FI84475C - Process for the preparation of quinoline carboxylic acid derivatives - Google Patents

Description

1 84475

The present invention relates to a process for the preparation of a compound of the formula

O COOH

/ \ I | (IV)

10 E -N

\ _ / I

F ch2ch2f wherein R 1 is a hydrogen atom or a methyl group.

These compounds of formula IV, 6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxo-7- (1-piperazinyl and 4-methyl-1-piperazinyl) -3-quinolinecarboxylic acid are useful as antimicrobial drugs.

By the method of the invention, the antimicrobial drugs of formula IV can be prepared in very pure form on an industrial scale.

The compounds of formula IV prepared by the process of the invention are known per se from Applicant's SE patent 440,354, which describes a process in which a quinolinecarboxylic acid is reacted with a piperazine, while in the process of the present invention a quinoline carboxylic acid ester is reacted with a piperazine derivative.

The process according to the invention for the preparation of a compound of the formula IV is characterized in that 1 to 5 moles of the compound of the formula II

OF

35 \ ._ / (II) 2 84475

wherein R 1 is as defined above, is reacted with a mole of a compound of formula I

O

5 F Jl COOR

YYjf m J ch2ch2f 10

wherein X is a halogen atom and R is a lower alkyl group having 1 to 3 carbon atoms, by heating them at room temperature to 150 ° C, preferably 40 to 120 ° C, in a solvent such as benzene, toluene, dimethyl sulfoxide, dimethylformamide , in the presence of acetonitrile or tert-butanol, and the compound of formula III thus obtained

0

20 F II COOR

(III) F ch2ch2f wherein R and Rj are as defined above, is hydrolyzed by heating in a dilute solution of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide at a temperature of 40 to 100 ° C, preferably 60 to 95 ° C.

The process of the present invention provides the final product of formula IV in better yield and purity than known processes. This is apparent from the following reaction schemes, in which the process of the invention 35 is illustrated in Schemes 2 and 3 and the process of SE Patent 440,354 in Scheme 1.

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In the known process shown in Scheme 1, the reaction between a medium of formula III and N-methylpiperazine using 8.5 moles of N-methylpiperazine per mole of compound of formula III is carried out at the boiling point of pyridine in 6 hours in a yield of 47% to the desired final product.

In the new process shown in Scheme 2, the reaction between a medium of formula II and N-methylpiperazine using 2 moles of N-methylpiperazine per mole of compound II is carried out at 85-90 ° C in 1.5 hours in a yield of 90.8% of formula V to a compound which is hydrolyzed to the desired final product in a total yield of 76.6%.

In the new process shown in Scheme 3, the reaction between a medium of formula II and piperazine using 5 moles of piperazine per mole of compound II is performed at 55-60 ° C in 1.5 hours to yield 88% of the compound of formula VI to give the desired final product. with a total yield of 83.6%.

The present invention is the result of our research into the preparation of an antimicrobial drug in an industrial scale, which product is very pure, obtained in good yields and easy to handle.

In practice, the preparation is carried out by heating a mixture of 1 mole of the starting material (I) and 1 to 4 moles of the piperazine derivative (II) in the temperature range from room temperature to 150 ° C, preferably 40 to 120 ° C in the presence of a solvent. Benzene, toluene, dimethyl sulfoxide, dimethylformamide, acetonitrile or tert-butanol can be used as the reaction solvent.

Alkyl 6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylate (III, Rx = CH3) can also be prepared by handling alkyl 6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylate. 84475 tia (III, Rj = H) with formaldehyde and reduction such as formic acid, as shown in the split FI patent application 910708.

Upon hydrolysis with the base, intermediate (III) is heated in a dilute solution of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide at a temperature in the range of 40 to 100 ° C, preferably 60 to 95 ° C.

The following examples illustrate and clarify the present invention without, however, limiting it. 10 Example 1

Ethyl 6,7,8-trifluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylate_

To a mixture of 5.36 kg of ethyl 6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate and 2.94 kg of sodium iodide in 20.5 l of dimethylformamide was added with stirring 2, 97 kg of anhydrous potassium carbonate. After the addition was complete, the mixture was stirred for 15 minutes at 95-100 ° C. 2.98 kg of 2-fluoroethyl tosylate were added over two hours and the mixture was heated at 95-100 ° C for 1.5 hours. 2.73 kg of 2-fluoroethyl lithosylate were added over a further two hours. After heating for four hours, an additional 0.82 kg of tosylate was added over 1.5 hours and the reaction mixture was heated for six hours at the same temperature.

After cooling, the mixture was added to 64 liters of ice-25 water. The precipitate formed was isolated by filtration, washed with water and suspended with stirring in 32 liters of methanol over 30 minutes. The crystals were isolated by filtration, dried to give 5.02 kg (80.0%) of the title compound, m.p. 188-190 ° C.

30 Analysis for C 14 H 11 F 4 NO 3

Calculated: C 53.00 H 3.50 N 4.42%

Found: C 52.99 H 3.40 N 4.47%

Example 2

Ethyl 6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-35 4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylate

To a hot (50 ° C) solution of 380 g of piperazine in 840 ml of dimethyl sulfoxide was added 210 g of the ethyl 6,7,8-trifluoro-1- (2-fluoroethyl) obtained in Example 1. 1,4-dihydro-4-oxo-3-quinolinecarboxylate. The reaction temperature was raised to 59 ° C. After 30 minutes, 70 g of carboxylate were added and the mixture was kept under stirring for one hour at 55-60 ° C. To the reaction mixture was added enough chloroform to become homogeneous, and then 3.5 liters of ice water containing 130 g of potassium carbonate was added.

The mixture was stirred and the organic layer was separated. The aqueous layer was extracted twice with chloroform. The combined chloroform layers were washed with water saturated with sodium chloride, dried over anhydrous sodium sulfate and concentrated in vacuo until crystals began to separate. To the mixture was added 2 L of hot acetone. The crystal precipitate was isolated by filtration to give 242 g of the desired compound, m.p. 193-195 ° C. A second crop (32 g) and a third crop (24 g) of compound were obtained from the filtrate.

Example 3 Ethyl 6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylate a) Hot, To a solution of 3.16 kg (31.6 mol) of N-methylpiperazine in 15.1 liters of 25 dimethyl sulfoxide heated at 65 ° C was added 5.02 kg (15.8 mol) of the ester obtained in Example 1.

The temperature of the mixture rose spontaneously to 85 ° C over 30 minutes and then the mixture was kept under heating at 85-90 ° C for 1.5 hours. After cooling, the mixture was diluted with 35 liters of water and a crystalline product precipitated, which was isolated by filtration, recrystallized from ethyl acetate to give 5.71 kg (90.8%) of ethyl 6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylate, m.p. 163-165 ° C. B) To a hot (65 ° C) solution of 6 g (0.06 mol) of N-methylpiperazine in 28.5 ml of acetonitrile was added 9.54475 g of the ester obtained in Example 1 and the mixture was heated at reflux for five hours. After cooling, the mixture was diluted with 65 ml of water and a crystalline product precipitated, which was recrystallized from ethyl acetate to give 10.7 g (89.9%) of the title compound, m.p. 160-163 ° C.

c) To a hot (65 ° C) solution of 6 g of N-methylliperiperazine in 28.5 ml of toluene was added 9.5 g of the ester obtained in Example 1 and the mixture was heated at reflux for 4 hours. After concentration in vacuo, the mixture was diluted with 67 ml of water and a crystalline product precipitated, which was recrystallized from ethyl acetate to give 7.8 g (65.5%) of the target product, m.p. 159-162 ° C.

D) To a hot (65 ° C) solution of 6 g of N-methylpiperazine in 38.5 ml of tert-butanol was added 9.5 g of the ester obtained in Example 1 and the mixture was heated at reflux for seven hours. After cooling, the mixture was diluted with 67 ml of water and a crystalline product precipitated, which was recrystallized from ethyl acetate to give 10.2 g (85.7%) of the target product, m.p. 161-163 ° C.

e) To a hot (65 ° C) solution of 6 g of N-methylliperiperazine in 28.5 ml of dimethylformamide was added 9.5 g of the ester obtained in Example 1. The temperature of the mixture rose spontaneously to 85 ° C over 30 minutes and then the mixture was maintained by heating at 85-90 ° C for seven hours. After cooling, the mixture was diluted with 67 ml of water and a crystalline product precipitated, which was recrystallized from ethyl acetate to give 9.7 g (81.5%) of the target product, m.p. 162-164 ° C.

Analysis for C19H22F3N3O3

Calculated: C 57.42 H 5.58 N 10.57%

Found: C 57.48 H 5.49 N 10.56% 10 84475

Example 4 6,8-Difluoro-1- (2-fluoroethyl) -1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid 5 a) Hot, 80 ° To a solution of 1.81 kg of sodium hydroxide in 61 liters of water heated to C was added 5.71 kg of the ester obtained in Example 3 and the mixture was heated at 90 ° C for 20-30 minutes and then at 90 ° C for 5 minutes. The pH of the mixture was adjusted to 6 by adding about 4 kg of 68% acetic acid. The crystals precipitated during cooling were isolated by filtration and dissolved in a mixture of 4.1 liters of 68% acetic acid and 33 liters of water. The solution was treated with 0.4 kg of activated carbon and filtered. To the filtrate heated at 40 ° C was added 17.3 kg of 35% sulfuric acid. After cooling, the precipitate (sulfate) was isolated by filtration and recrystallized from 91 liters of water. The sulfate was dissolved in a solution of 1.57 kg of sodium hydroxide in 65 liters of water. The solution was treated with 0.4 kg of activated carbon, filtered and then the pH was adjusted to 7.5 ± 0.2 by the addition of about 2.5 liters of 68% acetic acid. The precipitate was isolated by filtration and suspended with stirring for 30 minutes in 55 liters of ethanol or methanol, isolated by filtration, dried to give 4.48 kg (84.4%) of the target product, m.p. 269.5 ° C.

Analysis for C 17 H 18 F 3 N 3 O 3

Calculated: C 55.28 H 4.91 N 11.38%

Found: C 55.42 H 4.79 N 11.38% b) A mixture of 297 g of ethyl 6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxo- 7- (1-Piperazinyl) -3-quinolinecarboxylate, 600 mL formic acid and 200 mL 39% formalin were heated at reflux for two hours and then concentrated in vacuo. To the residue was added 500 ml of water, and the mixture was reconstituted with concentrate 84475. To the residue was added 3 liters of hot water, and the mixture was heated at 80 ° C and then treated with a basic aqueous solution containing 160 g of sodium hydroxide with stirring. Stirring was continued until the mixture became homogeneous, and then for another 10 minutes. 3 liters of hot water were added and the mixture was heated to 70-80 ° C and neutralized with 80 ml of acetic acid. The precipitated crystals were isolated by filtration, washed three times with water and twice with ethanol to give 10,272 g of 6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-7- (4-methyl-1-piperazinyl) -4- oxo-3-quinolinecarboxylic acid recrystallized from dimethyl sulfoxide, m.p. 269 ° C.

Analysis for C 17 H 18 F 3 N 3 O 3 15 Calculated: C 55.28 H 4.91 N 11.38%

Found: C 55.47 H 4.82 N 11.36%

Example 5 6,8-Difluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxo-7- (1-piperazinyl) quinoline-3-carboxylic acid 20 The ester (Example 2) was saponified in Example 4 (a). ).

The pH of the reaction mixture was adjusted to 7-8 by the addition of acetic acid, whereupon the title compound precipitated as a monohydrate, m.p. 263 ° C (decomposes).

25 Analysis for C16H16F3N3O3. H20

Calculated: C 51.48 H 4.86 N 11.26%

Found: C 51.26 H 4.78 N 11.26%

Test 1

Antibacterial Activity The antibacterial activity of the compounds of this invention was determined by a standard agar dilution spreading method against gram-negative and gram-positive bacteria (Chemotherapy 22, (1974) 1126).

i2 84475

The results obtained with the compounds and the known drug, nali-dixic acid (NA), are shown in Table 1. The compounds obtained according to the present invention are more active against gram-positive and gram-negative bacteria than nalidixic acid.

i3 84475

table 1

Antibacterial activity (minimum inhibitory concentration μg / ml) Organism Gram Example 5 Example 4 NA

Bacillus subtilis PCI219 + 0.39 0.10 6.25 5 11!

Staphylococcus aureus 209P + 3.13 0.78 100

Escherichia coli NIHJ JC-2 - 0.05 0.05 3.13 E. coli ATCC 10536 - 0.10 0.; 10 3.13 ^ q Proteus vulgaris 3167 - 0.05 0.05 3.13

Klebsiella pneumoniae IF03512 - 0.05 0.05 1.56

Shigella sonnei IID969 0.05 0.05 1.56

Salmonella enteritidis IID604 - 0.05 0.10 12.5 15 Pseudomonas aeruginosa V-1 - 6.25 3.13 100 P. aeruginosa IF012689 - 1.56 3.13 200 —11 1 - - - I ~ -

Claims (8)

A process for the preparation of a compound of formula IV 5. COOH / \ ^ I I (IV) \ / \ ' CH2CH2F wherein Rx is a hydrogen atom or a methyl group, characterized in that 1 to 5 moles of a compound of formula II wherein Rx is as defined above are reacted with a mole of a compound of formula I 25 0 C ° 0R ^ \ ((\\ mx TV 'CH_CH0F F 22 wherein X is a halogen atom and R is a lower alkyl group having 1 to 3 carbon atoms, by heating them at a temperature of 84475 ° C at room temperature to 150 ° C, preferably at 40 to 120 ° C, in a solvent such as benzene. -luene, dimethylsulfoxide, dimethylformamide, acetone triil or tert-butanol, and the compound of formula III 0 F II COOR thus obtained 10 R, -N ^ β (HI) 1 \ _ / I? F CH 2 CH 2 F 15 wherein R and R 1 are as defined above is hydrolyzed by heating in a dilute solution of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide at a temperature of 40 to 100 ° C, preferably 60 to 95 ° C. 1 «84475 Förfarande för framställning av en förening med formeln IV 5 0 COOH / - \ T i i, iv) V? \ / | »10 -] F CH2CH2F color Rx is not a hydrogen atom or a methyl group, kännne -tecknat därav, att 1-5 moler av en förening med formuleln II 15 / \ R1 ~ N ^ _ (II) 20 color Rx betecknar samma som ovan, equivalents with a molar form of IOF II C00R; w - F CH2CH2F 30 color X is a halogen atom ooh R is an alkyl group having 1-3 cholaters, the genome being upstream of the temperature at room temperature 150 eC, at a temperature of 40 to 120 ° C, in the range of 7 to 84475, benzene, toluene, dimethylsulfoxide, dimethylformamide, acetonitrile or tert-butanol, and anhydrous form of formula III 0 5. U C00R (111) p CH-CH-F 10 F 2 2 color R and Rx betecnar samma som ovan, hydrolysis of the genome up to the time of the addition of time metal hydroxide, Schisom sodium hydroxide or callium hydroxide, at a temperature between 40 and 100 ° C, at a temperature of 60 to 95 15 ° C.