Title of Invention

PROCESS FOR THE PREPARATION OF FLUOROQUINOLONECARBOXYLIC ACIDS

Abstract

"PROCESS FOR THE PREPARATION OF FLUOROQUINOLONECARBOXYLIC ACIDS" Process for the preparation of fluoroquinolonecarboxylic acids by hydrolysis of the corresponding C1-C4-alkyl esters with addition of water, acetic acid and sulphuric acid, characterized in that, relative to 1 mol of C1-C4-alkyl fluoroquinolonecarboxylate, 20 to 250 ml of water, 200 to 2000 ml of acetic acid and 2 to 25 g of sulphuric acid are employed, the amount of acetic acid relating to 100% strength acetic acid and the amount of sulphuric acid to 100% strength sulphuric acid, the reaction mixture is heated to reflux for 0.5 to 8 hours, then a mixture of acetic acid, Ci-C4-alkyl acetate, Ci-C4-alkyl alcohol and optionally water is distilled off until a bottom temperature in the range from 107 to 113°C results at normal pressure and finally the fluoroquinolonecarboxylic acid.

Full Text

FORM 2 THE PATENTS ACT, 1970 [39 OF 1970] & THE PATENTS (AMENDMENT) RULES, 2006 COMPLETE SPECIFICATION [See Section 10; rule 13] "PROCESS FOR THE PREPARATION OF FLUOROQUINOLONECARBOXYLIC ACIDS" LANXESS DEUTSCHLAND GMBH, a German company, of 51369 Leverkusen, Germany, The following specification particularly describes the nature of the invention and the manner in which it is to be performed:- The present invention relates to process for the preparation' of fluoroquinolonecarboxylic acids. The present invention relates to an advantageous process for the preparation of fluoroquinolonecarboxylic acids by acidic hydrolysis of the corresponding fluoro¬quinolonecarboxylic acid esters. Fluoroquinolonecarboxylic acids are important intennediates for the preparation of known pharmaceutically active compounds from the class consisting of the quinolones. It is known (see EP-A169 993) that cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-quinolinecarboxylic acid esters can be hydrolysed under acidic or basic conditions to give the corresponding quinolonecarboxylic acids (loc. cit. page 10, lines 4 to 7). The hydrolysis of 94g of ethyl l-cyclopropyl-6,7,8-trifluoro-l,4-dihydroxy-4-oxo-3-quinolinecarboxylate acid with addition of water, glacial acetic acid and 70 ml = 128.8 g of concentrated sulphuric acid (this corresponds to about 420 g of sulphuric acid per mole of the fluoroquinolonecarboxylic acid ester) is now described in more concrete terms, the reaction mixture being heated under reflux for 1.5 hours, then the suspension present being poured onto ice and then the precipitate which is present being filtered off with suction, washed and dried (loc. cit. page 28, last paragraph). The yield here is 96% of theory. A disadvantage of this process is the large amount of sulphuric acid which is needed, the large amounts of waste water and the disposal problems thus resulting, which result from the use of large amounts of sulphuric acid (this is then obtained as dilute acid) and ice and the necessity to wash the isolated product a number of times in order to remove adhering sulphuric acid residues. A process for the preparation of fluoroquinolonecarboxylic acids by hydrolysis of the corresponding C1-C4-alkyl esters with addition of water, acetic acid and sulphuric acid has now been found, which is characterized in that, relative to 1 mol of Le A 35 2Q7-Foreign Countries C1-C4-al]cyl fluoroquinolonecarboxylate, less than 30 g of sulphuric acid are employed, the reaction mixture is heated to reflux for 0.5 to 8 hours, then a mixture of acetic acid, C1-C4-alkyl acetate, C1-C4-alkyl alcohol and optionally water is distilled off and finally the fluoroquinolinecarboxylic acid prepared is isolated. Suitable C1-C4-alkyl fluoroquinolonecarboxylates to be employed are, for example, those of the formula (I) in which 10 Rl represents C1-C4-alkyl, R2 represents hydrogen, C1-C4-alkyl, C1-C4-alkoxy, halogen, nitro or cyano, 15 R3andR4 each represent halogen, R5 represents hydrogenC1-C4-alkyl, halogen or nitro, and Y represents C1-C6alkyl, cyclopropyl or phenyl, each of which can optionally 20 be substituted by halogen, where R2 and Y together can also represent a -CH2-CH2-O- or -CH(CH3)-CH2-0-bridge bonded to the nitrogen atom by a C atom and 25 where at least one of the radicals R2 to R5 represents fluorine. Starting from the C1-C4-aIkyl fluoroquinolonecarboxylates of the formula (T) to be employed, for example, it is possible to obtain the corresponding fluoro-quinolonecarboxylic acids of the formula (IT) in which the radicals R2 to R^ and Y have the meaning indicated in formula (T). Preferably, in the formulae (I) and (II) R2 represents hydrogen, methyl, methoxy, fluorine, chlorine, lutro or cyano, R3 represents fluorine or chlorine, R4 represents fluorine, R5 represents hydrogen, methyl, fluorine, chlorine or nitro and Y represents methyl, ethyl, isopropyl, cyclopropyl, fluorocyclopropyl, 4-fluoro-phenyl or 2,4-difluorophenyl. Preferably, in formula (I) R1epresents methyl or ethyl. The present invention relates to the process for the preparation of fluoroquinolonecarboxylic acids by hydrolysis of the corresponding Ci-C4-alkyl esters of the formula in which R1 represents C1-C4-aIkyl, R2 represents hydrogen, C1-C4-aIkyl,C1-C4-aIk:oxy, halogen, nitro or cyano, R3 and R4 each represent halogen, R5 represents hydrogen, Ci-C4-alkyl, halogen or nitro, and Y represents C1-C4-alkyl, cyclopropyl or phenyl, each of which can optionally be substituted by halogen, where R2 and Y together can also represent a -CH2-CH2-O- or -CH(CH3)-CH2-0-bridge bonded to the nitrogen atom by a C atom and where at least one of the radicals R2 to Rs represents fluorine, with addition of v/ater, acetic acid and sulphuric acid, characterized in that, relative to 1 mol of C1-C4-aIkyl fluoroquinolonecarboxylate, 20 to 250 ml of water, 200 to 2000 ml of acetic acid and 2 to 25 g of sulphuric acid are employed, the amount of acetic acid relating to 100% strength acetic acid and the amount of sulphuric acid to 100% strength sulphuric acid, the reaction mixture is heated to reflux for 0.5 to 8 hours, then a mixture of acetic acid, C1-C4-alk7l acetate, C1-C4-alkyl alcohol and optionally water is distilled off until a bottom temperature in the range from 107 to 113°C results at normal pressure and finally the fluoroquinolonecarboxylic acid of the formula in which the radicals R2 to Rs and Y have the meaning indicated in formula (I), is prepared and isolated. In the process according to the invention, acetic acid and sulphuric acid can be employed in water-containing or anhydrous form. The quantitative data described relate to 100% strength acetic acid and 100% strength sulphuric acid. If water-containing acetic acid and/or water-containing sulphuric acid is employed, less water Le A 35 207-Foreign Countries must be employed according to their water content. Acetic acid is preferably employed in the form of glacial acetic acid, sulphuric acid preferably in the form of 96 to 100% strength sulphuric acid. Relative to 1 mol of Ci-C4-alkyl fluoroquinolonecarboxylate, it is possible to employ in the process according to the invention, for example, 20 to 250 ml of water, 200 to 2000 ml of acetic acid and 2 to 25 g of sulphuric acid. Preferably, these amounts are 100 to 200 ml of water, 300 to 1000 ml of acetic acid and 3 to 15 g of sulphuric acid. The addition of water, acetic acid and sulphuric acid is preferably carried out such that the Ci-C4-alkyl fluoroquinolonecarboxylate, the water and the acetic acid are introduced and the sulphuric acid is then added. The reaction mixture is preferably heated to reflux for 1 to 5 hours. After completion of the heating to reflux, acetic acid, C1-C4-alkyl acetate, C1-C4-alkyl alcohol and water are distilled off from the reaction mixture. The distillation can be conducted, for example, until a bottom temperature in the range from 107 to 113°C results. The distillation is preferably conducted until a bottom temperature in the range from 108 to 110°C results. These temperatures relate to normal pressure. If the reaction is carried out at other pressures, these temperatures are to be set correspondingly lower or higher. The 3 to 4 components distilling off in the distillation distil, inter alia, in the form of azeotropes whose composition can change during the distillation. The heating of the reaction mixture to reflux and the subsequent distillation can be carried out at reduced pressure, atmospheric pressure or elevated pressure. For example, pressures in the range from 0.5 to 3 bar are possible. Preferably, both process steps are carried out at atmospheric pressure. Le A 35 207-Foreign Countries The fluoroquinolonecarboxylic acid prepared from the mixture present after the distillation can be isolated, for example, by diluting this mixture with water and filtering off the precipitate then present with suction, washing it with water and drying it. It is advantageous in this case to wash the isolated product a number of times in order to obtain it sufficiently free and largely without adhering sulphuric acid. Preferably, the isolation of the fluoroquinolonecarboxylic acid prepared is carried out by setting a pH in the range from 2 to 5, preferably 3 to 4, in the mixture present after the distillation by addition of a base. This can be achieved, for example, by addition of an appropriate amount of sodium hydroxide solution or sodium acetate. Preferably, a 1 to 20% strength by weight aqueous sodium acetate solution is used here. The pH optimal for the isolation of a specific fluoroquinolonecarboxylic acid can be determined by means of a simple titration. The pH resulting from the titration is therefore taken which on the one hand is as high as possible, but on the other hand still does not lead to the precipitation of the salts of the respective fluoroquinolone¬carboxylic acid. After the setting of the pH, the mixture can be cooled, for example, to 0 to 35°C and the precipitate then present filtered off, washed with water and dried. The drying is preferably carried out at elevated temperature and reduced pressure. As a rule, an adequately pure product is then obtained even with a single washing. Using the process according to the invention, fluoroquinolonecarboxylic acids are in general obtained in yields of 98% of theory and higher. In the manner according to the invention, it is in particular possible to obtain the following fluoroquinolonecarboxylic acids in an advantageous manner: l-cyclopropyl-6,7,8-trifluoro-l,4-dihydro-4-oxo-3-quinoline-carboxylic acid, l-cyclopropyl-6,7-difluoro-l,4-dihydro-4-oxo-3-quinoline-carboxylic acid, l-cyclopropyl-6,7-difluoro-8-cyano-l,4-dihydro-4-oxo-3-quinoline-carboxylic acid, Le A 35 207-Foreign Countries 1 -(2-fluoro)cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid, 1 -cyclopropyl-8-chloro-6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid and l-ethyl-6,7,8-trifluoro-l,4-dihydro-4-oxo-3-quinoline-carboxylicacid. The process according to the invention has the advantage that, compared v^ith the prior art, very much less sulphuric acid (only about 1 to 10% of the amount previously used) is employed therein and therefore the amount of dilute acid formed is significantly lower. If the advantageous, pH-controUed method for the isolation of the fluoroquinolonecarboxylic acids prepared is also used, washing operations can be avoided and further reductions in the amount of waste water realized. Finally, the yield of desired product is higher than previously. /■ The advantages resulting according to the invention are very surprising, since if only the amount of sulphuric acid is reduced compared with the prior art, but the distillation is not carried out or the amount of sulphuric acid is reduced and the mixture is only briefly heated to reflux, then the hydrolysis no longer proceeds almost quantitatively, but only incompletely, which leads to reductions in yield and product impurities (see comparison examples). Le A 35 207-Foreign Countries Examples Example 1 300 g of ethyl l-cyclopropyl-6,7,8-trifluoro-l,4-dihydro-4-oxo-3-quinoline-carboxy-late, 106.8 g of water and 426 g of acetic acid were introduced and 3.8 g of sulphuric acid were added. The mixture was heated to reflux for 3 hours. 310 ml of distillate were then distilled off until a bottom temperature of 109°C was reached. The mixture was then cooled to 80°C and 157.5 g of 4.8% strength by weight sodium acetate solution were added dropwise. The pH was then in the range 3 to 4. The mixture was then cooled to 20°C and the solid was filtered off with suction. The solid was washed with 200 ml of water and dried in vacuo at 50°C. 270.3 g of l-cyclopropyl-6,7,8-trifluoro-l,4-dihydro-4-oxo-3-quinoline-carboxylic acid were isolated, which cor¬responds to a yield of 99% of theory. Example 2 1500 g of ethyl l-cyclopropyl-6,7-difluoro-l,4-dihydro-4-oxo-3-quinoline-carboxy-late, 128.4 g of water and 4500 g of acetic acid were introduced and 53 g of sulphuric acid were added. The mixture was heated to reflux for 4 hours. 2020 ml of distillate were then distilled off until a bottom temperature of 109°C was reached. The suspension was then cooled to 80°C and 2204 g of 4% strength by weight sodium acetate solution were added dropwise. The pH was then in the range 3 to 4. The mixture was then cooled to 20°C and the solid was filtered off with suction. The solid was washed with 2000 ml of water and dried in vacuo at 50°C. 1329 g of l-cyclopropyl-6,7-difluoro-l,4-dihydro-4-oxo-3-quinoline-carboxylic acid were isola¬ted, which corresponds to a yield of 98%. Le A 35 207-Foreign Countries Comparison Example 1 300 g of ethyl l-cyclopropyl-6,7,8-trifluoro-l,4-dihydro-4-oxo-3-quinoline-carboxy-late, 106.8 g of water and 426 g of acetic acid were introduced and 3.8 g of sulphuric acid were added. The mixture was heated to reflux and 310 ml of distillate were immediately distilled off. The suspension was cooled to 80°C and 157.5 g of 4.8% strength aqueous sodium acetate solution were added dropwise. The reaction mixture was then cooled to 20°C and the solid was filtered off with suction. The solid was washed with 200 ml of water and dried in vacuo at 50°C. The solid consisted of a mixture of ethyl l-cyclopropyl-6,7,8-trifluoro-l,4-dihydro-4-oxo-3-quinoline-carboxylate (8%) and l-cyclopropyl-6,7,8-trifluoro-l,4-dihydro-4-oxo-3-quinoline-carboxylic acid (92%). This comparison example shows that the use of a small amount of sulphuric acid and only brief heating to reflux affords poorer yields than the prior art. Comparison Example 2 300 g of ethyl l-cyclopropyl-6,7,8-trifluoro-l,4-dihydro-4-oxo-3-quinoline-carboxy-late, 106.8 g of water and 426 g of acetic acid were introduced and 3.8 g of sulphuric acid were added. The mixture was heated to reflux for 1.5 hours, then cooled to 80°C and 157.5 g of 4.8%) strength aqueous sodium acetate solution were added dropwise. The reaction mixture was then cooled to 20°C and the soUd was filtered off with suction. The solid was washed with 200 ml of water and dried in vacuo at 50°C. The solid consisted of a mixture of ethyl l-cyclopropyl-6,7,8-trifluoro-l,4-dihydro-4-oxo-3-quinoline-carboxylate (11%>) and l-cyclopropyl-6,7,8-trifluoro-l,4-dihydro-4-oxo-3-quinoline-carboxylic acid (89%)). This comparison example shows that the use of a small amount of sulphuric acid without the distillation which is to be carried out according to the invention affords poorer yields than the prior art. We Claim: 1. Process for the preparation of fluoroquinolonecarboxylic acids by hydrolysis of the corresponding C1-C4-alkyl esters of the formula in which R1 represents C1-C4-alkyl, R2 represents hydrogen, C1-C4-alkyl, C1-C4-alkoxy, halogen, nitro or cyano, R3 and R4 each represent halogen, R3 represents hydrogen, C1-C4-alkyl, halogen or nitro, and Y represents C1-C4-alkyl, cyclopropyl or phenyl, each of which can optionally be substituted by halogen, where R^ and Y together can also represent a -CH2-CH2-O- or -CH(CH3)-CH2-0- bridge bonded to the nitrogen atom by a C atom and where at least one of the radicals R2 to R2 represents fluorine, with addition of water, acetic acid and sulphuric acid, characterized in that, relative to 1 mol of Ci-C4-alkyl fluoroquinolonecarboxylate, 20 to 250 ml of water, 200 to 2000 ml of acetic acid and 2 to 25 g of sulphuric acid are employed, the amount of acetic acid relating to 100% strength acetic acid and the amount of sulphuric acid to 100% strength sulphuric acid, the reaction mixture is heated to reflux for 0.5 to 8 hours, then a mixture of acetic acid, Ci-C4-alkyl acetate, Ci-C4-alkyl alcohol and optionally water is distilled off until a bottom temperature in the range from 107 to 113°C results at normal pressure and finally the fluoroquinolonecarboxylic acid of the formula //■ in which the radicals R2to R3and Y have the meaning indicated in formula (I), is prepared and isolated. 2. Process as claimed in claim 1 wherein in the formula (I), R1 represents methyl or ethyl, R2 represents hydrogen, methyl, m.ethoxy, fluorine, chlorine, nitro or cyano, R3 represents fluorine or chlorine, R4 represents fluorine, R5 represents hydrogen, methyl, fluorine, chlorine or nitro and Y represents methyl, ethyl, isopropyl, cyclopropyl, fluorocyclopropyl, 4-fluorophenyl or 2,4-difluorophenyl. 3. Process as claimed in claim 1, wherein in the formula (II), R2 represents hydrogen, methyl, methoxy, fluorine, chlorine, nitro or cyano, R.3 represents fluorine or chlorine, R4 represents fluorine, R5 represents hydrogen, methyl, fluorine, chlorine or nitro and Y represents methyl, ethyl, isopropyl, cyclopropyl, fluorocyclopropyl, 4-fluorophenyl or 2,4-difluorophenyl. 4. Process as claimed in claims 1 to 3, wherein l-cyclopropyl-6,7,8- trifluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1- cycIopropyl6,7-difluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid, l-cyclopropyl5,7-difluoro-8-cyano-l,4-dihydro-4-oxo-3- quinolinecarboxylic acid, l-(2-fluoro)cyclopropyl-6,7-difiuoro-l,4- dihydro-4-oxo-3-quinolinecarboxylic acid, l-cyclopropyl-8-chloro-6,7-difluoro-l,4-dihydro-4-oxo-3-quinoline-carboxylic acid and 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid are prepared. 5. Process as claimed in claims 1 to 4, wherein the acetic acid is employed in the form of glacial acetic acid and the sulphuric acid in the form of 96 to 100% strength sulphuric acid. 6. Process as claimed in claims 1 to 5, wherein, for the isolation of the fluoroquinolonecarboxylic acid prepared, a pH in the range 2 to 5 is set by addition of a base. 7. Process as claimed in claim 6, wherein, for setting the pH, a 1 to 20% strength by weight aqueous sodium acetate solution is used.

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