Process for the synthesis of 1-cyclopropyl-quinolone-carboxylic acids and their derivatives.

The invention relates to new intermediates for 1-cyclopropylquinolonecarboxylic acids and a process for the preparation of cyclopropylquinolonecarboxylic acids using these intermediates.

Amine-substituted 4-quinolone-3-3-carboxylic acids in the 7-position are known for their good antibacterial action. The 1-cyclopropyl compounds in particular stand out from this group due to their high level of activity.

An example of this class is 1-cyclopropyl-6-fluoro-1,4-dihydro-7- (1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid (ciprofloxacin).

The process according to the invention now makes it possible to produce the 1-cyclopropyl-quinolonecarboxylic acids or their derivatives which are valuable on account of the excellent action. The invention relates to a process for the preparation of quinolonecarboxylic acid derivatives of the formula (I)<chemistry id="chem0001" num="0001"><img file="EP0332930A2_D0001.tif" /></chemistry> in the R² represents hydrogen, C₁-C₃-alkyl or halogen, X¹ is hydrogen, C₁-C₃-alkyl, halogen or NR⁸R⁹, wherein R⁸ and R⁹ together with the nitrogen atom to which they are bonded form a 5- or 6-membered ring, which as ring members additionally form the atoms or groups<img file="EP0332930A2_D0002.tif" />NR¹⁰ or O can contain and which can be optionally substituted one to two times by C₁-C₃-alkyl, hydroxy, methoxy or NR¹¹R¹², wherein R¹⁰ represents hydrogen, C₁-C₃-alkyl, acetyl or t-butoxycarbonyl, R¹¹ represents hydrogen or C₁-C₃-alkyl, R¹² is hydrogen, C₁-C₃-alkyl, acetyl or t-butoxycarbonyl, X² and X³ can be the same or different and represent hydrogen, nitro or halogen, A represents nitrogen or a radical C-X⁴, where X⁴ for hydrogen, C₁-C₃-alkyl, alkoxy with 1 to 3 carbon atoms, alkyl mercapto with 1 to 3 carbon atoms, halogen, nitro, cyano or alkoxycarbonyl with up to 3 carbon atoms in the alcohol part and Y represents a nitrile group, an ester group COOR⁵ or an acid amide group CONR⁶R⁷, where R⁵ represents C₁-C₃-alkyl and R⁶ and R⁷ can be identical or different and represent hydrogen or C₁-C₃-alkyl and R⁶ can be substituted phenyl, characterized, that in a first step quinolonecarboxylic acid derivatives of the formula (II)<chemistry id="chem0002" num="0002"><img file="EP0332930A2_D0003.tif" /></chemistry> in the X¹, X², X³, A and Y have the meaning given above with cyclopropane derivatives of the formula (III)<chemistry id="chem0003" num="0003"><img file="EP0332930A2_D0004.tif" /></chemistry> in the X⁵ represents halogen, R¹ is alkyl having 1 to 3 carbon atoms, R² has the meaning given above and Z means oxygen or sulfur under HX⁵ elimination to 1-cyclopropylquinolonecarboxylic acid derivatives of the formula (IV) according to the following scheme<chemistry id="chem0004" num="0004"><img file="EP0332930A2_D0005.tif" /></chemistry> implements the one on it<chemistry id="chem0005" num="0005"><img file="EP0332930A2_D0006.tif" /></chemistry> be converted into the 1-cyclopropylquinolonecarboxylic acid derivatives I by reductive removal of the residue ZR¹.

The process for preparing quinolonecarboxylic acid derivatives of the formula (I) is preferred<chemistry id="chem0006" num="0006"><img file="EP0332930A2_D0007.tif" /></chemistry> in the R² represents hydrogen or halogen, X¹ is halogen or NR⁸R⁹, wherein R⁸ and R⁹ together with the nitrogen atom to which they are bonded form a 5- or 6-membered ring, which as ring members additionally form the atoms or groups<img file="EP0332930A2_D0008.tif" />NR¹⁰ or O can contain and which can be optionally substituted one to two times by C₁-C₃-alkyl, hydroxy, methoxy or NR¹¹R¹², wherein R¹⁰ represents hydrogen, C₁-C₃-alkyl, acetyl or t-butoxycarbonyl, R¹¹ represents hydrogen or C₁-C₃-alkyl, R¹² is hydrogen, C₁-C₃-alkyl, acetyl or t-butoxycarbonyl, X² represents fluorine, X³ is hydrogen, nitro or halogen, A is nitrogen or a radical C-X⁴, where X⁴ is hydrogen, Halogen or nitro stands and Y represents a nitrile group or an ester group COOR⁵, where R⁵ represents C₁-C₃-alkyl, characterized in that in a first step quinolonecarboxylic acid derivatives of the formula (II)<chemistry id="chem0007" num="0007"><img file="EP0332930A2_D0009.tif" /></chemistry> in the X¹, X², X³, A and Y have the meaning given above with cyclopropane derivatives of the formula (III)<chemistry id="chem0008" num="0008"><img file="EP0332930A2_D0010.tif" /></chemistry> in the X⁵ represents chlorine or bromine, R¹ is alkyl having 1 to 3 carbon atoms, R² has the meaning given above and Z means oxygen or sulfur under HX⁵ elimination according to the following scheme<chemistry id="chem0009" num="0009"><img file="EP0332930A2_D0011.tif" /></chemistry> to 1-cyclopropylquinolonecarboxylic acid derivatives of the formula (IV), which by reductive removal of the residue ZR¹.<chemistry id="chem0010" num="0010"><img file="EP0332930A2_D0012.tif" /></chemistry> be converted into the 1-cyclopropylquinolonecarboxylic acid derivatives I. The process for preparing quinolonecarboxylic acid derivatives of the formula (I) is particularly preferred<chemistry id="chem0011" num="0011"><img file="EP0332930A2_D0013.tif" /></chemistry> in the R² represents hydrogen, fluorine or chlorine, X¹ is chlorine, fluorine or NR⁸R⁹, wherein R⁸ and R⁹ together with the nitrogen atom to which they are attached form a 5- or 6-membered ring which, as ring members, also forms the group<img file="EP0332930A2_D0014.tif" />NR¹⁰ may contain and which may optionally be substituted once or twice by methyl, hydroxy, methoxy or NR¹¹R¹², wherein R¹⁰ represents hydrogen, methyl, acetyl or t-butoxycarbonyl, R¹¹ represents hydrogen or methyl, R¹² denotes hydrogen, acetyl or tert-butoxycarbonyl, X² represents fluorine, X³ means hydrogen or nitro, A stands for C-X⁴, where X⁴ represents hydrogen, methyl, fluorine or chlorine and Y represents an ester group COOR⁵, where R⁵ is methyl or ethyl, characterized in that in a first step quinolonecarboxylic acid derivatives of the formula (II)<chemistry id="chem0012" num="0012"><img file="EP0332930A2_D0015.tif" /></chemistry> in the X¹, X², X³, A and Y have the meaning given above with cyclopropane derivatives of the formula (III)<chemistry id="chem0013" num="0013"><img file="EP0332930A2_D0016.tif" /></chemistry> in the X⁵ represents bromine, R¹ is ethyl, R² has the meaning given above and Z means oxygen or sulfur with elimination of HX⁵ according to the following scheme<chemistry id="chem0014" num="0014"><img file="EP0332930A2_D0017.tif" /></chemistry> to 1-cyclopropylquinolonecarboxylic acid derivatives of the formula (IV), which by reductive removal of the residue ZR¹<chemistry id="chem0015" num="0015"><img file="EP0332930A2_D0018.tif" /></chemistry> be converted into the 1-cyclopropylquinolonecarboxylic acid derivatives I.

The compounds of formula IV are also the subject of the invention.

The quinolonecarboxylic acid derivatives I can be converted into the antibacterially active quinolonecarboxylic acids in a known manner, in an acidic or alkaline manner.

If, for example, 7-chloro-6-fluoro-1,4-dihydro-4-oxo-3-quinolonecarboxylic acid ethyl ester and 1-bromo-1-ethoxy-cyclopropane are used as starting materials, the course of the reaction can be represented by the following formula:<chemistry id="chem0016" num="0016"><img file="EP0332930A2_D0019.tif" /></chemistry> The compounds of the formula (II) used as starting materials are known or can be prepared by known methods (EP 87106123.0). Examples include: 7-chloro-6-fluoro-4-hydroxy-3-quinolinecarboxylic acid methyl ester, 6,7-difluoro-4-hydroxy-3-quinolinecarboxylic acid ethyl ester, 6,7-difluoro-4-hydroxy-3-quinolinecarboxylic acid methyl ester, 6,7,8-trifluoro-4-hydroxy-3-quinolinecarboxylic acid ethyl ester, 8-chloro-6,7-difluoro-4-hydroxy-3-quinolinecarboxylic acid ethyl ester, 7-chloro-4-hydroxy-8-methyl-3-quinolinecarboxylic acid ethyl ester, 7-chloro-6-fluoro-4-hydroxy-8-methyl-3-quinolinecarboxylic acid ethyl ester, 6-fluoro-4-hydroxy-7-methyl-3-quinolinecarboxylic acid ethyl ester, 6,7-dichloro-4-hydroxy-3-quinolinecarboxylic acid ethyl ester.

The cyclopropane derivatives of the formula III used as starting materials are known (J. Org. Chem. <u style="single">1985</u>, 3255; Recl. Trav. Chim, Pays-Bas<u style="single">100</u>, 184 (1981).

Examples include: 1-chloro-1-methoxy-cyclopropane, 1-bromo-1-methoxy-cyclopropane, 1-bromo-1-ethoxycyclopropane, 1-bromo-1-methyl-mercapto-cyclopropane.

The substitution reactions II + III → IV are carried out in a temperature range from 20 to 120 ° C., preferably 60 to 100 ° C.

The following can be used as diluents for this reaction: dimethylformamide, N-methylpyrrolidone, tetramethylurea, dimethylacetamide.

Inorganic and organic bases can be used as acid binders for this reaction. Examples include: 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] -undec-7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, pyridine, dimethylbenzylamine, potassium tert-butylate , Potassium carbonate, sodium hydrogen carbonate, sodium hydride.

The reaction can be carried out at normal pressure, but also at elevated pressure. Generally one works at pressures between about 1 and about 100 bar, preferably between 1 and 10 bar.

In the case of Z = O, the following are used as reducing agents for the reduction step IV → I: sodium cyanoborohydride, sodium borohydride, lithium aluminum hydride and preferably a 1: 1 mixture of sodium borohydride and boron trifluoride-diethyl ether complex. In the case of Z = S, known desulfurization reagents such as Raney nickel are used. The reaction can be carried out, for example, in a diluent such as tetrahydrofuran or dioxane.

The temperature range is between 0 and 100 ° C, preferably between 0 and 80 ° C.

The following example illustrates the invention.

example

<chemistry id="chem0017" num="0017"><img file="EP0332930A2_D0020.tif" /></chemistry>

7-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester

2.7 g (0.01 mol) of 7-chloro-6-fluoro-4-hydroxy-3-quinolinecarboxylic acid ethyl ester, 2.97 g (0.03 mol) of potassium carbonate and 4.95 g (0.03 mol) of 1- Bromine-1-ethoxy-cyclopropane are heated in 80 ml of N-methylpyrrolidone at 80 ° C for 8 hours. Then you remove everything volatile in a high vacuum. The residue is taken up in water and extracted with methylene chloride. The organic phase is dried over sodium sulfate and concentrated. The residue is purified by chromatography on silica gel with methylene chloride / methanol 99/1 as the eluent.

For the reduction, a mixture of 0.76 g (0.02 mol) of sodium borohydride and 2.83 g (0.02 mol) of boron trifluoride-diethyl ether complex in 50 ml of absolute tetrahydrofuran is prepared with ice cooling. The 7-chloro-1- (1-ethoxy-cyclopropyl) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester is added and the mixture is heated under reflux for 1.5 hours. The reaction mixture is then concentrated and the residue is recrystallized from glycol monomethyl ether. 1.86 g (60%) of the title compound with a melting point of 219-221 ° C. are obtained.