CZ264393A3 - Process for preparing 6-fluoro-4-oxo-7-(1-piperazinyl)-1-4- dihydroquinoline-3-carboxylic acid being substituted in position 1, novel intermediate of said process and process for preparing such intermediate - Google Patents

Description

Process for the preparation of 6-fluoro-4-oxo-7- (1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid substituted in the 1-position, a novel intermediate of said process and a process for the preparation of said intermediates

Technical field

The present invention is in the field of organic chemistry and relates to a process for the preparation of the biologically active compound 6-fluoro-4-oxo-7- (1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid substituted at the 1-position of formula II, .

wherein R 1 is lower alkyl, lower cycloalkyl or 2,4-difluorophenyl, further relates to novel intermediates 6-fluoro-4-oxo-7- (4-substituted-1-piperazinyl) -1,4-dihydroquinoline-3-carboxylate boron a diacetate substituted in the 1-position of formula I,

wherein R 1 is as defined above and R 2 is lower alkyl or optionally substituted phenyl, and processes for its preparation.

The compounds of formula (II) are used in medicine for the treatment of inflammatory diseases. The extent of their efficacy is very broad, as it acts against both gram-negative and gram-negative bacteria.

There is a need to provide a novel process for the preparation of biologically active compounds of formula II which allows nucleophilic substitution of a halogen atom with a secondary amine at the 7-position of the starting compound 6-fluoro-7-halo-4-oxo-1,4-dihydroquinoline-3-carboxylate boron diacetate substituted in position 1 of formula III,

AcO4, OAc

(lil)

R 1 is as defined above to reduce the amount wherein X is fluoro or chloro, under mild reaction conditions, of the substitution product at the 6-position.

BACKGROUND OF THE INVENTION

The synthesis of compounds of formula (II) is described in several patents, e.g., substitution of chlorine at the 7-position with 1-alkyl-6-fluoro-7-halo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid piperazine disclosed in JP 66686 / 1979 and JP 33453/1980, in DE 2840910 and DE 3308909, or the hydrolysis of the 3-position of an alkyl ester of 6-fluoro-7- (1-piperazinyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid alkyl ester in BE 390223.

It is characteristic of all these processes that the substitution reactions take place efficiently only at temperatures above 100 ° C, resulting in a large proportion of the competitive reaction at the 6-position.

ES 9001782 discloses nucleophilic substitution on boron, aluminum and silicon chelates, but the substitution product was not isolated and hydrolysis to a biologically active compound was carried out directly. HU 1505/87 discloses a nucleophilic halogen substitution at the 7-position on a boron chelating complex at a temperature above 100 ° C. In this case too, the substitution product was not isolated and hydrolysis was carried out directly.

SUMMARY OF THE INVENTION

A first object of the invention is a process for the preparation of 6-fluoro-4-oxo-7- (1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid substituted in the 1-position of formula II

Ό0Η (II)

HN wherein R 1 is lower alkyl, lower cycloalkyl or 2,4-difluorophenyl, or the preparation of a pharmaceutically acceptable addition salt thereof, e.g., hydrochloride or lactate, and the corresponding hydrates, characterized in that the compound of formula I,

And what

O

COOR 2 wherein R 1 is as defined above and R 2 is lower alkyl or optionally substituted phenyl is alkalinized and the resulting compounds of formula (II) are optionally converted to pharmaceutically acceptable addition salts, eg, hydrochloride or lactate, and the corresponding hydrates.

The alkaline hydrolysis takes place in an aqueous medium or in an aqueous ethanol medium, for example by treatment with an alkali hydroxide solution (10% KOH or 10% NaOH) at 50 ° C to Budvar, preferably at the boiling point of the reaction mixture.

After neutralization with an acid, preferably acetic acid, the resulting product (without purification) contains less than 0.5% of all impurities.

A second object of the invention is a novel intermediate 6-fluoro-4-oxo-7- (4-substituted-1-piperazinyl) -1,4-dihydroquinoline-3-carboxylate boron diacetate substituted in the 1-position of formula I, useful as a starting material for the above process for preparing a biologically active compound of formula II.

A further object of the invention is a process for the preparation of the novel intermediates of formula (I) which make it possible to carry out nucleophilic substitution at the 7-position to 6-fluoro-7-halo-4-oxo-1,4-dihydroquinoline-3-carboxylate boron diacetate substituted at the 1-position of formula III, with piperazine substituted at the 1-position of formula

H

N

COOR 2 wherein R 2 is as defined above.

The reaction takes place in an environment of organic solvents such as pyridine, dimethylsulfoxide, dimethylformamide, 1-methyl-2-pyrrolidone, preferably 1-methyl-2-pyrrolidone, at temperatures of 0 to 40 ° C, preferably 25 to 30 ° C. At these temperatures in 1-methyl-2-pyrrolidone, the reaction is complete in 10 to 15 hours, without the formation of by-products and also without hydrolysis of the boron salt. At reaction temperatures above 40 ° C, the decomposition of the boron salt is already apparent, and with increasing temperature the decomposition proceeds rapidly. The decomposition product, 3-carboxylic acid, is substantially less reactive and nucleophilic substitution takes place here at temperatures above

Mp 100 ° C.

Isolation of the compound of formula (I) obtained is very simple, ethanol precipitation leads to the pure compound and no further purification is necessary.

The compound of formula I is used as a starting material for the preparation of the compound of formula II in isolated form or in situ.

All reagents are either commercially available or can be obtained as described herein.

The following invention, X, R 1 reaction and R 2 have a scheme illustrating both of the above meanings.

ways of this

II

The following examples describe the invention in more detail, but do not limit it in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1 1-Cyclopropyl-6-fluoro-4-oxo-7- (4-carbethoxy-1-piperazinyl) -1,4 dihydroquinoline-3-carboxylate Boron diacetate

1-cyclopropyl-6-fluoro-4-oxo-7-chloro-1,4-dihydroquinoline-3-carboxylate boron diacetate (10 g; 0.0244 mol) and 1-carbethoxypiperazine (15.44 g; 0.0977 mol) ) were suspended in 1-methyl-2-pyrrolidone (40 mL) and stirred at 30 ° C for 12 hours. After completion of the reaction, absolute ethanol (60 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. The precipitate was filtered off under pressure, washed with ethanol and dried under vacuum at 80 ° C. The filtrate was cooled to 0-5 ° C, the precipitate formed was filtered off under pressure, suspended in 1-methyl-2-pyrrolidone / ethanol (2: 1), macerated for 2 hours, filtered under pressure and dried. The products were combined. The yield of chromatophosphorically pure 1-cyclopropyl-6-fluoro-4-oxo-7- (4-carbethoxy-1-piperazinyl) -1,4-dihydroquinoline-3-carboxylate boron diacetate was 10.75 g (83%) rt. t. 235 DEG-240 DEG.

Spectroscopic data:

¹ H NMR spectrum (CF 3 COOH, TMS) (recorded on a 300 MHz instrument):

OCH 2 (cyclopropyl) ⁼ 1.29 (m, J = 8Hz, 2H), OCH 3 = 1.30 (t, J = 8Hz, 3H), CH 2 (cyclopropyl) = 1.52 (m, J = 8Hz, 2H) δ c H 3 ⁼ 2.03 (s,

6H), OCH2 (piperazines1) = 3.42 (m, 4H), OCH2 (pipsrazines1) = 3.74 (m, 4H), Och (cyclopropyl) = 3.73 (m, J = 8Hz, 1H), 2 = 4.2 (q, J = 8Hz, 2H), CH8 = 7.48 (d, J = 8Hz, 1H), CH5 = 8.08 (d, J = 14.3Hz, 1H), CH2 = 9, 0 ppm (s, 1 H).

Ί

Infrared spectrum:

1700, 1630, 1480, 1370, 1275, 1240, 1060, 960 ^cm-first

Example 2

1-ethyl-6-fluoro-4-oxo-7- (4-carbethoxy-1-piperazinyl) -1,4-dihydroquinoline-3-carboxylate boron diacetate

1-ethyl-6-fluoro-4-oxo-7-chloro-1,4-dihydroquinoline-3-carboxylate boron diacetate (2.37 g; 0.006 mol) and 1-carbethoxypiperazine (3.78 g; 0.024 mol) were suspended in 1-methyl-2-pyrrolidone (9.5 mL) and the mixture was stirred at 30 ° C for 9 hours. After completion of the reaction, absolute ethanol (19 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. The obtained product was filtered off under pressure, washed with ethanol and dried under vacuum at 80 ° C to yield 2.7 g (87%) of 1-ethyl-6-fluoro-4-oxo-7- (4-carbethoxy-1-piperazinyl). 1,4-dihydroquinoline-3-carboxylate boron diacetate o. Mp 235-238 ° C.

Spectroscopic data:

¹ H NMR spectrum (CF 3 COOH, TMS) (recorded on a 60 MHz instrument):

δCH3 = 1.53 (t, J = 7Hz, 3H), δCH3 = 1.97 (t, J = 7Hz, 3H), δCH3 =

2.4 (s, 6H), 5cH 2 (piperazinyl) = 4.0 (m, 8H), ONCH 2 = 4.53 (q,

J = 7Hz, 2H), δοcH2 = 5.03 (q, J = 7Hz, 2H), δ8 = 7.7 (d, J = 6Hz,

1H), δΗs = 8.4 (d, J = 12 Hz, 1H), δκ = 9.6 ppm (s, 1H).

¹⁹ F NMR spectrum (CF 3 COOH, CFCI 3) (recorded on a 60 MHz instrument):

δ f = -114.0 ppm (dd, J = 12Hz; 6Hz)

Infrared spectrum:

1700, 1635, 1490, 1375, 1285, 1240, 1060, 970 CB ^-1 .

Example 3

1-Cyclopropyl-6-fluoro-4-oxo-7- (1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid

1-cyclopropyl-6-fluoro-4-oxo-7- (4-carbethoxy-1-piperazinyl) -1,4-dihydroquinoline-3-carboxylate boron diacetate (10 g; 0.0188 mol) was suspended in 10¾ KOH ( 187 ml) and the mixture heated to boiling for 1.5 hours. The reaction mixture was then cooled to room temperature and the pH adjusted to 7.2-7.4 with acetic acid. The reaction mixture was stirred for an additional 30 minutes, the precipitate was filtered off under pressure, washed with water and dried. 1-Cyclopropyl-6-fluoro-4-oxo-7- (1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid (5.95 g; 96%) was obtained. mp 258-263 ° C.

Example 4

1-Cyclopropyl-6-fluoro-4-oxo-7- (1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid hydrochloride monohydrate

1-cyclopropyl-6-fluoro-4-oxo-7- (4-carbethoxy-1-piperazinyl) -1,4-dihydroquinoline-3-carboxylate boron diacetate (3 g; 0.0056 mol) was suspended in 10¾ KOH ( 56 ml) and the mixture heated to boiling for 1.5 hours. After completion of the reaction, hydrochloric acid (8 mL) was added and the mixture was heated to 80 ° C for 30 minutes. After the reaction mixture was cooled to room temperature, ethanol (14 mL) was added and the reaction mixture was stirred for an additional 30 minutes. The resulting precipitate was filtered off under pressure, washed with water and dried to constant weight to yield 1-cyclopropyl-6-fluoro-4-oxo-7- (1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid hydrochloride monohydrate (1). 93 g; 92¾) o ^ *? T. Mp 282-288 ° C.

Example 5

1-ethyl-6-fluoro-4-oxo-7- (1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid

1-ethyl-6-fluoro-4-oxo-7- (4-carbethoxy-1-piperazinyl) -1,4-dihydroquinoline-3-carboxylate boron diacetate (1.04 g; 0.002 mol) was suspended in 10¾ KOH ( 16 ml) and ethanol (12 ml) and the mixture was heated to boiling for 11 hours. The reaction mixture was then cooled to 15 ° C, pH adjusted to 7.2-7.4 with 15¾ hydrochloric acid and stirred for an additional 30 minutes. The resulting precipitate was filtered off under pressure, washed with water and dried to constant weight in a vacuum oven at 100 ° C, yielding 1-ethyl-6-fluoro-4-oxo-7- (1-piperazinyl) -1,4-dihydroquinoline -3-carboxylic acid (0.6 g; 93¾) m.p. Mp 218-221 ° C.

Way

Claims (3)

Preparation of 6-fluoro-4-oxo-7- (1-piperazinyl) -1,4- The dihydroquinoline-3-carboxylic acid in the 1-position of formula II is substituted. (II) wherein R 1 is 2,4-difluorophenyl, an acceptable addition alkyl, a lower cycloalkyl, or the preparation of a pharmaceutically acceptable salt or salt thereof, e.g., the hydrochloride and the corresponding hydrates, wherein the compound of formula I or lactate is wherein R 1 is as defined above and R 2 is lower alkyl or optionally substituted phenyl, is alkali hydrolyzed and the resulting compounds of formula II are optionally converted to pharmaceutically acceptable addition salts, e.g., hydrochloride or lactate, and the corresponding hydrates. 6-fluoro-4-oxo-7- (4-substituted-1-piperazinyl) -1,4-dihydroquinoline-3-carboxylate boron diacetate substituted in the 1-position of formula I wherein R 1 is lower alkyl, lower cycloalkyl or 2,4-difluorophenyl and R 2 is lower alkyl or optionally substituted phenyl. 3. A process for the preparation of 6-fluoro-4-oxo-7- (4-substituted-1-piperazinyl) -1,4-dihydroquinoline-3-carboxylate boron diacetate substituted in the 1-position of the formula I, AcO4-OAc wherein R1 is lower alkyl, lower cycloalkyl or 2,4-difluorophenyl and R2 is lower alkyl or optionally substituted phenyl, which allows nucleophilic substitution at the 7-position to 6-fluoro-7-halogen -4-oxo-1,4-dihydroquinoline-3-carboxylate boron diacetate substituted at the 1-position of formula III, wherein X is F or Cl, R 1 is as defined above, piperazine substituted at the 1-position of formula H Ν ’ AND COORz wherein R2 is as defined above. 4. Way The preparation according to claim 1, characterized by s e by running in an aqueous environment; or in aqueous ethanol. 5. Way The preparation according to claim 1, characterized by s e by proceeding at a temperature of 50 ° C to boiling reaction mixtures. 6. Way The preparation according to claim 3, characterized by s e by running in an organic environment solvents such as pyridine, dimethylsulfoxide, dimethylformamide, 1-methyl-2-pyrrolidone, preferably 1-methyl-2-pyrrolidone. Process according to claim 3, characterized in that it is carried out at temperatures of 0 to 40 ° C, preferably 20 to 30 ° C.