolone derivatives with satisfactory yields and high purity by simple and easy operations. Particularly in cases where the starting quinolone derivative has an amino group as a substituent, the chlorination of such a compound using a hypochlorous acid ester as a chlorinating agent can be accomplished without the need to protect the amino group, while providing a satisfactory yield and purity of the product.

Although the process of the present invention is described in detail in the Examples, it will be apparent to those skilled in the art that various changes and modifications may be made to the process without departing from the spirit and scope of the invention.

Claims (10)

PATENT CLAIMS A process for the preparation of a compound of formula II wherein X is halogen, R ¹ is hydrogen, C 1-6 alkyl, or phenyl-C 1-6 -alkyl substituted on the phenyl with nitro, chloro or C 1-6 -alkoxy; and R ² is a 4- to 8-membered saturated heterocyclic group containing one or two nitrogen atoms in the ring, wherein said heterocyclic group may additionally contain one oxygen or sulfur atom and optionally one or more substituent groups such as an amino group, an amino group substituted with one or two C 1 -C 6 alkyl groups, a C 2 -C 7 alkylcarbonylamino group, a C 2 -C 7 alkoxycarbonylamino group, a C 2 -C 7 haloalkylcarbonyl group, 2 A C7 -C7 haloalkoxycarbonylamino group, a phenyl (C1-C6) alkoxycarbonylamino group substituted by a nitro group or a chlorine on the phenyl group, a C1-C6 alkyl group, a C2-C6 group and a heterocyclic group together with one of the carbon atoms of its ring, an alkylene group forming a spiro ring, a halogen atom and / or a C 1-6 alkoxy group. wear a group, For the preparation of 8-chloroquinolone derivatives characterized in that a compound of formula I wherein X, R ¹ GB 221,195 Β1 and R ² are as defined above quinolone was reacted with a chlorinating agent, optionally followed by a general formula (II) wherein X is halogen, R ¹ is within the scope, R ² is a 4- to 8-membered saturated heterocyclic group containing one or two nitrogen atoms in the ring, wherein said heterocyclic group may additionally contain one oxygen or sulfur atom and one or more amino groups, For the preparation of the 8-chloroquinolone derivative of the formula (II) thus obtained, wherein X is a halogen atom, R ¹ is within the scope and R ² represents a 4-8 membered saturated ring containing one or two nitrogen atoms in the ring, attached via the nitrogen atom a heterocyclic group, wherein, moreover, said heterocyclic group may contain an oxygen or sulfur atom, and one or more substituent groups, such as the ring 2 C 7 -C 7 alkylcarbonylamino, C 2 -C 7 alkoxycarbonylamino, C 2 -C 7 haloalkoxycarbonylamino, phenylalkoxycarbonylamino optionally substituted on the phenyl group with a nitro group or a chlorine atom , the amino group of the compound is deprotected. A process for the preparation of a compound of formula (II) according to claim 1 wherein X and R ^{2 are} as defined in claim 1 and R ^{1 is} hydrogen or C 1 -C 6 alkyl, characterized in that a compound of formula (I) hipoklórossavészterrel reacted with formula X, R ¹ and R ² as defined above, R ⁴ OC1 (IV) wherein R ⁴ C 1-6 alkyl, phenyl (C - C6) alkyl, chloro-phenyl ( (C 1 -C 6) alkyl. A process according to claim 1 for the preparation of compounds of formula II wherein X and R ^{2 are} as defined in claim 1 and R ^{1 is} hydrogen or C 1 -C 6 alkyl, characterized in that they are derived from appropriately substituted materials. 4. A process according to claim 3 wherein the chlorinating agent is sulfonyl chloride, chlorine or a hypochlorous acid ester of formula IV wherein R ^{4 is C} 1-6 alkyl, phenyl C 1-6 alkyl, or chlorophenyl (C1-C6) alkyl. 5. The method of claim 4, wherein R ⁴ OC1 using a chlorinating agent of the formula wherein R ⁴ is isopropyl, tert-butyl or benzyl. 6. The method of claim 4, wherein R ⁴ OC1 using a chlorinating agent of the formula wherein R ⁴ is a tertiary-butyl group. The process of claim 1 wherein the starting compound of formula (I) is a compound of formula (Ia) wherein R ¹ and X are as defined in claim 1. The process according to claim 1, which is 7- / 7- (S) -amino-5-azaspiro [2.4] heptan-5-yl / -8-chloro-6-fluoro-1 - ((1R, 2S) 2-fluoro). cyclopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, characterized in that it is based on appropriately substituted materials. The process according to claim 1, which is 7- (7-amino-5-azaspiro [2.4] heptan-5-yl) -8-chloro-6-fluoro-1- (1,2-cis-2-fluorocyclopropyl) -. For the preparation of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid, characterized in that the compound of the 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) and tert-butyl hypochloride as the chlorinating agent. The process of claim 1, wherein the 7- / 7- (S) -amino-5-azaspiro [2.4] heptan-5-yl] -8-chloro-6-fluoro-1 - ((1R, 2S) -2-fluoro) cyclopropyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, characterized in that 7- (7- (S) -amino-5-azaspiro [2.4] heptane-5) is a compound of formula (I) -yl-6-fluoro-11 - ((1R, 2S) -2-fluorocyclopropyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid and tert-butyl hypochlorite as the chlorinating agent.