HK40041680A - Process for the hydrolysis of quinolone carboxylic esters - Google Patents

Description

Process for hydrolysis of quinolone formates

The invention relates to a method for obtaining quinolone formic acid by hydrolyzing quinolone formic acid ester. Fluoroquinolone carboxylic acids are important intermediates for the preparation of known quinolone pharmaceutically active compounds. Specific examples include: dinofloxacin, binofloxacin, cinoxacin, ciprofloxacin, danofloxacin, difloxacin, enoxacin, enrofloxacin, fleroxacin, ibafloxacin, levofloxacin, lomefloxacin, marbofloxacin, moxifloxacin, norfloxacin, ofloxacin, orbifloxacin, pefloxacin, pipemidic acid, temafloxacin, tosufloxacin, sarafloxacin, sparfloxacin and pradoxacin.

Pridoxasin is a high-efficiency quinolone antibiotic in veterinary medicines. Their antibacterial action and indications, administration forms and suitable formulations are described, for example, in WO 97/31001 a1, WO 03/007995 a1, WO 03/101422 a1, WO 04/082658 a1, WO 05/018641 a1, WO 05/044271 a1 and WO 06/061156 a 1.

One step in the multistage synthesis of pridosacin is the hydrolysis of quinolone ethyl formate. To hydrolyze the quinolone formate, the pH can be lowered by hydrochloric acid or sulfuric/acetic acid. The hydrochloric acid process has the disadvantage that the reaction mixture is highly corrosive and therefore the equipment provided for carrying out the reaction must be correspondingly corrosion-resistant. This results in high costs. Furthermore, the mother liquor must be neutralized by invested costs before disposal, a large amount of waste is generated, and the process has a relatively large number of steps.

The sulfuric acid/acetic acid process has the advantage that the acetic acid used can be recovered by distillation and that less corrosive media can be used.

WO 98/26779A 1 discloses in example Z22 of the description the synthesis of 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid. For this purpose, 3.8 g (0.1 mol) of ethyl 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylate are heated at reflux for 3 hours in a mixture of 100 ml of acetic acid, 20 ml of water and 10 ml of concentrated sulfuric acid. After cooling, the precipitate is filtered off with suction in 100 ml of ice-water, washed with water and ethanol and dried at 60 ℃ under vacuum. 17.3 moles of acetic acid, 1.86 moles of sulfuric acid and 11 moles of water are used per mole of ester.

EP 0276700A 1 discloses in example 1 of the description the hydrolysis of ethyl 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylate. 1 g of this compound was heated to 140 ℃ and 145 ℃ for 4 hours together with 3.5 ml of acetic acid, 3 ml of water and 0.3 ml of sulfuric acid. Subsequently, the solid was diluted with water and separated. 0.7 g of free carboxylic acid are obtained, the melting point of which is 281-282 ℃.20 moles of acetic acid, 1.89 moles of sulfuric acid and 55.8 moles of water per mole of ester were used.

EP 0169993A 2 discloses in example A of the description that a mixture of 94 g of ethyl 1-cyclopropyl-6, 7, 8-trifluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylate, 600 ml of glacial acetic acid, 450 ml of water and 70 ml of concentrated sulfuric acid is heated at reflux for 1.5 hours. The hot suspension is then poured onto ice, the precipitate is filtered off with suction, washed with water and dried under vacuum at 100 ℃. In this way, 88.9 g of 1-cyclopropyl-6, 7, 8-trifluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid were obtained. For each mole of ester, 34.7 moles of acetic acid, 4.35 moles of sulfuric acid and 82.8 moles of water were used.

EP 1319656A 1 discloses in example 2 the reaction of 29.4 g ethyl 1-cyclopropyl-7-chloro-6-fluoro-8-methoxy-1, 4-dihydro-4-oxo-3-quinolinecarboxylate (0.088 mol), 160 ml acetic acid, 100 ml water and 18 ml concentrated sulfuric acid. Stirring at 100 ℃ and 110 ℃ for 40 minutes. The resulting mixture was cooled and filtered. The precipitate was recrystallized from chloroform-ethanol. This gives 23.8 g of free carboxylic acid. For each mole of ester, 31.8 moles of acetic acid, 3.84 moles of sulfuric acid and 61.1 moles of water were used.

EP 1236718A 1 in example 1 discloses initially charging 300 g of ethyl 1-cyclopropyl-6, 7, 8-trifluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylate, 106.8 g of water and 426 g of acetic acid and adding 3.8 g of sulfuric acid. The mixture was heated at reflux for 3 hours. Then 310 ml of distillate were distilled off until a bottom temperature of 109 ℃ was reached. The mixture was then cooled to 80 ℃ and 157.5 g of a 4.8% by weight solution of sodium acetate were added dropwise. The pH value is 3 to 4. The mixture was then cooled to 20 ℃ and the solid was filtered off with suction. The solid was washed with 200 ml of water and dried under vacuum at 50 ℃. 270.3 g of 1-cyclopropyl-6, 7, 8-trifluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid are isolated, corresponding to a yield of 99% of theory. For each mole of ester, 7.4 moles of acetic acid, 0.04 moles of sulfuric acid and 6.2 moles of water were used.

The object of the present invention is to provide an improved process for the hydrolysis of quinolone carboxylic esters, in which as little waste product as possible is formed to be disposed of and in which the resulting quinolone carboxylic acid has as high a purity as possible.

According to the invention, this object is achieved by a process for the hydrolysis of quinolone formates of the general formula (II) to quinolone formates of the general formula (I):

wherein in formula (II) R¹Is C₁-C₄-alkyl, and

in formulae (I) and (II):

R²is hydrogen, C₁-C₄Alkyl radical, C₁-C₄-alkoxy, halogen, nitro or cyano,

R³and R⁴Each of which is a halogen atom,

R⁵is hydrogen, C₁-C₄-alkyl, halogen or nitro, and

y is C₁-C₆-alkyl, cyclopropyl or phenyl, optionally substituted by halogen,

wherein R is²Together with Y may also be-CH bonded to the nitrogen atom of the formula via a carbon atom₂-CH₂-O-or-CH (CH)₃)-CH₂-O-bridge, and

wherein the radical R²-R⁵At least one of which is fluorine,

which comprises the following steps:

A) reacting a compound of formula (II) with a mixture comprising acetic acid, sulfuric acid and water.

In step A), from ≥ 30 to ≤ 40 mol of acetic acid, from ≥ 0.3 to ≤ 1 mol of sulfuric acid and from ≥ 0.9 to ≤ 2.5 mol of water are used per mole of the compound of formula (II). Preferably, from ≥ 32 to ≤ 38 mol of acetic acid, from ≥ 0.4 to ≤ 0.8 mol of sulfuric acid and from ≥ 0.9 to ≤ 2.3 mol of water are used per mole of compound of formula (II), more preferably from ≥ 33 to ≤ 35 mol of acetic acid, from ≥ 0.4 to ≤ 0.6 mol of sulfuric acid and from ≥ 0.9 to ≤ 2.2 mol of water.

In the process according to the invention, acetic acid and sulfuric acid can be used in aqueous or anhydrous form. The amount data described refer to 100% acetic acid and 100% sulfuric acid. If aqueous acetic acid and/or aqueous sulfuric acid is used, less water must be used depending on its water content. Acetic acid is preferably used in the form of glacial acetic acid and sulfuric acid is preferably used in the form of 96 to 100% sulfuric acid.

The addition of water, acetic acid and sulfuric acid is preferably carried out so that the ester (II), acetic acid and sulfuric acid are initially charged, and then water is added. It is also possible to initially charge the ester (II), water and acetic acid and then add sulfuric acid. Preferably, the reaction mixture is heated for 10 to 25 hours, more preferably 12 to 22 hours, particularly preferably 16 to 20 hours.

In step A), preferably no other chemically reactive or catalytically active compounds are used, apart from the ester (II), acetic acid, water and sulfuric acid.

Preferred embodiments of the process according to the invention are described below. They may be arbitrarily combined with each other unless the contrary is clear from the context.

In one embodiment of the process, in step A) 95 mol% or more of the compound of the formula (II) used is converted into the compound of the formula (I). The yield is preferably 96 mol% or more, more preferably 99.5 mol% or more.

In another embodiment of the process, the reaction in step A) is carried out at a temperature of ≥ 90 ℃ to ≤ 99 ℃. The temperature is preferably from ≥ 92 to ≤ 97 deg.C, more preferably from ≥ 94 to ≤ 95 deg.C. It has been found that higher reaction temperatures in this step lead to an increased impurity content (see analytical data further set forth below for examples and comparative examples).

The heating of the reaction mixture may be carried out under reduced pressure, atmospheric pressure or elevated pressure. For example, the pressure may be 0.5 to 3 bar. Unless otherwise indicated, all process steps described herein are typically operated at atmospheric pressure.

The process according to the invention has the advantage that no distillation is required and the product can be isolated directly from the reaction mixture by filtration. This is more cost effective than the comparative process with a distillation step.

The quinolone carboxylic acid obtained can be isolated, for example, from the mixture present, the precipitate present at this time being filtered off with suction, washed and dried. The precipitate is preferably washed with ethanol, particularly preferably first with acetic acid and then with ethanol. Washing with water can be avoided, whereby the collected acetic acid can also be recovered more easily. Advantageously, the separated product is washed several times in order to obtain the product in the form of substantially free and substantially non-adhering sulphuric acid. Here, no base needs to be added in the process according to the invention. This in turn avoids waste and costs.

In a further embodiment of the process, it applies that in the formulae (I) and (II) in agreement:

R²is hydrogen, methyl, methoxy, fluorine, chlorine, nitro or cyano,

R³is a fluorine or chlorine compound, and is,

R⁴is a fluorine compound, and is characterized in that,

R⁵is hydrogen, methyl, fluorine, chlorine or nitro,

y is methyl, ethyl, isopropyl, cyclopropyl, fluorocyclopropyl, 4-fluorophenyl or 2, 4-difluorophenyl,

and in formula (I) R¹Is methyl or ethyl.

May also be consistent in formulas (I) and (II):

R²is hydrogen, C1-C4-An alkoxy group or a cyano group, or a substituted or unsubstituted alkoxy group,

R³the presence of a halogen, especially chlorine,

R⁴is a fluorine compound, and is characterized in that,

R⁵is a hydrogen atom, and is,

y is a cyclopropyl group, and Y is a cyclopropyl group,

and in formula (I) R¹Is methyl or ethyl.

In another embodiment of the process, formula (I) is 1-cyclopropyl-6, 7, 8-trifluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-6, 7-difluoro-8-cyano-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1- (2-fluoro) cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-8-chloro-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1-ethyl-6, 7, 8-trifluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid or 1-cyclopropyl-6-fluoro-7-chloro-8-cyano-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid.

In another embodiment of the process, formulae (II) and (I) have the following definitions according to formulae (II-1) and (I-1):

in another embodiment of the process, the compound of formula (II) is obtainable by reacting a compound of general formula (III):

wherein R is¹-R⁵And Y has the aforementioned definition and X is halogen.

In another embodiment of the process, the compound of formula (III) is obtainable by reacting a compound of general formula (IV):

and wherein R¹-R⁵X and Y have the abovementioned meanings and R⁶Is C₁-C₄-an alkyl group.

In another embodiment of the process, the compound of formula (IV) is obtainable by reacting a compound of general formula (V):

wherein R is¹-R⁶X and Y have the aforementioned definitions and X' is halogen.

For a preferred preparation of the pradoxazone intermediate (I), the reaction sequence is:

in all the compounds of the formulae mentioned, R¹Is ethyl, R²Is cyano, R³Is chlorine, R⁴Is fluorine, R⁵Is hydrogen, R⁶Is methyl, X is chloro, X' is chloro, and Y is cyclopropyl.

Examples

The present invention is illustrated in more detail by the following examples, but is not limited thereto. The synthetic scheme is shown in figure 1.

Example 1

Synthesis of ethyl 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydroquinoline-3-carboxylate (formula (II-2) in FIG. 1)

To 11.8 kg of toluene were added 2.70 kg (18.8 mol) of ethyl (2E) -3- (dimethylamino) acrylate (. beta. -dimethylamino acrylate,. beta. -DAASE) and 2.12 kg (20.9 mol) of triethylamine, and heated to Ti = 45 ℃ to 55 ℃. A solution of 4.50 kg (17.8 mol) of 2, 4-dichloro-3-cyano-5-fluorobenzoyl chloride (formula (V-1) in fig. 1) in 11.6 kg of toluene is then metered in at 50 ℃. Stirred at 50 ℃ for 3 hours and cooled to 22 ℃. The suspension was filtered and the filter cake was washed with 3.4 kg of toluene. To the filtrate (formula (IV-1) in fig. 1) was metered 1.23 kg (20.5 mol) of acetic acid and a solution of 1.11 kg (19.4 mol) of cyclopropylamine in 2.40 kg of toluene over 2 hours at Ti-5-15 ℃ and stirring was continued for 5 hours at Ti-10 ℃. 13.5 kg of water were then added, the mixture was heated to 40 ℃ Ti and stirring was continued at this temperature for 30 minutes. The phases were then separated at Ti ═ 40 ℃. A solution of 300 g of sodium carbonate in 6.0 kg of water was added to the organic phase, the mixture was heated to 40 ℃ Ti, stirring was continued for 30 minutes, and the phases were separated at 40 ℃ Ti.

An amount of 22.6 liters was distilled off from the organic phase under vacuum until the jacket temperature was 60 ℃. Then 19.2 kg of N, N-dimethylformamide were added and stirred at 40 ℃ for at least 10 minutes. Subsequently, distillation was again carried out under vacuum until the jacket temperature Tm was 60 ℃ until no more distillate had passed, and the residue (formula (III-1) in fig. 1) was cooled to room temperature.

To the residue was added 2.22 kg (16.0 mol) of potassium carbonate, the suspension was heated to Ti 55 ℃ and stirred at this temperature for 5 h. Cool to 22 ℃ Ti and distill off 16.5 l of distillate under vacuum until jacket temperature is 80 ℃. To the residue was added 18.0 kg of water and stirring was continued at 55 ℃ Ti for at least 10 minutes. Then cooled to Ti 5 ℃ over 2 hours and stirred at this temperature for a further 2 hours.

The product obtained is filtered off, washed twice with 6.0 kg of water each time and stirred with 9.9 kg of ethyl acetate at Ti 22 ℃ for at least 3 hours. The suspension is filtered, the filter cake is washed twice more with 4.8 kg of ethyl acetate each time, and the crude product (formula (II-1) in FIG. 1) is dried at 50 ℃ under vacuum for at least 12 hours.

Yield: 5.08 kilograms; 85.1% of theory, based on 2, 4-dichloro-3-cyano-5-fluorobenzoyl chloride.

2.96 kg of the crude product are heated to 60 ℃ in 29.4 kg of N, N-dimethylformamide and the insoluble impurities are filtered off at this temperature. 3.8 kg of water were added to the filtrate, stirring was continued for 1.5 hours, and then 13.9 kg of water were metered in over 1.5 hours. The resulting suspension was cooled to 22 ℃ Ti, stirring was continued for 30 minutes, and the solid was filtered off. The filter cake was washed with 3.1 kg of water and then twice with 2.8 kg of ethanol each time and dried under vacuum at 50 ℃ for at least 12 hours (formula (II-2) in FIG. 1). The process described herein has the advantage that the ester (II-2) can be prepared in high purity. This is advantageous for preparing free quinolone carboxylic acids in high purity. (the ester of formula (II-2) is prepared from the ester of formula (II-1) by a purification step

Yield: 2.87 kg; about 97% of theory, based on the crude product.

Example 2

Hydrolysis of the product of example 1

To 20.0 g (59.8 mmol) of the product of example 1 (formula (II-2) in FIG. 1) were added 122.8 g (2.04 mol) of acetic acid, 3.37 g (33.0 mmol) of sulfuric acid and 1.1 g (63.0 mmol) of water. Heated to 95 ℃ and stirred at this temperature for 18.5 hours. The suspension was cooled to 10 ℃, the solid was filtered off with suction, washed with 48 ml of acetic acid and then 48 ml of ethanol and dried in a vacuum oven at 60 ℃ overnight.

Per mole (II-2) used: 34.11 moles of acetic acid, 0.55 moles of sulfuric acid and 1.05 moles of water.

Yield: 17.6 g; 96.1% of theory

For purity, see table below.

Example 3

Hydrolysis of the product of example 1

To 20.0 g (59.8 mmol) of the product of example 1 (formula (II-2) in FIG. 1) were added 122.8 g (2.04 mol) of acetic acid, 3.37 g (33.0 mmol) of sulfuric acid and 2.3 g (126.0 mmol) of water. Heated to 95 ℃ and stirred at this temperature for 18.5 hours. The suspension was cooled to 10 ℃, the solid was filtered off with suction, washed with 48 ml of acetic acid and then 48 ml of ethanol and dried in a vacuum oven at 60 ℃ overnight.

Per mole (II-2) used: 34.11 moles of acetic acid, 0.55 moles of sulfuric acid and 2.10 moles of water.

Yield: 17.8 g; 97.1% of theory

For purity, see table below.

Comparative example 1

Method according to example 1 of EP1236718

To 30.0 g (89.6 mmol) of the product of example 1 (formula (II-2) in FIG. 1) were added 39.6 g (656.1 mmol) of acetic acid, 0.20 ml (3.5 mmol) of sulfuric acid and 9.9 g (549.5 mmol) of water. Heat at reflux for 3 hours. 14.1 g of distillate were then distilled off until a bottom temperature of 109 ℃ was reached. The mixture was cooled to 80 ℃ and 40.1 g of a 4.8% by weight solution of sodium acetate was added dropwise. The pH value is 3 to 4. The mixture was then cooled to 20 ℃ and the solid was filtered off with suction. The solid was washed with 50 ml of water and dried under vacuum at 50 ℃.

Per mole (II-2) used: 7.32 moles of acetic acid, 0.04 moles of sulfuric acid and 6.13 moles of water.

Yield: 26.7 g; 97.2% of theory

For purity, see table below.

Comparative example 2

Method according to example 2 of EP1236718

To 30.0 g (89.6 mmol) of the product of example 1 (formula (II-2) in FIG. 1) were added 78.9 g (1.31 mol) of acetic acid, 0.51 ml (9.1 mmol) of sulfuric acid and 2.25 g (124.9 mmol) of water. Heat at reflux for 4 hours. Then 8.1 g of distillate were distilled off until a bottom temperature of 109 ℃ was reached. The mixture was cooled to 80 ℃ and 75.3 g of a 4.8% by weight sodium acetate solution were added dropwise. The pH value is 3 to 4. The mixture was then cooled to 20 ℃ and the solid was filtered off with suction. The solid was washed with 50 ml of water and dried under vacuum at 50 ℃.

Per mole (II-2) used: 14.62 moles of acetic acid, 0.10 moles of sulfuric acid and 1.39 moles of water.

Yield: 27.0 g; 98.2% of theory

For purity, see table below.

Comparative example 3

Method according to example Z22 of WO98/26779

To 9.5 g (28.4 mmol) of the product of example 1 (formula (II-2) in FIG. 1) were added 29.5 g (490.9 mmol) of acetic acid, 5.2 g (52.5 mmol) of sulfuric acid and 5.6 g (310.2 mmol) of water. Heated at reflux for 3 hours and cooled to 20 ℃. The mixture was then added to 28 g of ice water and the solid was filtered off with suction. The solid was washed with 100 ml water and 10 ml ethanol and dried under vacuum at 60 ℃.

Per mole (II-2) used: 17.28 moles acetic acid, 1.85 moles sulfuric acid and 10.92 moles water.

Yield: 8.5 g; 97.7% of theory

The following table summarizes the purity of the hydrolysates of formula I-1 obtained in the examples and comparative examples.

	Example 2	Example 3	Comparative example 1	Comparative example 2	Comparative example 3
						Residual content of Ethyl ester (II-2)	0.196	0.268	0.772	0.436	0.108
Total content of unspecified impurities	0.005	0.007	0.124	0.130	0.146
						Measuring i.d.s	100.116	100.349	97.904	97.398	99.6

Data in% area (determined by HPLC analysis)

Data in weight percent

i.d.s. means "on dry matter" (on dry matter).

It can be seen that the product obtained in the process according to the invention has a higher purity than the comparative process in which the ratio of reactant (II-2), acetic acid, sulfuric acid and water required according to the invention is not followed.

Claims (9)

1. A process for the hydrolysis of quinolone carboxylic acid esters of the general formula (II) to quinolone carboxylic acids of the general formula (I):

wherein in formula (II) R¹Is C₁-C₄-alkyl, and

in formulae (I) and (II):

R²is hydrogen, C₁-C₄Alkyl radical, C₁-C₄-alkoxy, halogen, nitro or cyano,

R³and R⁴Each of which is a halogen atom,

R⁵is hydrogen, C₁-C₄-alkyl, halogen or nitro, and

y is C₁-C₆-alkyl, cyclopropyl or phenyl, optionally substituted by halogen,

wherein R is²Together with Y may also be-CH bonded to the nitrogen atom of the formula via a carbon atom₂-CH₂-O-or-CH (CH)₃)-CH₂-O-bridge, and

wherein the radical R²And R⁵At least one of which is fluorine,

which comprises the following steps:

A) reacting a compound of formula (II) with a mixture comprising acetic acid, sulfuric acid and water

The method is characterized in that:

in step A), from ≥ 30 to ≤ 40 mol of acetic acid, from ≥ 0.3 to ≤ 1 mol of sulfuric acid and from ≥ 0.9 to ≤ 2.5 mol of water are used per mole of the compound of formula (II).

2. The process according to claim 1, wherein ≥ 95 mol% of the compound of formula (II) employed in step A) is converted into the compound of formula (I).

3. The process according to claim 1 or 2, wherein the reaction in step A) is carried out at a temperature of ≥ 90 to ≤ 99 ℃.

4. The method of any one of claims 1-3, wherein in formulas (I) and (II) are consistently:

R²is hydrogen, methyl, methoxy, fluorine, chlorine, nitro or cyano,

R³is a fluorine or chlorine compound, and is,

R⁴is a fluorine compound, and is characterized in that,

R⁵is hydrogen, methyl, fluorine, chlorine or nitro,

y is methyl, ethyl, isopropyl, cyclopropyl, fluorocyclopropyl, 4-fluorophenyl or 2, 4-difluorophenyl

And in formula (I) R¹Is methyl or ethyl.

5. The process according to any one of claims 1 to 4, wherein formula (I) is 1-cyclopropyl-6, 7, 8-trifluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-6, 7-difluoro-8-cyano-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1- (2-fluoro) cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1-cyclopropyl-8-chloro-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1-ethyl-6, 7, 8-trifluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid or 1-cyclopropyl-6-fluoro-7-chloro-8-cyano-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid.

6. The method of any one of claims 1-5, wherein formulae (II) and (I) have the following definitions according to formulae (II-1) and (I-1):

。

7. the process according to any one of claims 1 to 6, wherein the compound of formula (II) is obtainable by reacting a compound of general formula (III):

wherein R is¹-R⁵And Y has the aforementioned definition and X is halogen.

8. The process according to claim 7, wherein the compound of formula (III) is obtainable by reacting a compound of general formula (IV):

and wherein R¹-R⁵X and Y have the abovementioned meanings and R⁶Is C₁-C₄-an alkyl group.

9. The process according to claim 8, wherein the compound of formula (IV) is obtainable by reacting a compound of general formula (V):

and wherein R¹-R⁶X and Y have the aforementioned definitions and X' is halogen.