CA1251212A - Process for the preparation of quinoline carboxylic acid derivatives - Google Patents

Abstract

ABSTRACT

Valuable antimicrobial agents of the formula:
wherein R1 is a hydrogen atom or a methyl group, are prepared by saponifying a compound of the formula:

Description

~;25~Z~2 This invention relates to a process for the preparation of useful antimicrobial agents, 6,8-di-fluoro-1-~2-fluoroethyl)-1,4-dihydro-4-oxo-7-tl-pipe-razinyl or 4-methyl-1-piperazinyl)-3-quinolinecar-boxylic acid having the chemical structure (IV), R ~

2 2 tIV) wherein Rl is a hydrogen atom or methyl group, and more particular]y, it relates to a process for the industrial manufacturing of antimicrobial agents re-presented by the formula (IV) having a high purity.
The intermediate substances, alkyl 6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-7-(1-piperazinyl or 4-methyl-1-piperazinyl)-3-quinolinecarboxylate (III), are prepared by the reaction of the corresponding alkyl 6,8-difluoro-7-halogeno-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate (I), o F ~ \ ~ COOR

~ I
2 2 (I) wherein R is a lo~Jer alkyl group having 1 to 3 carbon atoms and X is a halogen atom, with a piperazine deriv-ative (II), and Rl-~ NH (II) wherein Rl is defined as above. And then, desired antimicrobial agents (IV) are prepared by hydrolysis of the intermediate compounds represented by the formula (III), ~2:5~2~

F ~ COOR
~ 1 11 11 Rl~ N ~ N /
2 2 (III) wherein Rl and R are defined as above.
The present invention was accomplished as a result of our studies for industrial preparation of the antimicrobial agent having a high purity, with good yield and easy treatment.
To put it concretely, a mixture of the start-ing material (I) (1 mol) and piperazine derivative (II) (1 to 4 mol) is heated in a range from room temperature to 150C, preferably 40 to 120C, in the presence or absence of a solvent and/or base as an acceptor for the hydracid which is formed by the condensation.
A base such as, for example, pyridine, pico-line, triethylamine or the like, may be used in the reaction. These organic bases may serve as the reac-tion solvent. Benzene, toluene, dimethyl sulfoxide, dimethylformamide, acetonitrile, tert-butanol or the like may be used as the reaction solvent.
Alkyl 6,8-difluoro-1-(2-fluoroethyl)-1,4-di-hydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecar-boxylate (III:Rl=CH3) is also prepared by treating alkyl 6,8-difluoro-1-(2-fluoro-ethyl)-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylate (III:Rl=H) with formaldehyde and a reducing agent such as formic acid.
In the hydrolysis reaction using an acid, it is desirable that the intermediate substance (III) is heated in a mixture of mineral acid such as hydro-chloric acid, sulfuric acid, and an organic solvent such as acetic acid. In the hydrolysis reaction using an alkali, -the intermediate substance (III) is heated ,~

~25~2~2 in a diluted alkali metal hydroxide such as sodium hydroxide, potassium hydroxide in a range from 40 to 100C, preferably at 60 to 95C.
The following examples serve to illustrate and explain the present invention without, however, being restrictive.
Example 1 Ethyl 6,7,8-trifluoro--1-(2-fluoroethyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate To a mixture of 6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (5.36 kg) and sodium iodide (2.94 kg) in dimethylformamide (20.5 liters), was added anhydrous potassium carbonate (2.97 kg) at 100C under stirring.
After the addition was completed, the mixture was stirred at 95 to 100C for 15 min. 2-Fluorethyl tosylate (2.98 kg) was added during a period of 2 hours and the mixture was heated at 95 to 100C for 1.5 hours. Further, 2.73 kg of 2-fluoroethyl tosylate were added during a period of 2 hours. After being heated for 4 hours, an additional 0.82 kg of the tosyl-ate was added during a period of 1.5 hours and the reaction mixture was heated for 6 hours at the same temperature.
After cooling, the mixture was added to ice-water (64 liters). The resultant precipitate was filtered, washed with water and suspended in methanol (32 liters) under stirring for 30 min. The crystals were collected by filtration and dried to give 5.02 kg (80.0~) of the objective compound, mp 188 - 190C.
Anal- Calcd- (~) for C14HllF4N3 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-di-hydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylate To a hot solution (50 C) of piperazine (380 g) in dimethyl sulfoxide (840 ml) was added ethyl 6,7,8-trifluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-3-~L 2! 5 ~ sd quinolinecarboxylate (210 g) obtained in Example 1.
The reaction temperature was raised to 59C. After 30 min, 70 g of the carboxylate was added and the mixture was maintained at 55 to 60C for 1 hour under stirring.
5 Chloroform was added to the reaction mixture until it became homogeneous and then ice-water (3.5 liters) containing potassium carbonate (130 g) was added.
The mixture was agitated and the organic layer was separated. A water layer was extracted twice with chloroform. The combined chloroform layer was washed with water saturated with sodium chloride, dried over anhydrous sodium sulfate and concentrated under a reduced pressure until the crystals began to sepa-rate. Hot acetone (2 liters) was added to the mixture.
The deposited crystals were collected by filtration to give the desired compound (242 g), mp 193 ~ 195C. From the filtrate, a second crop (32 g) and a third crop ~24 g) were obtained.
Example 3 Ethyl 6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-

3-quinolinecarboxylate a) To a hot solution heated at 65C of N-methyl-piperazine (3.16 kg, 31.6 mol.) in dimethyl sulfoxide (15.1 liters) was added the ester (5.02 kg, 15.8 mol.) obtained in Example 1.
The temperature of the mixture rose sponta-neously to 85C during 30 min. and was then maintained at 85 to 90C for 1.5 hours by means of heating.
After cooling, the mixture was diluted with water (35 liters) to deposite a crystalline product, which was collected by filtration and recrystallized from ethyl acetate to give 5.71 kg (90.8~) of ethyl 6,8-difluoro-l-(2-fluoroethyl)-1,4-dihydro 7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylate, mp 163 -165~.
b) To a hot solution (65C) of N-methylpipe-razine (6 g, 0.06 mol.) in acetonitrile (28.5 ml) was added the ester (9.5 g, 0.03 mol.) obtained in Example ~2512~:

1 and the mixture was heated under reflux for 5 hours.
After cooling, the mixture was diluted with 67 ml of water to deposit a crystalline product, which was re-crystallized from ethyl acetate to give the objective product (10.7 g, 89.9~), mp 160 - 163C.
c) To a hot solution (65C) of N methylpipe-razine (6 g) in toluene (28.5 ml) was added the ester (9.5 g) obtained in Example 1 and the mixture was heated under reflux for 4 hours. After being concentrated under a reduced pressure, the mixture was diluted with water (67 ml) to deposit crystalline product, which was recrystallized from ethyl acetate to give the objective product (7.8 g, 65.5~), mp 159 -162C.
d) To a hot solution t65C) of N-methylpipe-razine (6 g) in tert. butanol (38.5 ml) was added the ester (9.5 g) obtained in Example 1 and the mixture was heated under reflux for 7 hours. After cooling, the mixture was diluted with water (67 ml) to deposit a crystalline product which was recrystallized from ethyl acetate to give the objective product (10.2 g, 85.7~), mp 161 - 163C.
e) To a hot solution (65 C) of N-methylpipe-razine (6 g) in dimethylformamide (28.5 ml) was added the ester (9.5 g) obtained in Example 1. The temper-ature of the mixture rose spontaneously to 85C during 30 min. and was then maintained at 85 to 90C by heating for 7 hours. After cooling, the mixture was diluted with water (67 ml) to deposit a crystalline product, which was recrystallized from ethyl acetate to give the objective product (9.7 g, 81.5~), mp 162 -164C.
( ) 19 22 3 33 : C, 57.42;
H, 5.58; N, 10.57.
Found (~) : C~ 57.48i H, 5.49; N, 10.55.
Example 4 6,8-Difluoro-1-(2-fluoroethyl)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid 5~ 2 a) To a hot solution heated at 80C of sodium hydroxide (1.81 kg) in water (61 liters) was added the ester (5.71 kg) obtained in Fxample 3 and the mixture was heated to 90C for 20 to 30 min. ànd then at 90C
for 5 min. The mixture was brought to pH 6 by the addition of about 4 kg of 68~ acetic acid. The crystals, which precipitated from cooling, were collected by filtration and dissolved in a mixture of 68~ acetic acid (4.1 liters) and water (33 liters).
The solution was treated with charcoal (0.4 kg) and filtered. To the filtrate heated at 40C was added 35~ sulfuric acid (17.3 kg). After cooling, the pre-cipitate (Sulfate) was collectd by filtrationand re-crystallized from water (91 liters). The sulfate was dissolved in a solution of sodium hydroxide (1.57 kg) in water (65 liters). The solution was treated with charcoal (0.4 kg), filtered and then brough-t to pH 7.5 + 0.2 by adding 68~ acetic acid (about 2.5 liters).
The precipitate was filtered, and suspended in 55 liters of ethanol or methanol for 30 min. under stirring, collected by filtration and dried to give the objective product (4.48 kg, 84.4~), mp 269.5C.
Anal. Calcd. (~) for C17H18F3N3O3 H, 4.91; N, 11.38.
Found (~) : C, 55.42; H, 4.79; N, 11.38.
A mixture of ethyl 6,8-difluoro-1-(2-fluoro-ethyl)-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline-carboxylate (297 g), formic acid (600 ml) and 39~
formalin (200 ml) was refluxed for 2 hours and then concentrated under a reduced pressure. To the residue, water (500 ml) was added and the mixture was concen-trated again. Hot water (3 liters) was added to the residue and the mixture was heated at 80C, then treated with aqueous alkaline solution containing 160 g of sodium hydroxide under stirring. The stirring was continued until the reaction mixture became homogeneous and then further for another 10 min. Hot ~251Z~,2 water (3 liters) was added and the mixture was warmed to 70 to 80C, then neutralized with acetic acid (80 ml). Deposited crystals were collected by filtration, washed with water (3 times) and ethanol (2 times) to obtain 6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid (272 g) which was recrystallized from dimethyl sulfoxide. mp 269C.
Anal. Calcd. (~) for C17H18F3N3O3 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 The ester (Example 2) was saponified the same way as described in a) of Example 4.
The reaction mixture was brought to pH 7 to 8 by adding acetic acid to deposit the objective com-pGund as the monohydrate, mp 263C (decompd.) Anal. Calcd. (~) for C16H16F3N3O3 2 51.48; H, 4.86; N, 11.26.
Found (~) : C, 51.26; H, 4.78; N, 11.26.
Experiment 1 Antibacterial Activity The antibacterial activity of the compounds of this invention was assayed by the standard agar dilution streak method against Gram-positive and Gram-negative bacteria (Chemotherapy, 22, 1126 (1974)).
The result is as shown in Table 1 together with that of a known agent, nalidixic acid (NA). The compounds of the present invention are more active than nalidixic acid against Gram-positive and Gram-negative bacteria.

SiL~2~2 Table 1 An-tibacterial activity (Minimum inhibitory concentration, jugml) Organism Gram Ex.5 Ex.4 NA
Bacillus subtilis PCI219 + 0.39 0.10 6.25 Staphylococcus aureus 209P + 3.13 0.78 100 Escherichia coli NIHJ JC-2 - 0.05 0.05 3.13 E. coli ATCC10536 - 0.10 0.10 3.13 Proteus vulgaris 3167 - 0.05 0.05 3.13 Klebsiella pneumoniae IFO3512 - 0.05 0.05 1.56 Shigella sonnei IID969 - 0.05 0.05 1.56 Salmonella enteritidis IID604 - 0.05 0.10 12.5 Pseudomonas aeruginosa V-l - 6.~5 3.13 100 P. aeruginosa IFO12689 - 1.56 3.13 200

Claims (4)

The embodiments of the invention, in which an exclusive property or privilege is claimed, are defined as follows:

1. A process for the preparation of compounds having the formula:

(IV) wherein R1 is a hydrogen atom or a methyl group, which comprises saponifying a compound of the formula:

(III) wherein R is a lower alkyl group having 1 to 3 carbon atoms and R1 is a hydrogen atom or a methyl group.

2. A process according to claim 1, wherein the compound of formula (III) is prepared by reacting a compound of the formula:

(II) wherein R1 has the aforesaid meaning, with a compound of the formula:

(I) wherein X is a halogen atom and R has the aforesaid meaning.

3. A process for the preparation of a compound having the formula:

(IV-a) which comprises saponifying a compound of the formula:

(III-b) wherein R is a lower alkyl group having 1 to 3 carbon atoms.

4. A process according to claim 3, wherein the compound of the formula (III-b) is prepared by reacting a compound of the formula:

(III-a) wherein R has the aforesaid meanings, with formaldehyde and formic acid.