HU193597B - Process for producing quinolin-carboxylic acid derivatives - Google Patents

Abstract

The cpds. are of formula (IV), in which R1 is H or CH3. They are made by hydrolysis of the ester of formula (III) in which R is 1-3C alkyl, which is prepd. by reaction of a cpd. of formula (II) with a cpd. of formula (I), in which X is a halogen atom.

Description

The present invention relates to a novel process for the preparation of valuable quinoline carboxylic acid derivatives having antimicrobial properties.

More particularly, the present invention relates to a process for the use of 6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxo-7- (1-piperazinyl) 4-methyl-1-piperazinyl) -3-quinolinecarboxylic acids wherein R, hydrogen or methyl. The present invention relates in particular to the industrial preparation of compounds of general formula (IV) of high purity.

Quinoline carboxylic acid derivatives are disclosed in British Patent No. 2,093,018. Examples 4 and 5 of this specification refer to the most potent pharmaceutically active compounds, including 6-difluoro-1- (2-fluoroethyl) -1,4-dibydro-7- (1-piperidinyl) and 4-methyl-1 piperazinyl) -4-oxo-3-quinolinecarboxylic acid and its preparation.

The corresponding 1- (2-fluoroethyl) derivative of 6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolecarboxylic acid ethyl ester is hydrolyzed to the free carboxylic acid according to known procedures. (40% yield) followed by reaction with piperazine and N-methylpiperazine (47% yield).

According to our process, the quinolinecarboxylic acid derivatives of formula IV, R, hydrogen or methyl, are prepared by:

a) ^e w (I) a compound of formula - R 1-3 alkyl and X is halogen atom - with a piperazine of formula (II): - R, as defined above - are reacted, followed by hydrolysis of the compound of formula (III), or

(b) reacting a compound of formula (IIa) R with the above formaldehyde and formic acid to produce a compound of formula (IVa) and hydrolyzing the resulting compound of formula (IIaa).

The overall yield (61% and 66% respectively) of the two processes of the present invention was about the same starting compound, known as the ethyl ester of 6,7,8-trifluoro-1,4-dihydro-1,4-dihydro-4-β-3-quinolone. about 3 times the total yield of the process (19%).

Both methods can be carried out under more moderate reaction conditions than known; in the known process, the reaction with N-methylpiperazine, carried out with an excess of 8.5 times the molar excess, is carried out at the boiling point of pyridine for 6 hours; in process (a) of the invention, the double molar excess of N-methylpiperazine is preferably reacted at 85-90 ° C and the reaction time is 1.5 hours. In process (b), when used in a five molar excess of unsubstituted piperazine, preferably 55-60 ° C, the reaction time is 1.5 hours.

The alkyl-6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxo-7- (1-piperazinyl) or 4-methyl-alkyl- The intermediate 1-piperazinyl) -3-quinolinecarboxylate, wherein R 1 is C 1 -C 3 alkyl and R 2 is as described above, is prepared by reacting an appropriate alkyl-6,8-difluoro-compound of formula I 7-halo-1- (2-fluoroethyl) -1,4-dihydro-4-oxo-3-quinolinecarboxylate, wherein R is as defined above and X is halogen, a piperazine of formula II; with a compound of the formula wherein R is as defined above. The intermediate (III) is hydrolyzed to give the desired antimicrobial compound (IV).

In the process according to the invention, a mixture of 1 mol of the starting compound of the formula I and 1 mol of the piperazine derivative of the formula II is optionally in the presence of a solvent and / or a base to remove the hydroacid formed during condensation. Heat at 40-120 ° C. Suitable bases useful in the reaction include pyridine, picoline, triethylamine or the like. These organic bases may also serve as solvents for the reaction. Benzene, toluene, dimethylsulfoxide, dimethylformamide, acetonitrile, tert-butanol or the like can also be used as solvents in the reaction.

Alkyl 1-6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylate (III: R, = - CH ₃ ) is also produced ^! alkyl 6,8-difluoro-1- (2-fluoro-ethyl) -1,4-dihydro-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylate (III; R = - H) with formaldehyde and a reducing agent such as formic acid.

In the acid hydrolysis reaction, the intermediate (III) is conveniently heated in a mixture of a mineral acid such as hydrochloric or sulfuric acid and an organic solvent such as acetic acid. Using an alkali in the hydrolysis reaction, the intermediate (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.

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.

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 liters of dimethylformamide

Anhydrous potassium carbonate (2.97 kg) was added while the reaction mixture was stirred at 100 ° C. After the addition was complete, the mixture was stirred at 95-100 ° C for 15 minutes. thereafter

2.98 kg of 2-fluoroethyl tosylate was added over 2 hours to the reaction mixture and heated at 95-100 ° C for 1.5 hours, followed by addition of 2.73 kg of 2-fluoroethyl tosylate over 2 hours. The mixture was heated for 4 hours then

An additional 0.82 kg of tosylate was added over 1.5 hours and heated at the above temperature for 6 hours. The reaction mixture was cooled and

-2193597 liters of ice water. The precipitate formed is filtered off, washed with water and suspended in methanol (32 L) with stirring (30 minutes). The crystalline product was filtered off and dried, yielding 5.02 kg (80%) of the title compound, m.p. 188-190 ° C.

Analysis for C ₁₄ H ₁₁ F ₄ NO _3: Calcd: 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-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylate

To a solution of 380 g of piperazine in 840 ml of dimethylsulfoxide at 50 ° C was prepared 210 g of ethyl 6,7,8-trifluoro-1- (2-fluoroethyl) -1,4-dihydro-4- oxo-3-quinoline carboxylate is added. The reaction temperature was raised to 59 ° C. After 30 minutes, another 70 g of carboxylate was added to the reaction mixture and the mixture was stirred at 55-60 ° C for 1 hour. Chloroform was added to the reaction mixture until homogeneous, followed by 3.5 liters of ice water containing 130 g of potassium carbonate. The mixture is stirred and the organic phase is separated. The aqueous phase was extracted twice with chloroform. The combined chloroform phases are washed with water saturated with sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure until crystals begin to precipitate. 2 liters of hot acetone are then added to the mixture. The precipitated crystals were collected by filtration to give 242 g of the title compound, m.p. 193-195 ° C. The filtrate gave 32 g of the second crop and 24 g of the third crop.

Example 3

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

a) To a solution of 3.16 kg (31.6 mol) of N-methylpiperazine in 15.1 liters of dimethyl sulfoxide heated to 65 ° C is added 5.02 kg (15.8 mol) of the ester prepared in Example 1. The temperature of the mixture spontaneously rises to 85 ° C over 30 minutes followed by heating

Keep at 85-90 ° C for 1.5 hours. The mixture was cooled, diluted with water (35 L) to give a crystalline product which was filtered off and recrystallized from ethyl acetate. 5.71 kg (90.8%) of 1-6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-7- (4-methyl-1-piperazinyl) -4 Oxo-3-quinoline carboxylate is obtained, m.p. 163-165 ° C.

b) To a solution of N-methylpiperazine (6 g, 0.06 mol) in acetonitrile (28.5 ml) was added the ester (9.5 g, 0.03 mol) prepared in Example 1 and the reaction mixture was stirred for 5 hours. over reflux. The mixture was cooled and diluted with water (67 mL) to give a crystalline product 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 solution of 6 g of N-methylpiperazine in 28.5 ml of toluene at 65 ° C

9.5 g of the ester prepared in Example I are added and the mixture is refluxed for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water (67 mL) to give a crystalline product which was recrystallized from ethyl acetate. 7.8 g (65.5%) of the title compound are obtained, m.p. 159-162 ° C.

d) To a solution of 6 g of N-methylpiperazine in 38.5 ml of tert-butanol at 65 ° C was added 9.5 g of the ester prepared in Example 1 and refluxed for 7 hours. The mixture was cooled and diluted with water (67 mL) to give a crystalline product which was recrystallized from ethyl acetate. 10.2 g (85.7%) of the title compound are obtained, m.p. 161-163 ° C.

e) To a solution of 6 g of N-methylpiperazine in 65.5 ° C in 28.5 ml of dimethylformamide was added 9.5 g of the ester prepared in Example 1. The reaction temperature rises spontaneously to 85 ° C over 30 minutes. The mixture was heated at 85-90 ° C for 7 hours. The reaction mixture was cooled and diluted with water (67 mL). A crystalline product precipitates which is recrystallized from ethyl acetate. Yield: 9.7 g (81.5%), m.p. 162-164 ° C.

(Elemental analysis calculated for Ε ₁₉ Η ₂₂ Ε ₃ Ν ₃ Ο ₃ : C, 57.42; H, 5.58; N, 10.57. Found: C, 57.48; H, 5.49; N : 10.56%

Example 4

6,8-Difluoro-1- (2-fluoroethyl) -1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid

(a) To a solution of 1.81 kg of sodium hydroxide in 61 liters of water at 80 ° C is added 5.71 kg of the ester prepared in Example 3 and the mixture is heated at 80 ° C for 20-30 minutes and then at 90 ° C. Heat for 5 minutes. The pH of the mixture was then adjusted to 6 by addition of about 4 kg of 68% acetic acid. After cooling, crystals precipitate out, which are filtered off 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. 17.3 kg of 35% sulfuric acid were added to the filtrate heated to 40 ° C. After cooling, a precipitate (sulphate) was formed which was filtered off and recrystallized from 91 L 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 adjusted to pH 7.5 ± 0.2 by adding about 2.5 liters of 68% acetic acid. The precipitate was filtered off, suspended in ethanol or methanol (55 L) for 30 minutes with stirring, and the precipitate was filtered off and dried. Yield: 4.48 kg (84.4%), m.p. 269.5 ° C. _f

Elemental analysis of C | ₇ H ₁₈ F ₃ N ₃ O _3: Calcd: C, 55.28; H, 4.91; N, 11.38% Found: 'C: 55.42, H: 4.79, N: 11, 38%

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b) 297 g of 6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylate, 600 ml of formic acid and 200 ml The 39% formaldehyde mixture was refluxed for 2 hours and then concentrated under reduced pressure. Water (500 mL) was added to the residue and the mixture was concentrated again. To the residue was added 3 liters of hot water and the mixture was heated to 80 ° C and treated with an aqueous alkaline solution containing 160 g of sodium hydroxide with stirring. The mixture was stirred until homogeneous and then for another 10 minutes. Then 3 L of hot water was added to the reaction mixture, the mixture was heated to 70-80 ° C and neutralized with 80 ml of acetic acid. The crystals formed are filtered off and washed three times with water and twice with ethanol. 272 g of 6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-3-quinoline carboxylic acid are obtained, m.p. m.p. 269 ° C after recrystallization from dimethyl sulfoxide.

Elemental Analysis for C _I7 H | ₈ F ₃ N ₃ O _3: Calcd: 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

The ester of Example 2 was saponified as described in Example 4a). The reaction mixture was then adjusted to pH 7-8 with acetic acid to precipitate the title compound as a monohydrate, m.p. 263 ° C with decomposition.

Analysis for C ₁₆ H _I6 F ₃ N ₃ O ₃ .h ₂ O Calcd:

H, 4.86; N, 11.26 Found: C, 51.26; H, 4.78; N, 11.26.

Experimental part:

Effect against bacteria

The antibacterial activity of the compounds of the present invention was tested in a standard agar dilution scanning culture on Gram-positive and Gram-negative bacteria (Chemotherapy, 22, 1126 (1974)).

The results are shown in the table in comparison with that of nalidixic acid (NA). The compounds of the present invention are much more potent than nalidixic acid against Gram25-positive and Gram-negative bacteria.

Claims (6)

A process for the preparation of a quinoline carboxylic acid derivative of the Formula IV wherein R, H or methyl are characterized in that 3) reacting a compound of formula I wherein R 1 is C 1 -C 3 alkyl and X halogen with a piperazine of formula II R, and the resulting compound of formula III R and R is as defined above, or b) for the preparation of a compound of formula IV wherein R, a methyl group, is reacted with formaldehyde and formic acid, a compound of formula IHb, R 1 -C 3 alkyl, and the resulting compound of formula IIa, R meaning - hydrolyze. Process (a) according to claim 1, characterized in that the compound of formula (I) and the piperazine of formula (II) are reacted in the presence of an organic solvent. Process (a) according to claim I or Process according to claim 2, characterized in that the reaction is carried out in the presence of an organic base, preferably pyridine or picoline. Process (a) according to claim 1 or process according to claim 2 or claim 3, therewith The reaction is carried out at room temperature to 150 ° C. Process b) according to claim 1, characterized in that the formaldehyde and formic acid are reacted with the compound of the formula IIIb between room temperature and the reflux temperature of the reaction mixture. Process (a) or (b) according to claim 1, characterized in that the hydrolysis is carried out in the presence of an acid, preferably hydrochloric or acetic acid, or an alkali metal hydroxide, preferably sodium or potassium hydroxide, at 40-100 ° C.