NO172743B - PROCEDURE FOR THE PREPARATION OF QUINOLINCARBOXYLIC ACID DERIVATIVES - Google Patents

Description

- - The present invention relates to a method for producing compounds of general formula I

in which

r^" denotes phenyl optionally substituted with 1 or 2 halogen-6 7 8 atoms, or a group of the general formula -CH-CR RR in which R 6 , R 7 and R 8 denote hydrogen or halogen;

R 2 denotes piperazinyl or 4-methylpiperazinyl;

R denotes hydrogen or fluorine, provided that either R<1>

contains a halogen atom or that R3 is fluorine

and pharmaceutically acceptable salts thereof.

It is known that a group of the 7-substituted carboxylic acid derivatives of general formula I (in which R 2 denotes piperazinyl, 4-methylpiperazinyl, R denotes a group of

6 7 8 6 7 8

general formula -CH,CR R R (in which R , R and R denote hydrogen or halogen) and R 3 denotes fluorine) exhibits high antibacterial activity (J. Med. Chem. 1986, 29, 445; Drugs of Fut. 1984, 9, 246; 23rd Intersci. Conf. Antimicrob. Agents Chemother. 1983, Abst. 658, 7th Int. Symp. Fut. Trends Chemother. 1986, 86). These compounds can be prepared by reacting 6,7,8-trifluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and cyclic amines (Belgian patent 887874, British patent 2057444, Austrian patent 537813 and European patent 1064489 ).

Another group of the 7-substituted-quinoline-3-carboxylic acids of general formula I (in which R<1> denotes phenyl optionally substituted with 1 or 2 halogen atoms, R 2 denotes piperazinyl or 4-methyl-piperazinyl, and R<3> denotes hydrogen, also exhibits high antibacterial activity (24th Intersci. Conf. Antimicrob. Agents Chemother, 1984, Abst. 72-78., Antimicrob. Agents Chemother. 1987, 619, Antimicrob. Agents Chemother. 1986., 192-208). These compounds can be prepared by reacting 1-substituted-phenyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and cyclic amines in the presence of a solvent at a temperature of 100° C for 20 hours

(European patent 131839, J. Med. Chem. 1985, 1558, J. Med. Chem. 1987, 504.). Several methods are known for the production of oxacin derivatives of

see Table I below

According to methods 1 and 2 shown in table 1, the products are prepared by reacting the corresponding 6-fluoro-7-chloro-quinolinecarboxylic acid or ester with piperazine or N-methylpiperazine.

The disadvantage of the above-mentioned methods is that amination with piperazine or N-methylpiperazine does not take place selectively at the 7-position, but that nucleophilic substitution takes place at both the 6- and 7-position.

In the case of difloxacin, by-product formation amounts to

15% by weight according to the applicants' attempts. For norfloxacin, this byproduct formation is described in J. Med. Chem. 23, 1358 (1980).

To improve the selectivity, two ways are possible:

- to use F as a more active substituent instead of Cl in the 7-position, and in the case of ofloxacin in the 10-position and/or

- to activate these positions.

For activation of the 7-position and 10-position, BF2 chelate starting materials were first used (JP 59-122470 (reaction 7 in Table I) and JP 58-29789 (reaction 6 in Table I)).

However, production of the BF2 chelates requires temperatures above 200 °C, requires special chemical reagents and equipment, and furthermore, a large amount of fluorinated acid waste is formed in the process, which makes the method unsuitable for production on a large scale.

To avoid this disadvantage for the production of ofloxacin, boric anhydride was used as starting material (reaction 3 in Table I) (JP 58-188138).

Although according to the definition of Xx and X2 at the 9-position and 10-position, where Xx and X2 are the same or different halogen atoms, -. the description only indicates examples of 9, 10- d luorutg■■ :•...jsmaterials.

The applicant has found that by using a tricyclic starting material described in JP 58-188138, and with a fluorine substituent in the 9-position (corresponding to the 6-position in the starting material according to the invention) and a chlorine substituent in the 10-position (corresponding to 7 -position in the starting material according to the invention), the desired nucleophilic substitution of the piperazinyl or N-alkyl-piperazinyl substituent for the chlorine substituent will not take place according to the reaction conditions described in the Japanese patent and present application.

No reaction takes place at all at room temperature.

At 80 °C and 110 °C the applicant was able to separate 10-chloro-2,3-dihydro-3-methyl-9-(1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de ][1,4]-benzoxazine-6-carboxylic acid by-product instead of the desired product.

It is therefore surprising when using the 6-fluoro-7-chloro starting material according to the invention that the desired end product can be obtained with a high yield and with a high purity. The present method cannot therefore be considered professional based on knowledge of these publications, and the present method and process products cannot be considered to be professional in light of JP 59-122470.

The reason for this is that the BF2 group activates the 7 and 10 positions to a greater extent than the boronic anhydride group. This can be supported by the fact that using (9-fluoro-10-chloro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4] benzoxazine-6-carboxylate-O<6>,07)-difluoro-boron compound instead of (9-fluoro-10-chloro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido The [1,2,3-de][1,4]benzoxazine-6-carboxylate-0<6>,0<7>)-bis(acetate-0)-boron compound will give the desired

product is obtained.

The method according to the invention is characterized

in that a compound of general formula II

in which R denotes halogen or an aliphatic acyloxy group containing 2 to 6 carbon atoms, R4 denotes fluorine or chlorine is reacted with a piperazine derivative of general formula III (wherein R<5> denotes hydrogen or raethyl) or a salt thereof, and that the thus obtained compound of general formula IV

12 3

(in which R, R , R and R are as above), subjected to hydrolysis without isolation, and if desired that the

thus obtained compound of general formula I is converted to

.a salt thereof or released from its salt.

The advantage of the method according to the invention is

that it enables the preparation of the compounds of general formula I in a simple way with very high yields and during a short reaction time.

The boron derivatives of general formula IV are new compounds.

According to a preferred embodiment of the method according to the invention, the boron derivative of general formula IV is converted to the desired quinoline-3-carboxylic acid of general formula I without isolation.

The boron derivatives of general formula II can be reacted with the amine of general formula III if desired in the presence of an inert organic solvent and an acid-binding agent.

An acid amide (e.g. dimethylformamide, dimethylacetamide), a ketone (e.g. acetone, methyl ethyl ketone), an ether (e.g. dioxane, tetrahydrofuran, diethylether), an ester (e.g. . ethylacetate, methylacetate, ethylpropionate), a sulfoxide (e.g. dimethylsulfoxide), an alcohol (e.g. methanol, ethanol, 1-decanol, butanol).

An organic or inorganic base can be used as an acid-binding agent. From the group of organic bases, mention may be made of trialkylamines (e.g. triethylamine, tributylamine), cyclic amines (e.g. pyridine, 1,5-diazabicyclo[5.4.0]-undec-5-ene, 1,5-diazabicyclo[ 4.3.0]-non-5-ene, 1,4-diazabi-cyclo[2.2,2]octane), while hydroxides or carbonates of alkali or alkaline earth metals are preferably used as inorganic bases. Thus, potassium carbonate, potassium hydrogencarbonate, sodium hydroxide, calcium hydroxide, etc., or an excess of the amine of general formula III can be advantageously used as an acid-binding agent.

The boron derivative of general formula II and the amines of general formula III can be reacted at a temperature between 0 and 200° C, depending on the solvent used. The reaction time can vary between half an hour and 10 hours. The reaction time also depends on the reaction temperature. If the reaction is carried out at a higher temperature, the reaction time can be shortened. The reaction conditions stated above are preferred values and other conditions can also be used.

The compounds of general formula IV are hydrolyzed without isolation to the desired quinoline-3-carboxylic acids of general formula I, under acidic or basic conditions.

Basic hydrolysis can preferably be carried out by heating, using a hydroxide or carbonate of an alkali metal or alkaline earth metal hydroxide, used as an aqueous solution. An aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, calcium hydroxide can preferably be used. However, organic amines (eg triethylamine) can also be used in the hydrolysis step.

Acid hydrolysis can preferably be carried out using an aqueous inorganic acid. One can preferably proceed by hydrolyzing a compound of general formula IV by heating with an aqueous solution of hydrochloric acid, hydrogen, bromide, sulfuric acid or phosphoric acid. Hydrolysis can also be carried out using an organic acid (e.g. acetic acid, propionic acid, etc.).

Hydrolysis of the compounds of general formula IV can also be carried out in an aqueous medium in the presence of a water-miscible organic solvent. For this purpose, for example, alcohols (e.g. methanol, ethanol), a ketone (e.g. acetone), an ether (e.g. dioxane), an acid amide (e.g. dimethylformamide), a sulfoxide (e.g. .eg dimethylsulfoxyd), or pyridine is used.

. The thus obtained quinoline-3-carboxylic acid of general formula I can be isolated, for example, by adjusting the pH value of the aqueous solution to a suitable value and separating the precipitated crystals, e.g. by filtration or centrifugation or by lyophilization of the aqueous reaction

tion mixture.

The compounds of general formula I can be converted into pharmaceutically acceptable salts thereof in a known manner. Thus, acid addition salts can preferably be formed, for example salts formed with hydrogen halides, sulphonic acids, sulfuric acid or organic acids. Chlorides, bromides, arylsulphonates, methanesulphonates, maleates, fumarates, benzoates etc. can preferably be formed. The compounds of general formula I also form salts with alkali or alkaline earth metals or other metal ions. Accordingly, sodium, potassium, magnesium, silver, copper salts etc. can be produced.

The compounds of general formula I and pharmaceutically acceptable salts thereof can be converted into hydrates (e.g. hemihydrates, trihydrates, etc.) by methods known per se.

The starting materials of general formula II can be prepared by reaction of 1-phenyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (European patent 131 839) or 1-ethyl-6 ,7,8-trifluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (British Patent 2,057,440) with a border derivative (eg a compound of general formula V

(in which R is halogen or an aliphatic acyloxy group containing 2 to 6 carbon atoms)) or with fluoroborate in aqueous or organic medium.

Further details of the present invention can be found in the following examples without limiting the scope of protection to the specified examples.

Example 1

1.59 g of (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-0 3 ,0 4 )-difluoro-boron was reacted with 1.29 g piperazine in 8 ml of dimethyl sulfoxide at 100° C. for 3 hours. A 6 w/v% aqueous solution of 12.6 ml of sodium hydroxide was added and the hydrolysis was carried out by heating for 2 hours. The reaction mixture was filtered, the pH was adjusted to 7 with 96 w/v% acetic acid and was diluted with 15 ml of water. The crystalline reaction mixture was cooled overnight and the precipitated crystals were filtered, washed with water and dried. 1.61 g of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid were thus obtained.

Sm.p. is 234 - 236° C.

Analysis for the formula C]_6H]_7<F>2N3°3:

Example 2

1.99 g of (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quicholine-3-carboxylate-0 3 ,0 4 )-bis(diacetate-O)-boron was reacted with 1.29 g of piperazine in 8 ml of dimethyl sulfoxide at 110° C. for 2 hours. A 3 w/v% aqueous solution of 20 ml of 3 w/v% sodium hydroxide was added. The reaction mixture was refluxed for 1 hour and then filtered and the pH was adjusted to 7 with 96 w/v% acetic acid. After cooling and diluting with 10 ml of water, the precipitated crystals were filtered and dried. 1.59 of ocher colored 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid was obtained. Sm.p. 234°C.

Analysis for the formula C,gH,7F2N3°3:

Example 3

According to Example 2, 1.06 g of (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-0 3 ,0 4 )-bis(propionate-0) -boron reacted with 0.64 g of piperazine in 4 ml of dimethylsulfoxyd. A 6 w/v% aqueous solution of 6.3 ml of sodium hydroxide was added, and the reaction mixture was refluxed for 1 hour. After filtration, the pH was adjusted to 7 with 96 w/v% acetic acid, 10 ml of water was added and the reaction mixture was cooled overnight. The precipitated crystals were filtered, washed with water and dried. 0.74 g of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid was thus obtained. Sm.p. is 232 - 236° C.

Analysis for the formula C]_6Hi<_>7F2N3°3:

Example 4

According to example 1, 1.59 g of (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-0 3 ,0 4 )-difluoro-boron was reacted with 1 .5 g of 1-methylpiperazine in 8 ml of dimethylsulfoxide. 1.54 g of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-methyl-piperazino)-quinoline-3-carboxylic acid were thus obtained. Sm.p. is 237 - 240° C.

Analysis for the formula C, _,H, nF-N,0, :

Example 5

According to Example 2, 1.99 g of (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-0 3 ,0 4 )-bis(acetato-0) -boron reacted with 1.5 g of 1-methylpiperazine. 1.5 g of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-methyl-piperazino)-quinoline-3-carboxylic acid were thus obtained. Sm.p. 238 - 240° C. Analysis for the formula C, 7H, -F-N^O-.:

Example 6

According to Example 3, 1.06 g of (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-0 3 ,0 4 )-bis(propionate-0) -boron reacted with 0.75 g of 1-methylpiperazine. 0.79 g of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-methyl-piperazino)-quinoline-3-carboxylic acid was thus obtained. Sm.p. is 239 - 240° C.

Analysis for the formula C,_H,qF2N3°3<:>

Example 7

0.46 g 1-(4<1->fluorophenyl)-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-0 3 ,0 4 )-bis(acetate- 0)-boron was reacted with 0.6 g of N-methylpiperazine in 5 ml of dimethylsulfoxide at 110° C. for 1 hour. 10 ml of 5 w/v% aqueous sodium hydrogencarbonate solution was added, the reaction mixture was refluxed for 2 hours after which the pH was adjusted to 7 with 96 w/v% acetic acid. The reaction mixture was cooled and the precipitated crystals were filtered and washed with cold water.

3.54 g of 1-(4'-fluorophenyl)-6-fluoro-7-(N-methyl-piperazinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid were thus obtained. Melting point is 282 - 284° C. The carboxylic acid thus obtained was dissolved in a weak solution of hydrochloric acid under heating, the solution was evaporated in vacuo and the hydrochloride salt of 1-(4<1->fluorophenyl)-6-fluoro-7-(N -methyl-piperazinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid was thus obtained.

The product decomposes above 270° C.

Analysis for the formula C21H, qF2N30., :

Claims (8)

1. Process for the preparation of compounds of general formula I in which R"*" denotes phenyl optionally substituted with 1 or 2 halogen 6 7 8 atoms, or a group of general formula -CH„CR R R 6 7 8 wherein R , R 1 and R 2 represent hydrogen or halogen; R 2 denotes piperazinyl or 4-methylpiperazinyl; R<3> denotes hydrogen or fluorine, provided that either R<1 > contains a halogen atom or that R<3> is fluorine and pharmaceutically acceptable salts thereof, characterized in that a compound of general formula II in which R denotes halogen or an aliphatic acyloxy group containing 2 to 6 carbon atoms, R 4 denotes fluorine or chlorine is reacted with a piperazine derivative of general formula III (in which R<5> denotes hydrogen or methyl) or a salt thereof, and that the thus obtained compound of general formula IV (in which R, R 1, R 2 and R 3 are as indicated above), is subjected to hydrolysis without isolation, and if desired that it thus obtained compound of general formula I is converted into a salt thereof or released from its salt. 2. Process according to claim 1, characterized in that a compound of general formula II is reacted with an amine of general formula III in the presence of an organic solvent, preferably an acid amide, sulfoxide, ketone, alcohol, ether or ester. 3. Method according to claim 2, characterized in that dimethylsulfoxide is used as organic solvent. 4.. Method according to claim 3, characterized in that an amine or an excess of the compound of general formula III is used as an acid-binding agent. 5. Method according to claim 1, characterized in that the hydrolysis is carried out in an acidic medium. . 6. Method according to claim 5, characterized in that the reaction is carried out using an organic or inorganic acid, preferably hydrochloric acid, sulfuric acid or acetic acid. 7. Method according to claim 1, characterized in that the hydrolysis is carried out in an alkaline medium. 8. Method according to claim 7, characterized in that an alkali metal hydroxide, an alkaline earth metal hydroxide or an organic base, preferably an aqueous triethylamine solution, is used.