NO175859B - - Google Patents

Description

The present invention relates to a new process for the production of 1-cyclopropyl-7-substituted-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid derivatives and pharmaceutically acceptable salts thereof.

It is known that the 1-cyclopropyl-7-substituted-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid derivatives of general formula I

(wherein R denotes piperazinyl, 4-methyl-piperazinyl or

4-ethyl-piperazinyl group) exhibits high antibacterial activity (Eur. J. Clin. Microbiol. 1983, 2, p. 111; J. Clin. Pharmacol. 1985, 25_, p. 82; Drugs Exptl. Clin. Res. 1985, 5, p. 317).

The quinoline carboxylic acids of general formula I can be prepared by reacting 1-cyclopropyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and a cyclic amine in the presence of a solvent at a temperature of 135-140°C for 2 hours (German off. 3.033.157; German off. 3.142.854). There are several known processes for the preparation of oxazine derivatives of the formulas

Ia, where X<1>= F

R<1> = H

R<2> = CH3 ofloxacin

R<3> = CH3

Ib, where X<1>= F

R = C 2 H 5

R<3>= H norfloxacin

R<1> = H

Ic, where X<1> = F

R = C 2 H 5

R<3> = CH3<p>efloxacin

R<1> = H

Id, where X<1> = F

R<1> = H

R = cyclopropyl ciprofloxacin

R<3> = CH3

le, where X<1> = F

R<1> = H

R = -NH-CH 3 amifloxacin

R<3> = CH3

See comparison example A.

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

(References: EP 0 047 005 ofloxacin

US 4,146,719

US 4,472,579 norfloxacin

THE 2,840,910

DE 284 366 pefloxacin

EP 004 935 cyprofloxacin

EP 090 424 amifloxacin).

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

In the case of cyprofloxacin, by-product formation amounts to 16% by weight according to the applicant's experience. For norfloxacin, this byproduct formation is described in J. Med. Chem. 23, 1358

(1980).

To improve the selectivity, there are two possible ways: 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 comparative example A) and JP 58-29789 (reaction 6 in comparative example A). Production of the BF2 chelate, however, requires temperatures above 200 °C, requires special chemical reagents and equipment, and in addition, a large amount of fluorinated, acidic waste is formed, which makes the method unsuitable for large-scale production.

In order to avoid this disadvantage in the production of ofloxacin, boric anhydride was used as starting material (reaction 3 in comparative example A) JP 60-78986 and JP 58-188138).

According to the definition of X1 and X2 at the 9-position and 10-position, Xx and X2 are indicated to be the same or different halogen atoms, but in the description, however, there are only examples of 9,10-difluoro starting materials.

It has been found that when using a tricyclic starting material described in JP 58-188138 and which has 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 invention (comparative example B).

As can be seen from comparative example B, no reaction takes place at room temperature.

At 80 °C and 110 °C, only 10-chloro-2,3-dihydro-3-methyl-9-(1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de] could be separated The [1,4]benzoxazine-6-carboxylic acid by-product instead of the desired product.

On the basis of the comparative examples in comparative example B, it is surprising that use of the 6-fluoro-7-chloro starting material according to the invention will give the desired end product in a high yield with high purity.

Nor can the present method be considered professional in light of JP 59-122470.

The reason is that the BF2 group activates the 7- and 10-positions in a stronger way than the boronic anhydride group.

This is 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>,0<7->)difluoroboron compound instead of (9-fluoro-10-chloro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[l, 2, 3-de] [1,4]-benzoxazine-6-carboxylato-O6,07-bis-(acetato-O)-boron compound, the desired product is obtained (see comparative example C).

According to the present invention, a method for the preparation of compounds of general formula I is provided

wherein R denotes piperazinyl, 4-methyl-piperazinyl or 4-ethyl-piperazinyl group and pharmaceutically acceptable salts thereof, which method is characterized in that a compound of general formula II

wherein R and R denote an aliphatic acyloxy-

group containing 2 to 6 carbon atoms optionally substituted with halogen, or denotes an aromatic acyloxy group containing 7 to 11 carbon atoms, is reacted with a piperazine derivative of general formula III

wherein r<3> denotes hydrogen, methyl or ethyl or a salt thereof, and that the thus obtained compound of general formula IV'

wherein R, Rx and R are as above are subjected to hydrolysis after or without isolation, and, if desired, that the compound of general formula I is converted into a salt thereof or that the acid is released from its salt.

The advantage of the method according to the invention is that it makes the desired compound of general formula I available in a simple way with high yields and during a short reaction time.

According to a preferred embodiment of the method according to the invention, the borate derivative of general formula IV (in which R, R-<1-> and R^ are as indicated above) is converted to the desired quinoline-3-carboxylic acid of general formula I without isolation.

The borate derivatives of general formula IV are new compounds.

The invention thus also relates to compounds of general formula IV

in which R denotes piperazinyl, 4-methyl-piperazinyl or 4-ethyl-piperazinyl group, R<1> and R<2> denotes halogen, an aliphatic acyloxy group containing 2 to 6 carbon atoms, optionally substituted with halogen, or denotes an aromatic acyloxy group containing 7 to 11 carbon atoms.

The borate derivatives of general formula II and the cyclic amine of general formula III can optionally be reacted in

presence of an inert organic solvent and an acid-binding agent.

Acid amides (e.g. dimethylformamide, dimethyl acetamide), ketones (e.g. acetone, methyl ethyl ketone) are preferably used as inert organic solvents.

ethers (e.g. dioxane, tetrahydrofuran, diethyl ether), esters (e.g. ethyl acetate, methyl acetate, ethyl propionate),

sulfoxides (e.g. dimethylsulfoxide), alcohols (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

5

mention may be made of trialkylamines (e.g. triethylamine, tri-butylamine), 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-diazabicyclo [2 , 2 , 2}octane), while as inorganic

bases preferably hydroxides or carbonates of alkali or alkaline earth metals can be used. Potassium carbonate, potassium hydrogencarbonate, sodium hydroxide, calcium hydroxide, etc., or an excess of the amines of general formula III can thus preferably be used as an acid-binding agent.

The boron derivative of general formula II and the cyclic amine of general formula III can be reacted at a temperature varying from 0 to 200°C, depending on the solvent used. The reaction time can vary between 0.5 hours and 10 hours depending on the reaction temperature. If the reaction is carried out at an elevated temperature, the reaction time can be shortened. The reaction conditions given above are only preferred values, and other conditions may also be used.

The borates of general formula IV (in which R, and R<2> are as indicated above) can be hydrolyzed to the desired

quinoline-3-carboxylic acids of general formula I after or without isolation, under acidic or basic conditions. The compound of general formula IV (in which R is as indicated above) is precipitated from the reaction mixture, for example by cooling, and can be separated, for example by filtration or centrifugation if desired.

Basic hydrolysis can preferably be carried out by heating an aqueous solution of hydroxides or carbonates of alkali metals or hydroxides of alkaline earth metals. An aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, calcium hydroxide, potassium hydrogen carbonate can preferably be used. 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 borate of general formula IV by heating this with an aqueous solution of hydrochloric acid, hydrogen bromide, sulfuric acid or phosphoric acid. The hydrolysis can also be carried out using organic acids (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, alcohols (e.g. methanol, ethanol), ketones (e.g. acetone), ethers (e.g. dioxane), acid amides (e.g. formamide, dimethylformamide), sulfoxides (e.g. eg dimethylsulfoxide) or pyridine.

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 mixture.

The compounds of general formula I can be converted into pharmaceutically acceptable salts thereof by methods known per se. thus acid addition salts are preferably formed with hydrogen halides, sulphonic acids, sulfuric acid or organic acids. One can preferably form chlorides, bromides, 4-methyl-phenyl-sulphonates, methanesulphonates, maleates, fumarates, benzoates, etc. 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 can be prepared.

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.

According to another feature of the present invention, new compounds of general formula IV (in which R, R<1> and R are as indicated above) have been provided.

The starting materials of general formula II can be prepared, e.g. by reacting 1-cyclopropyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (German off. 3,141,854) with a boron derivative such as a compound of general formula V

(in which R , R<2> and R<5> denote halogen, an aliphatic acyloxy group containing 2 to 6 carbon atoms, optionally substituted with halogen, or an aromatic acyloxy group containing 7 to 11 carbon atoms) or with fluoroborate in an aqueous or organic medium.

To 2.07 g (5 mmol) (9-fluoro-10-chloro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine -6-carboxylato-0<6>,0<7>)-bis(acetate-0)-boron compound (prepared from ethyl-9-fluoro-10-chloro-2,3-dihydro-3-methyl-7-oxo -7H-pyrido[1,2,3-de]-[1,4]benzoxazine-6-carboxylate with acetic anhydride and boric acid) was added to 10 ml of dimethylsulfoxide, 1.29 g (15 mmol) of piperazine and 0.5 g of triethylamine , and the mixture was heated to 110°C for 2 hours.

Processing:

The mixture was cooled overnight. No precipitation was observed. Triethylamine was then removed in vacuo, and 15 mL of acetone was added. The pH was adjusted to 1 with concentrated aqueous hydrochloric acid and the mixture was stirred on a magnetic stirrer for 30 minutes. The pH was adjusted to 3 with concentrated aqueous ammonia and the mixture was cooled. The precipitate was collected and crystallized from methanol.

Product: 0.49 g crystals. Melting point: >270°C.

The product showed melting point depression with the authentic sample of 2,3-dihydro-9-fluoro-3-methyl-10-(1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de][1,4 ]benzoxazine-6-carboxylic acid

(N-desmethyl ofloxacin). The melting point of N-desmethyl ofloxacin is: 258-260°C (decomposition).

<1>The Hnmr spectrum of the product in CDC13 exhibited characteristic signals at:

6 = 8.72 ppm (1H, singlet) for C(5)H

6 = 7.83 ppm (1H, singlet) for C(8)H

The singlet appearing for C(8)H suggested the absence of the fluorine group in the 9-position.

(Respective characteristic signals for N-desmethyl ofloxacin in CDC13:

6 = 8.64 ppm (1H, singlet) for C(5)H

6 = 7.76 ppm (1H, doublet) for C(8)H).

Elemental analysis of the product, calculated for C17<H>18C1N304:

was consistent with the formula supporting that the product was 10-chloro-2,3-dihydro-3-methyl-9-(1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de][1 ,4]benzoxazine-6-carboxylic acid. b) To 2.07 g (5 mmol) (9-fluoro-10-chloro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4 ]benzoxazine-6-carboxy-lato-0<5>,0<7>)-bis(acetate-O)-boron compound (prepared from ethyl-9-fluoro-10-chloro-2,3-dihydro-3-methyl -7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate and acetic anhydride and boric acid) was added to 10 ml of dimethylsulfoxide, 1.29 g (15 mmol) of piperazine and 0. 5 g of triethylamine, and the mixture was heated to 80°C for 1 hour. Triethylamine was then removed in vacuo, and 25 mL of acetone was added. The pH was adjusted to 1 with concentrated aqueous hydrochloric acid, and the mixture was stirred with a magnetic stirrer for 30 minutes. The resulting precipitate was collected and refluxed in a mixture of 40 ml of ethanol and 5 ml of a concentrated aqueous solution of ammonia. After refluxing for 1 hour, ethanol was distilled off in vacuo and the remaining mixture was kept refrigerated overnight. The precipitate was collected, washed with water, dried and crystallized from methanol to form 0.49 g of crystals, m.p.: 270°C. The product showed melting point depression with the authentic sample of N-desmethyl ofloxacin. <1>The Hnmr spectrum of the product in CDC13 exhibited characteristic signals at:

6 = 8.72 (1H, singlet) for C(5)H

6 = 7.83 (1H, singlet) for C(8)H

The singlet that appeared for C(8)H suggested the absence of the fluorine group in the 9-position.

(Respective characteristic signals of N-desmethyl ofloxacin in CDC13:

6 = 8.64 (1H, singlet) for C(5)H

6 = 7.78 (1H, doublet) for C(8)H).

Elemental analysis of the product calculated for C17<H>18C1N304:

was consistent with the formula, supporting that the product was 10-chloro-2,3-dihydro-3-methyl-9-(1-piperidinyl)-7-oxo-7H-pyrido[1,2,3-de][ 1,4]benzoxazine-6-carboxylic acid. c) The same test conditions as above were used, except that the reaction temperature was lowered from 80°C to room temperature (22°C). No reaction whatsoever took place.

To 1.73 g (5 mmol) (9-fluoro-10-chloro-2,3-dihydro-8-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine -6-carboxylato-0<6>,0<7>)-difluoro-boron compound (prepared from ethyl-9-fluoro-10-chloro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[ 1,2,3-de][1,4]benzoxazine-6-carboxylate and boron trifluoride), 8 mL of dimethylsulfoxide, 1.29 g (15 mmol) of piperazine, and 0.5 g of triethylamine, and the mixture was heated to 110 °C for 2 hours.

Processing:

The reaction mixture was cooled, the precipitate was filtered off, washed with 5 ml of methanol and crystallized from a mixture of chloroform, methanol and water.

Product: 0.64 g crystals, m.p.: >256-260°C (decomposition).

The product showed no melting point depression with the authentic sample of 2,3-dihydro-9-fluoro-3-methyl-10-(1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de][1, 4]benzoxazine-6-carboxylic acid (N-desmethyl ofloxacin). The melting point of N-desmethyl ofloxacin is 258-260°C (decomposition).

<1>The Hnmr spectrum of the product in CDC13 exhibited characteristic signals at:

6 = 8.64 ppm (1H, singlet) for C(5)H

6 = 7.76 ppm (1H, doublet) for C(8)H

The doublet that appeared for C(8)H proves the presence of the fluorine group at the 9-position.

Elemental analysis of the product, calculated for C17H18FN3d4 • 3/2 H20

was consistent with the formula, supporting that the product, obtained in 58% yield, was the expected 2,3-dihydro-9-fluoro-3-methyl-10-(1-piperazinyl)-7-oxo-7H- pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid.

Further details of the present invention can be found in the following examples.

Example 1

4.1 g (1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-O-^,O^)-bis-(aceto-O)-boron and 2.8 g of piperazine anhydride were heated in 16 ml of dimethylsulfoxide to 110°C with stirring. 40 ml of a 3% w/v aqueous sodium hydroxide solution was added to the brown-red

solution, and the reaction mixture was refluxed for 1 hour. The warm, pale yellow solution was filtered and the pH adjusted to 7 by adding 1.8 ml of 96% acetic acid. The reaction mixture was cooled to room temperature, the precipitated white crystals were filtered, washed with water and methanol and dried. The impure product was purified by boiling in 10 ml of water. 2.99 g of 1-cyclopropyl-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid were thus obtained. The product decomposes at 255°C.

Analysis for the formula C^- yE^ gFN^ 0^ '•

Calculated: C=61.62% H=5.48% N=12.68%

Found: C=61.58% H=5.50% N=12.61%.

Example 2

By reaction of (1-cyclopropyl-6-fluoro-4-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-O^,O^)-bis-(acetato-O)-boron and N -methyl-piperazine according to Example 1, 1-cyclopropyl-6-fluoro-7-(4-methyl-piperazino)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid was prepared. The product decomposes at 248-250°C.

Example . 3

4.1 g (1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-O^,0<4>)-bis-(acetato-O)- boron and 3.7 g of N-ethyl-piperazine were heated in 16 ml of dimethylsulfoxide to 90°C with stirring. After 10 minutes, 40 ml of a 3% w/v aqueous sodium hydroxide solution was added and the reaction mixture was boiled for 1 hour under reflux. The hot solution was filtered, and the pH was adjusted to 7 with 96% acetic acid. The reaction mixture was cooled, and the precipitated crystals were filtered and washed with water. Thus, 3.3 g of 1-cyclopropyl-7-(4-ethyl-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-

quinoline-3-carboxylic acid. M.p.: 183-185°C.

Analysis for the formula C-^1122^3<0>3:

Calculated: C=63.35% H=6.17% N=ll.69%

Found: C=63.31% H=6.21% N=11.70%.

Example 4

3.3 g of (1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-0^,0^)-difluoroboron was reacted with 3.7 g N-ethyl-piperazine according to example 3. Thus 3.4 g of 1-cyclopropyl-7-(4-ethyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-quinoline were obtained -3-carboxylic acid which, in mixture at any ratio with the product according to example 3, showed no melting point depression.

Claims (8)

!• Process for the preparation of compounds of general formula I wherein R denotes piperazinyl, 4-methyl-piperazinyl or 4-ethyl-piperazinyl group and pharmaceutically acceptable salts thereof, characterized in that a compound of general formula II wherein R<1> and R<2> denote an aliphatic acyloxy group containing 2 to 6 carbon atoms optionally substituted by halogen, or denote an aromatic acyloxy group containing 7 to 11 carbon atoms, is reacted with a piperazine derivative of general formula III in which R<3> denotes hydrogen, methyl or ethyl or a salt thereof, and that the thus obtained compound of general formula IV in which R, R<1> and R2 are as indicated above are subjected to hydrolysis after or without isolation, and, if desired, that the compound of general formula I is converted into a salt thereof or that the acid is released from its salt. 2. Method according to claim 1, characterized in that a compound of general formula II is reacted with a piperazine derivative 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. Process according to claim 1, characterized in that the reaction between the compounds of general formula II and III is carried out in the presence of an acid-binding agent. 5. Method according to claim 4, characterized in that an amine or an excess of the compound of general formula III is used as acid binding agent. 6. Method according to claim 1, characterized in that the hydrolysis is carried out in a basic medium. 7. Method according to claim 6, characterized in that an alkali metal hydroxide, an alkaline earth metal hydroxide or an organic base, preferably an aqueous triethylamine solution, is used as the base. 8. Compounds of general formula IV in which R denotes piperazinyl, 4-methyl-piperazinyl or 4-ethyl-piperazinyl group, R<1> and R2 denote halogen, an aliphatic acyloxy group containing 2 to 6 carbon atoms, optionally substituted with halogen, or denotes a aromatic acyloxy group containing 7 to 11 carbon atoms.