NZ211495A - Preparation of quinoline carboxylic acids - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £11495 2 1 14 * o wad i V i inti i /OJ * IIP DRAWINGS Priority Date(s): .... rrrrn-.

Complete Specification Filed: Class: coqohoi./p^.:, .C£.10.*J£.JD6 p" '30Mi987.'" Publication Date: P.O. Journal, No: .. iM# PATENTS FORM NO. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION "A PROCESS FOR THE PREPARATION OF QUINOLINE CARBOXYLIC ACID DERIVATIVES" WE KYORIN SEIYAKU KABUSHIKI KAISHA a Japanese Body Corporate, of 2-5, Kanda Surugadai, Chiyoda-ku, Tokyo, Japan, hereby declare the invention, for Which I/we pray that a patent may be granted to me/us, and the method by Which it is to be performed, to be particularly described in and by the following statement ^Uowec) lpt_/ lex. 495 N.Z. PATENT Of Pk f SMAR'9S5 .> cCEiv? •••; SPECIFICATION o o TITLE OF THE INVENTION: A process for the preparation of quinoline carboxylic acid derivatives.

ABSTRACT OF THE INVENTION: This invention relates to a process for the preparation of valuable antimicrobial agents. More particularly, it relates to the process for the preparation of quinoline^carboxylic acid derivatives.

DETAILED DESCRIPTION OF THE INVENTION: This invention relates to a. process for the preparation of useful antimicrobial agents, 6,8-difluoro-l -(2-fluoroethyl)-1,4-dihydro-4-oxo-7-(l-piperazinyl or 4-methyl -1-piperazinyl)-3-quinolinecarboxylic acid having the chemical structure (IV), COOH (IV) ^ CHaCH*F 21 wherein R^ is/hydrogen atom or methyl group, and more particularly, it relates to a . process foir thSindustflal manufacturing.ofantimicrobial agents represented by the formula a (IV) having/high purity. The intermediate substances, alkyl 6,8-difluoro-l-(2-fluoroethyl)-l,4-dihydro-4-oxo-7-(1-piperazinyl f or 4-methyl-l-piperazinyl)-3-quinolinecarboxylate'k (III), are - la.- prepared by the reaction of the corresponding alkyl 6,8-difluoro -7-halogeno-l-(2-fluoroethyl)-l,4-dihydro-4-oxo-3-guinoline-carboxylate (I), F>^N/ SV£°oR (I) wherein R is a lower alkyl group having 1 to 3 carbon atoms ar*3 X is a a halogen a ton, with/piperazine derivative (II), and Fr\ (II) wherein R^ is defined as above. And then, desired antimicrobial agents (IV) are prepared by hydrolysis of the intermediate compounds represented by the formula (III), 0 RrNs / (III) IhzCrtz F wherein R^ 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 purityTVTjood yield and easy treatment.

To put it concretely, a mixture of the starting material (I) (1 mol) and piperazine derivative (II) (1 to 4 mol) is heated in a range from room temprature to 150*C, preferably 40 to 120'C, in a the presence or absence of/solvent and/or base as an acceptor for the hydracid which is formed by the condensation.

A base such as, for example, pyridine, picoline, triethylamine # - V or the like, may be used in the reaction. These organic bases 7 . ' /> ' ' ~ v ' / - J ^ 2 I 1495 may serve as the reaction solvent. Benzene, toluene, dimethyl sulfoxide, dimethylformamide, acetonitrile, tert—butanol or the like may be used as the reaction solvent.

Alkyl 6,8-difluoro-l-(2-fluoroethyl)-l,4-dihydro-7-(4-methyl-l-piperazinyl)-4-oxo-3-quinolinecarboxylate (III:R^sCH^) is also prepared by treating alkyl 6,8-difluoro-l-(2-fluoroethyl )-l, 4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylate a (III:R^=H) with formaldehyde and/teducing 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 hydrochloric acid, sulfuric acid, and an organic solvent such as acetic acid. In the hydrolysis reaction using an alkali, the intermediate substance (III) is heated in a diluted alkali metal hydroxide such as sodium hydroxide, potassium hydroxide a range^*840 to 100°C, preferably at 60 to 95 °C.

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)-l,4-dihydro -4-oxo-3-quinolinecarboxylate To a mixture of 6,7,8-trifluoro-l,4-dihydro-4-oxo -3-quinolinecarboxylate (5.36 kg) and sodium iodide (2.94 kg) in ddLmethylformamide (20.5 liters),was added anhydrous potassium carbonate (2.97 kg) at 100"C under stirring.

After the addition was completed, the mixture was stirred at 95 f to 100*C for 15 min. 2-Fluoroethyl tosylate (2.98 kg) was added " \ , N — ) " ' %; J - *■ . " "' " "' —-»--« ! *> l o 21 14 9 during a period of 2 hours and the mixture was heated at 95 to 100'C 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, ah additional 0.82 kg of the tosylate w&g.- 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 - 190*C.

Anal. Calcd. (%) for C^H^F^O-j : 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-l-(2-fluoroethyl)-1,4-dihydro -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-l-(2 -fluoroethyl)-l,4-dihydro-4-oxo-3-quinolinecarboxylate (210 g) obtained in Example 1. "Reaction temperature was. raised to'39°C . After 30 min, 70 g of the carboxylate was added and the mixture was maintained at 55 to 60*C for 1 hour under stirring.

Chloroform was added to the reaction mixture until it beceime [ ~ homogeneous and then ice-water (3.5 liters) containing potassium carbonate (130 g) was added. aP The mixture was agitated and the organic layer was separated.

A tiater 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/reduced pressure untif ^crystals began to separate.

*TJ\o Hot acetone (2 liters) was added to the mixture. (deposited crystals were collected by filtration to give the desired a compound (242 g), mp 193 - 195°C. From the filtrate,/second crop (32 g) andaJhhjpl crop (24 g) were obtained.

Example 3 Ethyl 6,8-difluoro-l-(2-fluoroethyl)-l,4-dihydro -7-(4-methyl-l-piperazinyl)-4-oxo-3-quinoline-carboxylate a) To a hot solution heated at 65°C of N-methylpiperazine (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" spontaneously to 85°C during 30 min. and was-1has maintained at 85 to 90#C for 1.5 hours by means of heating. After cooling, the mixture was diluted a with water (35 liters) to deposit/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-l-piperazinyl)-4-oxo-3-quinoline~ carboxylate, mp 163 - 165"C. b) To a hot solution (65*C) of N-methylpiperazine (6 g, 0.06 mol.) in acetonitrile (28.5 ml) was added the ester (9.5 g, 0.03 mol.) obtained in Example 1 and the mixture was heated under reflux for 5 hours. After cooling, the mixture was diluted with a * 67 ml of water to deposit /crystalline product, which was o 211495 recrystallized from ethyl acetate to give the objective product (10.7 g, 89.9 %), mp 160 - 163"C. c) To a hot solution (65°C) of N-methylpiperazine (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 a concentrated under/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 - 162"C. d) To a hot solution (65°C) of N-methylpiperazine (6 g) in tert. butanol (38.5 ml) was added the ester (9.5 g) obtained in Example 1 and the mixure was heated under reflux for 7 hours.

After cooling, the mixture was diluted with water (67 ml) to a deposit /crystalline product which was recrystallized from ethyl acetate to give the objective product (10.2 g, 85.7 %), mp 161 - 163 °C. e) To a hot solution (65°C) of N-methylpiperazine (6 g) in dimethylformamide (28.5 ml) was added the ester (9.5 g) obtained in Example 1. The temperature of the mixture rbse.. spontaneously to 85°C during 30 min. and was-then maintained at 85 to 90°C by heating for 7 hours. After cooling, the mixture a was diluted with water (67 ml) to deposit/crystalline product, which was recrystallized from ethyl acetate to give the objective product (9.7 g, 81.5 %), mp 162 - 164°C.

Anal. Calcd. (%) for C19H22F3N3C>3 : C, 57.42; H, 5.58; N, 10.57.

Found (%) : C, 57.48; H, 5.49; N, 10.56. \ -*/" - •• . naa;» 2 1 Example 4 6, 8-Difluoro-1-(2-fluoroethyl)-l,4-dihydro-7-(4 -methyl-l-piperazinyl)-4-oxo-3-quinolinecarboxylic acid a) To a hot solution heated at 80"C of sodium hydroxide (1.81 kg) in water (61 liters) was added the ester (5.71 kg) obtained in Example 3 and the mixture was heated to 90"C ' for 20 to 30 min. and then at 90°C 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 ^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 40°C was added 35 % sulfuric acid (17.3 kg). After cooling, the precipitate (Sulfate) was collected by filtration and recrystallized 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 brought to pH 7.5 t 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 269.5*C.

Anal. Calcd. (%) for C17H18F3N3C>3 -. C, 55.28; H, 4.91; N, 11.38.

Found (%) : C, 55.42; H, 4.79; N, 11.38. b) A mixture of ethyl 6,8-difluoro-l-(2-fluoroethyl)-l,4 «r % *-» -dihydro-4-oxo-7-(l-piperazinyl)-3-quinolinecarboxylate (297 g). formic acid (600 ml) and 39% formalin (200 ml) was refluxed for a 2 hours and then concentrated under/reduced pressure.

To the residue, water (500 ml) was added and the mixture was concentrated again. Hot water (3 liters) was added to the residue and the mixture was heated at 80°C, 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 fttrtrher-f or-another 10 min. Hot water (3 liters) was added and the mixture was warmed to 70 to 80"C, 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)-l,4-dihydro-7-(4-methyl-i-piperazirtyl)-4 -oxo-3-quinolinecarboxylic acid (272 g) which was recrystallized from dimethyl sulfoxide. mp 269°C.

Anal. Calcd. (%) for C17H18F3N303 : C, 55.28; H, 4.91; N, 11.38.

Found (%) : C, 55.47; H, 4.82; N, 11.36.

Example 5 6,8-Difluoro-l-(2-fluoroethyl)-l,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 compound as the monohydrate, mp 263°C (decompd.).

Anal. Calcd. (%) for C16H16F3N3°3*H2° ! C' 51.48; H, 4.86; N, IA.26^-

Claims (5)

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)). is. as The result shown in Table 1 together with that of a known agent, nalidixic acid (NA). The compounds of the present invention . tare more active than nalidixic acid against Gram-positive and Gram-negative bacteria. Table 1 Antibacterial activity (Minimum inhibitory concentration, ^ug/ml) Orgainsms Gram Ex.5 Ex.4 NA Bacillus subtilis PCI219 + 0 .39 0 o H • 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 1F03512 - 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 .25 3 .13 100 P. aeruginosa IF012689 - 1 .56 3 .13 200 21 1495 S>: o. What we claim is :

1. A process for the preparation of a compound of the formula (IV), D .cooh (IV) b. HzCHzF wherein R^ is a hydrogen atom or^methyl group, which comprises saponifying a compound of the formula (III), COOK tHzCHzT- (III) wherein R is^ lower alkyl group^and R, is^hydrogen atom or methyl ^ having 1 to 3 carton atctns) -group, which is prepared by the reaction of a compound of the formula (II), / ^ (II) f?,-V NH wherein R^ has the above-stated meaning, with a compound of the formula (I), ;o6"°k » F £tfzCHz F wherein X is a halogen atom and R has the above-stated meaning. O

2. A process for the preparation of a compound of the formula (IV-a), 0 F c (IV-a) CH2CHzt- HD- 211495 which comprises saponifying a compound of the formula (III-b)# (Ill-b) wherein R is a lower alkyl grouft, which is prepared by the reaction t having 1 to 3 carbon atans) of a compound of the formula (Ill-a), 0 wherein R has the above-stated meanings, with formaldehyde and formic acid.

3. A process as claimed in claim 1 substantially as hereinbefore described with reference to either of the Examples 2 or 3.

4. A process as claimed in claim 2 substantially as hereinbefore described with reference to Example 4.

5. A compound of formula (IV) or (IV-a) when prepared by the process of any one of the preceding claims. (IH-a) r 24 APR 1937