DK161316B - Process for preparing 1,4-dihydro-4-oxo-3- quinolinecarboxylic acid derivatives - Google Patents

Description

DK 161316 B

The present invention relates to a particular process for the preparation of valuable antimicrobial agents, more particularly 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid derivatives having the general formula IV shown in the preamble of claim 1 wherein R is a hydrogen atom or a methyl group. . The process is suitable for industrial preparation of the compounds of formula IV in high purity and is characterized by the characterizing part of the claim.

Belgian Patent Specification No. 887,574 discloses a process for the preparation of compounds of the formula IV shown in the claim. The final step in the process thus known is reacting 6,7,8-trifluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid with piperazine or N-methylpiperazine. The full course of the reaction according to the Belgian script can be reproduced as 0 to 8

hydrolysis C °° H

20

F H A F CH2CH2F B F CH CH? F C

(yield 40% from A)

CH3N3H F ^ Year COOH

25 / - ^ X 1Γ T] j

-> CH.N

3 λ -, T, F CH 2 CH 2 F d Total yield 19% from A (yield 47% from C) 30 while the corresponding full reaction course of the present process is 35

DK 161316 B

2

; φ5τ "ίι_ X) 6", '^ «, d00r A

* H A F CH 2 CH 2 F B P CH 2 CH 2 F e 2 (yield 80% from A) (yield 90.8% from B)

ISLAND

hydrolysis °°° Η - * V *! '

F CH2CH2F D Total yield 61% from A

10 (yield 84.4% from E)

The yields are in both cases calculated in accordance with the examples in the respective writings, and it is seen that reversal of the order of introduction of the piperazine or methyl piperazine group on the one hand and the hydrolysis (saponification) on the other hand results in an approx. tripling the yield, calculated from the same starting material. The yield of the step in which the piperazine substituent is introduced increases in isolation from 47 to 91%. The present method is therefore industrially advantageous in relation to that known from the Belgian patent.

From Danish Patent Application No. 3806/81 (cf. Patent No. 154,763), there is known a process for preparing 1-ethyl-6-fluoro-7- (1-piperazinyl) -4-oxo-1,4- dihydroquinoline-3-carboxylic acid of the formula

ISLAND

F yfyKcOOK

v

30 HN. N ^ N

N 'CH2CH3 and consists in reacting a 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ester of the general formula F viVV C00Ra

CCJ

Cl? CH2CH3

DK 161316B

3 where Ra is a lower alkyl group, with piperazine and then hydrolyzes the compound obtained by the general formula? a

F COOR

5 η, μΛΑκ VI1 CH2CH3 where Ra has the meaning given above.

The compound of formula V is prepared by this process in higher yields and with higher purity than if it is prepared by the process in which the order of amination with piperazine and ester hydrolysis is reversed.

In view of this, it would be possible to expect that the compounds of formula IV of claim 1 are prepared in higher yields and in higher purity by the process according to the invention than by the process known from BE patent specification 887574. However, a threefold increase in yield could not be expected.

In carrying out the process, a mixture 20 of the starting material I (1 mol) and the piperazine derivative II (1-4 mol) is heated to the range of room temperature to 150 ° C, preferably 40-120 ° C, in the presence or absence of a solvent and / or a base as an acceptor of the halo-hydrochloric acid formed by the condensation.

As a base, for example, the reaction may be used, for example, pyridine, picoline or triethylamine. These organic bases can also serve as reaction solvents. Also used as the reaction solvent are, for example, benzene, toluene, dimethylsulfoxide, dimethylformamide, acetonitrile or t-butanol.

In the hydrolysis reaction using an acid, it is desirable that a compound III be heated in a mixture of a mineral acid such as hydrochloric or sulfuric acid and an organic solvent such as acetic acid. In the hydrolysis reaction using alkali, compound III is heated in a dilute alkali metal hydroxide such as sodium hydroxide or potassium hydroxide to a temperature of 40-100 ° C, preferably 60-95 ° C.

DK 161316B

4

The following examples serve to elucidate the method of the invention.

Example 1 (i) Ethyl 6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-3-quinoline carboxylate a) To a solution of 3.16 kg (31.6 mol) of N-methylpiperazine in 15.1 liters of dimethylsulfoxide heated to 65 ° C was added 5.02 kg (15.8 mol) of ethyl 6,7,8-trifluoro-1 - (2-fluoroethyl) - 1,4-dihydro-4-oxo-3-quinoline carboxylate.

The temperature of the mixture increased spontaneously to 85 ° C over 30 minutes and then kept at 85-90 ° C for 1.5 hours by heating. After cooling, the mixture was diluted with 35 liters of water to deposit a crystalline product which was collected by filtration and recrystallized from ethyl acetate to 5.71 kg (90.8%) of ethyl 6,8-difluoro-1- (2-fluoroethyl) - 1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-3-quinoline carboxylate, m.p. 163-165 ° C.

B) To a 65 ° C hot solution of 6 g (0.06 mol) of N-methylpiperazine in 28.5 ml of acetonitrile was added 9.5 g (0.03 mol) of ethyl 6,7,8-trifluoro -1- (2-fluoroethyl) -1,4-dihydro-4-oxo-3-quinoline carboxylate, whereupon the mixture was heated under reflux for 5 hours. After cooling, the mixture was diluted with 67 ml of water to give a crystalline product which was recrystallized from ethyl acetate to give 10.7 g (89.9%) of the desired compound, m.p. 160-163 ° C.

c) To a 65 ° C hot solution of 6 g of N-methylpiperazine in 28.5 ml of toluene was added 9.5 g of ethyl 6,7,8-trifluoro-1- (2-fluoroethyl) -1,4 -dihydro-4-oxo-3, quinoline carboxylate and the mixture was heated under reflux for 4 hours. After being concentrated under reduced 35, the mixture was diluted with 67 ml of water to give a crystalline product which was recrystallized from ethyl acetate to give the desired compound in an amount of 7.8 g (65.5%) and m.p. 159-162 ° C.

DK 161316 B

D) To a 65 ° C hot solution of 6 g of N-methylpiperazine in 38 ml of t-butanol was added 9.5 g of ethyl 6,7,8-trifluoro-1- (2-fluoroethyl) -1,4- dihydro-4-oxo-3-quinoline carboxylate and the mixture was heated under reflux for 7 hours. After cooling, the mixture was diluted with 67 ml of water to give a crystalline product which was recrystallized from ethyl acetate to give 10.2 g (85.7%) of the desired compound and m.p. 161-163 ° C.

E) To a 65 ° C hot solution of 6 g of N-methylpiperazine in 28.5 ml of dimethylformamide was added 9.5 g of ethyl 6,7,8-trifluoro-1- (2-fluoroethyl) -1. 4-dihydro-4-oxo-3-quinolinkarboxy methacrylate. The temperature of the mixture increased spontaneously to 85 ° C over 30 minutes and then maintained at 85-90 ° C by heating for 7 hours. After cooling, the mixture was diluted with 67 ml of water to deposit a crystalline product which was recrystallized from ethyl acetate to give the desired compound in an amount of 9.7 g (81.5%), m.p. 162-164 ° C.

Calcd for C, nHooFoNoO: C 57.42 H 5.58 N 10.57 ± y zz j ό j

Found: C 57.48 H 5.49 N 10.56% (ii) 6,8-Difluoro-1- (2-fluoroethyl) -1,4-dihydro-7- (4-methyl-1-piperazinyl) - 4-oxo-3-quinolinkarboxylsyre_

n c O

a) To a heated to 80 ° C solution of 1.81 kg of sodium hydroxide in 61 liters of water was added 5.71 kg of the ester obtained in paragraph (i) and the mixture was heated to 90 ° C over 20-30 minutes and then kept at 90 ° C for 5 minutes. The mixture was brought to pH 6 by the addition of ca. 4 kg of 68% acetic acid. The crystals which precipitated upon cooling were collected 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 charcoal and filtered. To the filtrate heated to 40 ° C was added 17.3 kg of 35% sulfuric acid. After cooling, the precipitate (sulfate) was collected by filtration and recrystallized from 91 liters of water. The sulfate was dissolved

DK 161316 B

6 in a solution of 1.57 kg of sodium hydroxide in 65 liters of water. The solution was treated with 0.4 kg of charcoal and filtered and then brought to pH 7.5 - 0.2 by adding approx.

2.5 liters of 68% acetic acid. The precipitate was filtered off and suspended in 55 liters of ethanol or methanol for 30 minutes with stirring and then collected by filtration and dried to give 4.48 kg (84.4%) of the title compound, m.p. 269.5 ° C.

Calculated for C C-H ^ gFFN₂O₂: C 55.28 H 4.91 N 11.38 Found: C 55.42 H 4.79 N 11.38%

Example 2 a) Ethyl 6,7,8-trifluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxo-3-quinoline carboxylate

To a mixture of 5.36 kg of ethyl 6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline carboxylate and 2.94 kg of sodium iodide in 20.5 liters of dimethylformamide was added 2.97 kg of anhydrous potassium carbonate at 100 ° C with stirring.

After the addition was complete, the mixture was stirred at 95-100 ° C for 15 minutes. Over a period of 2 hours, 2.98 kg of 2-fluoroethyl tosylate was added and the mixture was heated to 95-100 ° C for 1.5 hours. Further, 2.73 kg of 2-fluoroethyl tosylate was added over a period of 2 hours. After heating for 4 hours, another 0.82 kg of the tosylate was added over 1.5 hours and the reaction mixture was heated for 6 hours to the same temperature.

After cooling, the mixture was poured into 64 liters of ice water. The resulting precipitate was filtered off, washed with water and suspended in 32 liters of methanol with stirring for 30 x 30 minutes. The crystals were collected by filtration and dried to 5.02 kg (80%) of the title compound, m.p. 188-190 ° C.

Calculated for C CH ^F ^NO ^: C 53.00 H 3.50 N 4.42

Found: C, 52.99; H, 3.40; N, 4.47;

DK 161316B

b) Ethyl 6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxo-7- (1-piperazinyl) -3-quinoline carboxylate

To a 50 ° C hot solution of 380 g of piperazine in 840 ml of dimethyl sulfoxide was added 210 g of ethyl 6,7,8-trifluoro-5- (2-fluoroethyl) -1,4-dihydro-4-oxo-3- quinoline carboxylate, obtained as described above. The reaction temperature was raised to 59 ° C. After 30 minutes, 70 g of the carboxylate was added and the mixture maintained at 55-60 ° C for 1 hour with stirring. Chloroform was added to the reaction mixture 10 until it became 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 separated.

An 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 under reduced pressure until crystals began to separate. 2 liters of hot acetone were added to the mixture.

The deposited crystals were collected by filtration to give 242 g of the desired compound, m.p. 193-195 ° C. From the 20 filtrate, a further yield of 32 g and a third yield of 24 g were obtained.

c) 6,8-Difluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxo-7- (1-piperazinyl) quinoline-3-carboxylic acid The ester of section b) is saponified as be written in Example 1 (ii).

The reaction mixture was brought to pH 7-8 by the addition of acetic acid to deposit the desired compound as the monohydrate with m.p. 263 ° C (dec.).

Calculated for C] ]HHg6FFN3 ° 3, H₂:: C ^ 1 * 48 H 4.86 N 11.26 Found: C 51.26 H 4.78 N 11.26%

DK 161316 B

8

Experiment 1

Antibacterial activity

The antibacterial activity of the compounds of formula IV was assessed by the standard agar dilution method against gram-positive and gram-negative bacteria (Chemotherapy 22, 1126 (1974)).

The results are shown in Table 1 together with the results for a known compound, nalidixic acid (NA). The compounds of the invention are more active than nalidixic acid 10 against gram-positive and gram-negative bacteria.

Table 1 Antibacterial activity (minimum inhibitory concentration, μg / ml)

Organism Gram- Ex. 2c Ex. 1 (ii) NA

2q 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 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

Pseudomonas aeruginosa V-1 - 6.25 3.13 100 P. aeruginosa IF012689 - 1.56 3.13 200 30 ~ 35

Claims (3)

A process for the preparation of 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid derivatives of the general formula 5 wherein: R 1 is a hydrogen atom or a methyl group characterized by reacting a piperazine derivative with the general formula 15 ι / Λran nh II W where R1 has the meaning given above, with a compound of the general formula O FVs ^ v> JL> vC00R 25. I | F CH 2 CH 2 F where X is a halogen atom and R is an alkyl group of 1-3 carbon atoms to form a compound of the al-2Q of formula 0 f-v ^ JLcoor in / -λ ΤΤΎ 111 RX-6 N '-' F CH2CH2F DK 161316B wherein R and R have the above meanings which are then saponified to form a compound of formula IV.