LV10863B

LV10863B - Process for preparing 1-substituted-6-fluoro-4-oxo-7-(1-piperazinyl)-1,4-dihydroquinoline-3-carboxylic acid, a novel intermediate useful in said process, and a process for preparing said intermediate

Info

Publication number: LV10863B
Application number: LV931317A
Authority: LV
Inventors: Natasa Zupancic; Martin Barbo; Boris Sket; Pavel Zupet
Original assignee: Krka Tovarna Zdravil
Priority date: 1992-12-11
Filing date: 1993-12-10
Publication date: 1996-08-20
Also published as: HU9302940D0; PL301045A1; SK140093A3; ATA249793A; PL173784B1; YU76593A; RU2127270C1; AT401648B; CA2111181A1; LTIP1558A; LV10863A; SI9200377A; EE9400277A; CZ284715B6; LT3084B; HUT75319A; HRP931485A2; CZ264393A3

Description

1 LV 10863

Process for preparing l-substituted-6-fluoro-4-oxo-7-(l-piperazinyl)-l,4-dihydro-quinoline-3-carboxylic acid, .a novel intermediate useful in said process, and a process for preparing said intermediate

Technical Field

The present invention belongs to the field of organic chemistry and relates to a process for preparing a bioactive compound l-substituted-6-fluoro-4-oxo-7-(l-piperazinyl)-l,4-dihydroquinoline-3-carboxylic acid of the general formula II

wherein Rj represents lower alkyl, lower cycloalkyl or 2,4-difluorophenyl, to a novel intermediate l-substituted-6-fluoro-4-oxo-7-(4-substituted-l-piperazinyl)-

l,4-dihydroquinoline-3-carboxylate boron diacetate of the general formula I

AcO· . OAc \ /

vvherein Rj has the above meaning and represents a lower alkyl or an optionally substituted phenyl, and to a process for the preparation thereof.

The compounds of the formula II are used in medicine for treatment of inflam-matory diseases. The activity spectrum thereof is broad since they are active against gram-positive as well as against gram-negative bacteria. 2

Technical Problem

There was a need to provide a novel process for preparing bioactive compounds of the general formula II, wherein a nucleophilic substitution of halo atom in 7-position in the starting compound l-substituted-6-fluoro-7-halo-4-oxo-l,4-dihydroquinoline-3-carboxylate boron diacetate of the general formula III

\vherein X represents F or Cl, whereas Rx has the above meaning, with a secondary amine could be carried out under milder reaction conditions in order to reduce the proportion of the obtained substitution product in 6-position.

PriorArt

The synthesis of the compounds of the general formula II is described in several patent documents, e.g. as a substitution of chloro in 7-position of l-alkyl-6-fluoro-7-halo-4-oxo-l,4-dihydroquinoline-3-carboxylic acid with piperazine in JP 66686/1979 and JP 33453/1980, in DE 2840910 and DE 3308909 and as a hydrolysis reaction of an alkyl ester in 3-position of l-alkyl-6-fluoro-7-(l-piperazinyl)-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid in BE 890223.

It is characteristic for ali these processes that the substitution reaction takes place ef-fectively only at temperatures above 100 °C which gives rise to a large percentage of the competitive reaction in 6-position.

In ES 9001782 there is disclosed a nucleophilic substitution in boron, aluminum and Silicon chelates, however the substitution product obtained was not isolated and the hydrolysis to the bioactive compound was immediately carried out. In HU 1505/87 there is also disclosed a nucleophilic substitution of the halo atom in 7-position in a 3 LV 10863 boron chelate complex, which substitution takes place at temperatūras above 100 °C. AJso in this case the substitution product obtained was not isolated and the hydrolysis was carried out immediately.

The Description of the Inventive Solution

The first object of the invention is a process for preparing l-substituted-6-fluoro-4-oxo-7-(l-piperazinyl)-l,4-dihydroquinoline-3-carboxylic acid of the general formula II 0

E

wherein Ra represents lower alkyl, lower cycloalkyl or 2,4-difluorophenyl, or a pharmaceutically acceptable acid addition salt thereof such as hydrochloride or lactate and hydrates thereof, characterized in that a compound of the general formula I

wherein has the above meaning and represents a lower alkyl or an optionally substituted phenyl, is subjected to an alkaline hydrolysis and, if desired, the obtained compounds of the general formula I is converted into a pharmaceutically acceptable acid addition salt thereof such as hydrochloride or lactate and hydrates thereof. 4

The alkaline hydrolysis is carried out in an aqueous or aqueous-ethanolic medium e.g. with an alkali hydroxide solution such as 10% KOH or 10% NaOH, at a tera-perature from 50 °C to the reflux temperature, preferably at the reflux temperature of the reaction mbcture.

After the neutralisation with an acid, preferably acetic acid, there is obtained a product containing (\vithout additional purification) under 0.5% of total impurities.

Another object of the invention is a novel intermediate, i.e. l-substituted-6-fluoro-4-oxo-7-(4-substituted-l-piperazinyl)-l,4-dihydroquinoline-3-carboxylate boron diacetate of the general formula I, useful as a starting material in the above process for preparing the bioactive compound of the general formula II.

Stili another object of the invention is a process for preparing the novel intermediate of the general formula I, vvherein in 1-substituted 6-fluoro-7-halo-4-oxo-l,4-dihydro-quinoline-3-carboxylate boron diacetate of the general formula III a nucleophilic substitution of the halo atom in 7-position is carried out with 1-substituted piperazine of the formula

H

1 COOR2 wherein has the above meaning.

The reaction is carried out in an organic solvent such as pyridine, dimethylsulfoxide, dimethylformamide, l-methyl-2-pyrrolidone, preferably in l-methyl-2-pyrrolidone, at temperatures from 0 °C to 40 °C, preferably from 25 °C to 30 °C. At these tempera-tures the reaction is completed in l-methyl-2-pyrrolidone as a solvent in 10 to 15 hours, no by-products are formed and also the hydrolysis of the boron salt does not occur. At the reaction temperatures above 40 °C the decomposition of the boron salt is noticeable and increases very rapidly with the elevated temperature. The 3-carboxylic acid formed as a result of this decomposition is much less reactive since the nucleophilic substitution occurs at temperatures above 100 °C. 5 LV 10863

The isolation of the obtained compound of the formula I is very simple, since at precipitating with alcohol it is obtained in a pure form and no additional purification is necessary.

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

Ali reactants are either commercially available or may be obtained as described herein.

Both inventive processes are illustrated by the following reaction scheme, vvherein X, Rj and Rj have the above meanings.

AC°\ /°AC

III

II 6

The invention is disclosed more in detail in the following Examples but it is in no way limited thereto.

Example 1 l-cyclopropyl-6-fluoro-4-oxo-7-(4-carboethoxy-l-piperazinyl)-l,4-dihydroquinoline-3-carboxylate boron diacetate l-cyclopropyl-6-fluoro-4-oxo-7-chloro-l,4-dihydroquinoline-3-carboxylate boron diacetate (10 g; 0.0244 moles) and l-carboethoxypiperazine (15.44 g; 0.0977 moles) was suspended in l-methyl-2-pyrrolidone (40 ml) and stirred at the temperature of 30 °C for 12 hours. After the reaction was completed, absolute ethanol (60 ml) was added to the reaction mixture and it was stirred at room temperature for 2 hours. The precipitate obtained was suction-filtered, washed with ethanol and dried in vacuo at 80 °C. The filtrate was cooled to 0 - 5 °C and the obtained precipitate was suction-filtered, suspended into a l-methyl-2-pyrrolidone/ethanol mixture (2:1) and macerated for 2 hours, suction-filtered and dried. The products were combined. Thus a chromatographically pure l-cyclopropyl-6-fluoro-4-oxo-7-(4-carboethoxy-l-piperazinyl)-l,4-dihydroquinoline-3-carboxylate boron diacetate (10.75 g; 83%), m.p. 235 to 240 °C, was obtained.

Spectroscopic data: *H NMR spectrum (CF3COOH, TMS) (recorded on a 300 MHz instrument): ^CH2(cyclopropyl) = (m> ^=^Ηζ, 2H), 5cm = 1.30 (t, J=8Hz, 3H), SCH2(cyclopropyl) = 1.52 (m, J=8Hz, 2H), 5CH3 = 2.03 (s, 6H), 5CH2(pjpcrazinyl) = 3.42 (m, 4H), 5CH2(pipcrazinyi) = 3.74 (m, 4H), SCH(cycļopropyl) = 3.73 (m, J=8Hz, 1H), S0CH2 = 4.2 (q, J=8Hz, 2H), δΗ8 = 7.48 ppm (d, J=8Hz, 1H), δΗ5 = 8.08 (d, J=14.3Hz, 1H), δΗ2= 9.0 ppm (s, 1H). IR spectrum: 1700,1630,1480,1370,1275,1240,1060,960 cm1. 7 LV 10863

Example 2 l-ethyl-6-fluoro-4-oxo-7-(4-carboethoxy-l-piperazinyl)-l,4-dihydroquinoline-3-carboxylate boron diacetate l-ethyl-6-fluoro-4-oxo-7-chloro-l,4-dihydroquinoline-3-carboxylate boron diacetate (2.37 g, 0.006 moles) and l-carboethoxypiperazine (3.78 g; 0.024 moles) were suspended in l-methyl-2-pyrrolidone (9.5 ml) and stirred at 30 °C for 9 hours. After the reaction was completed, absolute ethanol (19 ml) was added to the reaction mix-ture and it was stirred at room temperature for 2 hours. The obtained product was suction-filtered, washed with ethanol and dried in vacuo at 80 °C. Thus l-ethyl-6-fluoro-4-oxo-7-(4-carboethoxy-l-piperazinyl)-l,4-dihydroquinoline-3-carboxylate boron diacetate (2.7 g; 87%), m.p. 235 to 238 °C, was obtained.

Spectroscopic data: Ή NMR spectrum (CF3COOH, TMS) (recorded on a 60 MHz instrument): SCH3 = 1.53 (t, J=7Hz, 3H), 5CH3 = 1.97 (t, J=7Hz, 3H), 5CH3 = 2.4 (s, 6H), ^CH2(piperazinyi) ~ ^-0 (m> ^NCH2 = ^-53 3 = 7Hz, 2H), 5QCH2 = 5.03 (q, J = 7Hz, 2H), δΗ8 = 7.7 (d, J=6Hz, 1H), δΗ5 = 8.4 (d, J=12Hz, 1H), δΗ2 = 9.6 ppm (s, 1H). 19F NMR spectrum (CF3COOH, CFC13) (recorded on a 60 MHz instrument): δρ= -114.0 ppm (dd, J=12Hz; 6Hz). IR spectrum: 1700,1635,1490,1375,1285,1240,1060, 970 cm-1.

Example 3 l-cyclopropyl-6-fluoro-4-oxo-7-(l-piperazinyl)-l,4-dihydroquinoline-3-carboxylic acid l-cyclopropyl-6-fluoro-4-oxo-7-(4-carboethoxy-l-piperazinyl)-l,4-dihydroquinoline-3-carboxylate boron diacetate (10 g; 0.0188 mole) was suspended in 10% KOH (187 ml) and heated at reflux temperature for 1.5 hours. Then the reaction mixture was cooled to room temperature and the pH was adjusted to 7.2-7.4 with acetic acid. The reaction mixture was stirred for another 30 minūtes, the precipitate was suction- 8 filtered, washed with water and dried. Thus l-cyclopropyl-6-fluoro-4-oxo-7-(l-piperazinyl)-l,4-dihydroquinoline-3-carboxylic acid (5.95 g; 96%), m.p. 258 to 263 °C, was obtained.

Example 4 l-cyclopropyl-6-fluoro-4-oxo-7-(l-piperazinyl)-l,4-dihydroquinoline-3-carboxylic acid hydrochloride monohydrate l-cyclopropyl-6-fluoro-4-oxo-7-(4-carboethoxy-l-piperazinyl)-l,4-dihydroquinoline-3-carboxylate boron diacetate (3 g; 0.0056 moles) was suspended in 10% KOH (56 ml) and heated at reflux temperature for 1.5 hours. After the reaction was com-pleted, concentrated HC1 (8 ml) was added and it was heated at the temperature of 80 °C for 30 minūtes. Then the reaction mixture was cooled to room temperature, ethanol (14 ml) was added, it was stirred for another 30 minūtes, the obtained precipitate was suction-filtered, washed with water and dried to the constant weight. Thus l-cycIopropyl-6-fluoro-4-oxo-7-(l-piperazinyl)-l,4-dihydroquinoline-3-carbo-xylic acid hydrochloride monohydrate (1.98 g; 92%), m.p. 282 to 288 °C, was obtained.

Example 5 l-ethyl-6-fluoro-4-oxo-7-(l-piperazinyl)-l,4-dihydroquinoline-3-carboxylic acid l-ethyl-6-fluoro-4-oxo-7-(4-carboethoxy-l-piperazinyl)-l,4-dihydroquinoline-3-carbo-xylate boron diacetate (1.04 g; 0.002 mole) was suspended in 10% KOH (16 ml) and ethanol (12 ml) and heated at the reflux temperature of the mixture for 11 hours. Then the mixture was cooled to 15 °C, the pH was adjusted to 7.2-7.4 with 15% HC1 and it was stirred at this temperature for further 30 minūtes. The precipitate obtained was suction-filtered, washed with water and dried to a constant weight in a vacuum drier at 100 °C. Thus l-ethyl-6-fluoro-4-oxo-7-(l-piperazinyl)-l,4-dihydro-quinoline-3-carboxylic acid (0.6 g; 93%), m.p. 218 to 221 °C, was obtained. 9 LV 10863

GLAIMS

1. Process for preparing l-substituted-6-fluoro-4-oxo*7-(l-piperazinyl)-l,4-dihydro-quinoline-3-carboxylic acid of the general formula II 0

tt \vherein R2 represents a lower alkyl, a lower cycloalkyl or 2,4-difluorophenyl, or a pharmaceutically acceptable acid addition salt thereof such as hydrochloride or lactate and hydrates thereof,

characterized in that a compound of the general formula I

I vvherein Rļ has the above meaning and R^ represents a lower alkyl or an optionally substituted phenyl, is subjected to an alkaline hydroIysis and, optionally, the obtained compound of the general formula II is converted into a pharmaceutically acceptable acid addition salt thereof such as hydrochloride or lactate and hydrates thereof.

2. l-substituted-6-fluoro-4-oxo-7-(4-substituted-l-piperazinyl)-l,4-dihydroquinoIine-3-carboxylate boron diacetate of the general formula I 10

vvherein Rx represents a lower alkyl, a lower cycloalkyl or 2,4-difluorophenyl and represents a lower alkyl or an optionally substituted phenyl.

3. Process for preparing l-substituted-6-fluoro-4-oxo-7-(4-substituted-l-piperazinyl)-l,4-dihydroquinoline-3-carboxylate boron diacetate of the general formula I

vvherein Rļ represents a lower alkyl, a lower cycloalkyl or 2,4-difluorophenyl and R^ represents a lower alkyl or an optionally substituted phenyl, characterized in that in l-substituted-6-fluoro-7-halo-4-oxo-l,4-dihydroquinoline-3-carboxylate boron diacetate of the general formula III

vvherein X represents F or Cl, whereas Rļ has the above meaning, 11 LV 10863 a nucleophilic substitution of the halo atom in 7-position is carried out with 1-substituted piperazine of the formula

H

wherein has the above meaning. 4. Process according to claim 1, characterized in that it is carried out in an aqueous or ethanolic/aqueous medium. 5. Process according to claim 1, characterized in that it is carried out at a tempera-ture from 50 °C to the reflux temperature of the reaction mixture. 6. Process according to claim 3, characterized in that it is carried out in an organic solvent such as pyridine, dimethylsulfoxide, dimethylformamide, l-methyl-2-pyrro-lidone, preferably in l-methyl-2-pyrrolidone. 7. Process according to claim 3, characterized in that it is carried out at temperatures from 0 °C to 40 °C, preferably ffom 20 °C to 30 °C. 12 LV 10863

ABSTRACT

Disclosed is a process for preparing l-substituted-6-fluoro-4-oxo-7-(l-piperazinyl)-l,4-dihydroquinoline-3-carboxylic acid of the formula II 0

H

wherein Rj represents a lower alkyl, a lower cycloallcyl or 2,4-difluorophenyl, wherein l-substituted-6-fluoro-4-oxo-7-(4-substituted-l-piperazinyl)-l,4-dihydro-quinoline-3-carboxylate boron diacetate of the formula I

AcO^ ^.OAc -B

000¾. wherein represents a lower alkyl or an optionally substituted phenyl, is subjected to an alkaline hydrolysis. Compounds of the formula Π are used in medicine for the treatment of inflammatory diseases.

The compound of the formula I is novel. It is obtained by a nucleophilic substitution of the halo atom in 7-position in the compound of the formula III

13 with 1-substituted piperazine of the formula

H

COOR2

Claims

000¾ where R ·) is the lowest alicyl, lower cycloalkyl or 2,4-difluorophenyl group and R2 is lower alkyl or optionally substituted phenyl, characterized in that 1-substituted-6-fluoro-7-halogen-4-oxy -1,4-dihydroquinoline-3-carboxylate boron diacetate of the general formula (III)

where X is F or Cl, and R 1 is as defined above, the nucleofllo of the halogen atom is placed in the 7-position with 1-substituted piperazine of formula H

COORg and wherein R2 is as defined above.

000¾ where R 1 is the lowest alkyl, lower cycloalkyl or 2,4-difluorophenyl and R 2 is the lower alkyl or optionally substituted phenyl.

000¾ where R is the above and R2 is the lower alkyl or optionally substituted phenyl is subjected to alkaline hydrolysis and optionally the resulting compound of general formula (II) is converted to a pharmacologically compatible acid addition salt such as hydrochloride or lactate and hydrates thereof.

2. 1-substituted-6-fluoro-4-oxy-7- (4-substituted-1-piperazinyl) -1,4-dihydroquinofin-3-carboxylate boron diacetate of the general formula (I) AcO OAc

A method for the preparation of 1-substituted-6-fluoro-4-oxy-7- (1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid having the general formula (II) 0.

Where R 1 is the lower alkyl, lower cycloalkyl or 2,4-difluorophenyl group or a pharmacologically compatible acid addition salt such as hydrochloride or lactate and their hydrates, characterized in that the compound of the general formula (I) AcO OAc

3. A process for the preparation of 1-substituted-6-fluoro-4-oxy-7- (4-substituted-1-piperazinyl) -1,4-dihydroquinoline-3-carboxylate boron diacetate having the general formula (I).

Method according to claim 1, characterized in that it is carried out in a water or an alcohol / water environment.

Method according to claim 1, characterized in that it is carried out at a temperature of from 50 ° C to the temperature of the reaction mixture.

A process according to claim 3, characterized in that it is carried out in an organic solvent such as pyridine, dimethylfoxide, dimethylformamide, 1-methyl-2-pyrrolidone, preferably in 1-methyl-2-pyridone.

Method according to claim 3, characterized in that it is carried out at a temperature between 0 ° C and 40 ° C, preferably between 20 ° C and 30 ° C.