DD283386A5 - Process for the preparation of 1-substituted-6-fluoro-4-oxo-7- (1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid - Google Patents

Abstract

The invention relates to a process for the preparation of 1-substituted * of the formula I, wherein R is CH 2 CH 3, cyclopropyl, CH 2 CH 2 OH, CH 2 OCH 2 CH 2 OH, in which one has a 1-substituted * or their ethyl esters of the general formula II, wherein R has the above meaning and R is hydrogen or ethyl, hydrolyzed in a basic medium. The compounds produced by the process of the present invention are used in medicine for the treatment of infectious diseases. They have a broad spectrum of activity. Formula I, II {method; manufacture; substituted carboxylic acid; Medicine; Treatment of infectious diseases; broad spectrum of activity}

Description

COOR ¹

COiDCH ₂ CH ₃

wherein N has the above meaning and R 'is hydrogen or ethyl, hydrolyzed in a basic medium.

2. The method according to claim 1, characterized in that in the reaction, a mixture of ethanol and aqueous solution of a base, such as KOH, NaOH, is used.

3. Process nor claims 1 and?, Characterized in that the reaction takes place at the reflux temperature of the reaction mixture.

Field of application of the invention The invention belongs to the field of organic chemical synthesis. Characteristic of the known state of the art The preparation of 1-substituted e-FluoM-oxo-y-O-piperazinylMAdihydrochinolin-S-carboxylic acid of general formula I.

COOH

wherein R is CH ₂ CH ₃ , cyclopropyl, CH ₂ CH ₂ OH, CHiOCH ₂ CH ₂ OH, is described in the patent literature, e.g. As the reaction of the substitution of the chlorine atom in the 7-position with piperazine in JP applications 66686/1979 and 33453/1980, in DE-OS 2840910 and DE-OS 3308909 and as the reaction of the hydrolysis of alkyl ester in BE-PS 890223.

Object of the invention

There was a need for a new process for preparing the compound of Formula I. Both synthesis and isolation should be simple and provide high yields.

The compounds of the formula I are used in medicine for the treatment of inflammatory diseases. Their spectrum of activity is broad, because they are effective against both Gram-positive and Gram-negative bacteria.

Explanation of the essence of the invention

The invention has for its object to provide a novel process for the preparation of compounds of formula I. The process according to the invention is carried out in such a way that a 1-substituted-6-fluoro-4-oxo-7- (3-carbethoxy-1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid or its ethyl ester of the general formula II

COOR. ¹

COOCH ₂ CH ₃

wherein R has the meaning mentioned above and R 'is hydrogen or ethyl, hydrolyzed in a basic medium, wherein a compound of formula I is formed.

The hydrolysis is preferably carried out in a KOH or NaOH solution. Man working at reflux temperature of the reaction mixture.

The resulting crude 1-substituted-6-fluoro-4-oxo-7- (1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid in salt form is neutralized and then recrystallized, e.g. B. from a Ν, Ν-dimethylformamide-ethanol mixture.

The compound of formula II in which R 'is ethyl is a novel compound and is also one of the aspects of the invention. The novel ethyl ester is prepared from the ethyl ester of 1-substituted-6-fluoro-7 by a process which is also a subject of the invention -halo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. Also, the compound of formula II wherein R 'is hydrogen is prepared from the 1-substituted e-fluoro-y-halo -oxo-i / t-dihydroquinoline-S-carboxylic acid as apparent from the scheme:

COOCH ₀ CH,

COOR '

base

COOR '

COOCH ₂ CH ₂

R = CH ₂ CH ₃ , cyclopropyl, CH ₂ CH ₂ OH, CH ₂ OCH ₂ CH ₂ OH

R '= H, CH ₂ CH ₃

X = halogen, in particular F, Cl

The reaction is preferably carried out in polar organic solvents and mixtures thereof, such as Ν, Ν-dimethylformamide, acetonitrile, pyridine, 2-methyl-5-ethyl-pyridine, 1-methyl-pyrrolidone, dimethyl sulfoxide, etc., in the presence of a base for binding the liberated HX performed. These may be equal to the reagent 1-carboxypiperazine or another base, for. As sodium or potassium carbonate can be used.

The present process for the preparation of the compound of general formula I is novel and not yet in the literature

described. The preparation and isolation of the compound of formula I are simple and high yields are achieved.

The invention will be further described by the following examples, without being limited thereto. embodiments example 1

i-ethyl-e-fluoMi-oxo ^ -d-piperaiinyO-IAdihydrochinolin-S-carboxylic acid

0.838 g (0.002 mol) of ethyl 1-ethyl-6-fluoro-4-oxo-7- (4-carbethoxy-1-piperazinyl) -1,4-dihydroquinoline-3-carboxylate are dissolved in a mixture of 12 ml of ethanol and 18 ml of 10 % aqueous KOH solution and at reflux temperature of the

Reaction mixture heated for 10 hours (the reaction is carried out by thin layer chromatography: S1O2; Ethanol! Ammonia = 72:20). After completion of the reaction, the solvent is distilled off in vacuo, with 15ml

15% HCl added, the solution is filtered, and then the pH of the solution is adjusted to 7 with 10% KOH. The precipitate is filtered off, washed with water and dried. Thus, 0,478g (75%) of 1-ethyl-6-fluoro-4-oxo ^ -Cl-piperazinyD-IAdihydrochinolin-a-carboxylic acid, mp. 216-22O ⁰ are obtained C. The spectroscopic data agree

Literature data match. Example 2

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

0.391 g (0.001 mol) of 1-ethyl-6-fluoro-4-oxo-7- (4-carbethoxy-1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid are in a

Suspended mixture of 6 ml of ethanol and 8 ml of 10% aqueous KOH solution and at reflux temperature of the Reaction mixture heated for 10 hours (the reaction is carried out by thin layer chromatography: SiO ₂ ; Ethanol! Ammonia = 72:20). After completion of the reaction, the solvent is distilled off in vacuo, mixed with 10 ml of 15% HCl, the cloudy solution

is filtered and neutralized with 10%: according to KOH. The precipitate is filtered off with suction, washed with water and dried. There are 0.240 g (75%) of i-ethyl-e-fluoM-oxo ^ -d-piperazinylJ-i ^ -dihydro-quinoline-S-carboxylic acid, m.p.

216-220 ° C, is obtained. The spectroscopic data agree with literature data.

Example 3

1-Cyclopropyl-6-fluoro-4-oxo-7- (1-piperazinyl) -1,4-dihydro-quinoline-3-carboxylic acid 0.431 g (0.001 mol) of 1-cyclopropyl-6-fluoro-7- (4 -carbethoxy-1-piperazinyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester are suspended in 6 ml of ethanol and 9 ml of 10% aqueous KOH solution and heated at reflux temperature of the reaction mixture for 8 hours. Then the solvent is distilled off in vacuo, the dry residue is treated with 5 ml of water and the pH is adjusted to 1 with a 15% aqueous HCl solution, the turbid solution is filtered, and with a 10% aqueous KOH solution the pH is adjusted to 7. The precipitate is filtered off, washed with water and dried. Thus, 0.286 g (86%) of i-cyclopropyl-e-fluoroMl-oxo ^ -d-piperazinyl-M-dihydroquinoline-3-carboxylic acid of mp 255-257 ° C is obtained. The spectroscopic data agree with literature data.

Example 4

1- (2-Hydroxyethyl) -6-fluoro-4-oxo-7- (1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid 0.407g (0.001 mol) of 1- (2-hydroxyethyl) -6-fluoro 4-oxo-7- (4-carbethoxy-1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid are suspended in 6 ml of ethanol and 9 ml of 10% aqueous KOH solution and at reflux temperature of the reaction mixture for 14 hours and 45 Heated for a few minutes. After completion of the reaction, the solvent is removed in vacuo, the residue is mixed with 5 ml of water and acidified to pH 1 with 15% aqueous HCl solution. The cloudy solution is filtered, neutralized with a 10% aqueous KOH solution to pH 7 and the precipitate is filtered off. Thus, 0.320 g (96%) of 1- (2-hydroxyethyl) -6-fluoro-4-oxo-7- (1-piperazinyl) -1,4-dihydroquinoline-3-carboxylic acid with mp.> 300 ° C (recrystallization : Ethanol-water). The spectroscopic data agree with literature data.

Example 5

i-Aethyl-.beta.-fluoroM-oxo ^^ - carbethoxy-i-piperazinyl-1-dihydro-quinoline-D-carboxylic acid ethyl ester 0.562 g (0.0020 mol) of 1-ethyl-6,7-difluoro-4-oxo-1,4 dihydro-quinoline-3-carboxylic acid ethyl ester, 0.348 g (0.0022 mol) of 1-carbethoxy-piperazine and 0.303 g (0.0022 mol) of potassium carbonate are suspended in 6 ml of Ν, Ν-dimethylformamide and at

Reflux temperature of the reaction mixture heated for 4 hours. The reaction is carried out by thin layer chromatography

(SiO ₂ , AethanohAmmoniak = 72:20). After completion of the reaction, the solvent is distilled off in vacuo, mixed with 20 ml of water and extracted with chloroform. The chloroform layer is dried, the solvent is distilled off in vacuo, the dry residue is washed once more with water and recrystallized from ethanol. Thus, 0.448 g (53%) of 1-ethyl e-fluoM-oxo ^^ carbethoxy-1-piperazinyl-O-dihydroquinoline-S-carboxylic acid ethyl ester, m.p.

198-202 ⁰ C, obtained.

Spectroscopic data

¹ H NMR spectrum (CDCl 3, TMS): 5 _C hj = 1.20-1.33 ppm (m, 9H), 6 _H (pip ,, inyi) = 3.25 ppm (m, 4H), 3, 67 ppm (m, 4H),

Bchj = 4.00 to 4.60 ppm (m, 6 H), δ '= 6.70 ppm (d, ⁴ J _{PH (=} 7 Hz, 1 H), _δ Η = 7.95 ppm (d , ³ J _fH , = 13 Hz, 1 H), δ _Ηΐ = 8.32 ppm (β, 1 H).

"F NMR spectrum (CDCI ₃ , CCI ₃ F): ö _f = -123.00ppm (dd, ³ J _H F, = 13Hz, ⁴ Jm, = 7Hz).

Mass measurement: calculated mass for C ₂ IH ₂₆ FN ₃ O ₆ : 419.185635

measured mass: 419.1853 mass spectrum m / e: 420 (M ⁺ - + 1.4%) m 419 (M ⁺ -, 16%), 348 (20), 347 (100), 245 (8), 318 ( 9), 56 (27), 32 (12).

Example β

1-ethyl-6-fluoro-4-oxo-7- (4-carbethoxy-1-piperazinyl) -1,4-dehydroquinoline-3-carboxylic acid 0.270 g (0.001 mol) of i-ethyl-e-fluoro ^ - chloM-oxo-1-dihydroquinoline-S-carboxylic acid and 0.632 g (0.004 mol) of 1-carbethoxypiperazine are suspended in 4 ml of 2-methyl-5-ethyl-pyridine and 2 ml of 1-methylpyrrolidine and heated at reflux temperature of the reaction mixture for 4 hours. After completion of the reaction, 10 ml of chloroform are added and the solution is washed with a 10% aqueous HCl solution and then with water until neutral. The chloroform layer is dried and the solvent is distilled off in vacuo. The dry greasy residue is washed with ethanol and dried. Thus, 0.195 g (50%) of 1-ethyl-6-fluoro-7- (4-carbethoxy-1-piperazinyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid, m.p. 270-273 ° C, receive.

Spectroscopic data

¹ H NMR spectrum (CF ₃ COOH ₁ TMS): δ _0Η , = 1.42 ppm ( ³ J = 6.4 Hz, t, 3H), δ _C H, = 1.78 ppm (t, J = 6.4 Hz, 3H), δH (pip. »I! Nyi> = 3.88 ppm (m, 8H), 6 _CHI = 4.41 ppm (q, J = 6.4 Hz, _2H ), 6 _CH , = 4 , 84 ppm (q, J = 6.4 Hz, 2 H),

δ _Η , = 7.40 ppm (d, ⁴ JfH ₁ = 6.5Ηζ, 1Η), δ _Η , = 8.27 ppm (d, ³ J _FH , = 13Hz, 1H), δ _Hj = 9.2bppm ( s, 1 H). ¹⁹ F NMR spectrum (CF ₃ COOH, CCI ₃ F): Sf = -112.07 ppm (dd, ³ J _fH , = 13 Hz, ⁴ J _{FH |} = 6.5 Hz).

Mass spectrum m / e: 329 (M ⁺ + 1.3%), 391 (M ⁺ , 15%), 348 (15), 347 (100), 151 (14), 83 (12), 56 (19), 44 (15), 43 (11). Mass measurement: calculated mass for CiSH ₂₂ FN ₃ O ₆ : 391.154 measured mass: 391.154

Example 7

1-Cyclopropyl-6-fluoro-7- (4-carbethoxy-1-piperazinyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester 0.449 g (0.0015 mol) of i-cyclopropyl-ej-difluoroM-oxo -I-dihydro-quinoline-S-carboxylic acid ethyl ester, 0.261 g (0.00165 mol) of 1-carbethoxypiperazine and 0.228 g (0.00165 mol) of potassium carbonate are suspended in 5 ml of Ν, Ν-dimethylformamide and heated at reflux temperature of the reaction mixture for 4 hours. After completion of the reaction, the solvent is distilled off in vacuo, mixed with 20 ml of water and extracted with chloroform. The chloroform layer is dried and the solvent is distilled off. There are obtained 0.529 g (82%) of 1-cyclopropyl-6-fluoro-7- (4-carbethoxy-1-piperazinyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester. The product is recrystallized from ethanol, mp 225-229 ⁰ C.

Spectroscopic data

¹ H NMR spectrum (CDCL ₃ , TMS): oc ^ c ^ hicyciopropyi) = 1.45 ppm (m, 10H), OH (Pip, _fli i., Yi) .H (cyclop, opyi) = 3.32 ppm (m, 5H), 3.73 ppm (m, 4H), OCH ₁ CH, = 4.32 ppm (rn, _4H ), δ _Η , = 7.20 ppm (d, ⁴ J _FHl = 6 , 4 Hz, 1 H), δ _{Η |} = 7.87 ppm (d, ³ J _fH , = 13 Hz, 1H), δ «, = 8.43 ppm (s, 1H). ¹⁹ F NMR spectrum (CF ₃ COOH, CCI ₃ F): ö _f = -112.57 ppm (dd, ³ J _FH , = 131 ⁴ J _FM1 = 6.5 Hz). Mass spectrum m / e: 432 (M ⁺ - + 1.6%), 431 (M ⁺ -, 21%), 386 (8), 360 (21), 359 (100), 329 (6), 257 (6 ), 230 (6), 229 (5), 56 (26).

Example 8

1-Cyclopropyl-6-fluoro-7- (4-carbethoxy-1-piperazinyl) -4-oxo-1,4-dihydroquinino-3-carboxylic acid 0.265 g (0.001 mol) of i-cyclopropyl-ej-difluoro-M oxo-1-dihydroquinoline-S-carboxylic acid, 0.174 g (0.0011 mol) of 1-carbethoxypiperazine and 0.152 g (0.0011 mol) of potassium carbonate are suspended in 10 ml of Ν, Ν-dimethylformamide and heated at reflux temperature of the reaction mixture for 2.5 hours. After completion of the reaction, the solvent is distilled off in vacuo, the dry residue is mixed with 10 ml of water and the pH of the suspension is adjusted to neutral with 15% HCl. The precipitate is filtered off and dried. The product is recrystallized from dimethylformamide. Thus, 0.282 g (70%) of 1-cyclopropyl-6-fluoro-7- (4-carbethoxy-1-piperazinyl) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid, mp> 250 ^° C., are obtained ,

-5- 283 386 Spoktroskoplsche data

¹ H NMR spectrum (CF ₃ COOH, TMS): oct ^ Hicyeiopropyi) = 1.50 ppm, 7H), ÖHiPipw.nnyii.Hicydopiopyii = 3.93 ppm (m, 9H),

6 _CH , = 4.41 ppm (q, J = 6.4 Hz, 2 H), δ _Η , = 7.88 ppm (d, ⁴ J _FH , = 6.5 Hz, 1 H), 6h, = 8.27 ppm (d, ³ J _FH , = 13 Hz, 1 H), δ _Η , = 9.32 ppm (s,

¹⁹ FNMR spectrum (CF ₃ COOH ₁ CFCI ₃ ): 6 _f = -112.40ppm (dd, ³ J _fH , = 13Hz, ⁴ J _FH , = 6.5i.i /.

Mass spectrum m / e: 404 (M ⁺ + 1.4%), 403 (M ⁺ -, 21%), 360 (28), 359 (100), 347 (14), 289 (14), 287 (15) , 257 (12), 240 (17), 57 (11), 56 (30), 44 (26).

Mass measurement: calculated mass for CwH ₂₂ FN ₃ O ₆ : 403.154 measured mass: 403.150

Example 9

1-Cyclopropyl-6-fluoro-7- (4-carbethoxy-1-piperazine) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid 0.281 g (0.001 mol) of 1-cyclopropyl-6-fluoro-7 < : Hlor-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 0.832 g (0.004 mol) of 1-CarbSuioxy-piperazine are suspended in 8 ml of 2-methyl-5-ethylpyridine and 2 ml of 1-methylpyrrolidine and refluxed at Reaction mixture heated for 4 hours. After completion of the reaction, the cooled solution is mixed with 20 ml of chloroform and washed with a 15% aqueous HCl solution and then with water until neutral. The chloroform layer is dried and the solvent is distilled off. The residue is washed with ethanol and dried. Thus, 0.222 g (55%) of 1-cyclopropyl-6-fluoro-7- (4-carbethoxy) -4-oxo-1,4-dihydroquinoline-3-carboxylic acid, m.p.

> 25O ⁰ C, received.

The product is recrystallized from Ν, Ν-dimethylformamide.

Claims (1)

claims: A process for the preparation of i-substituted-fluoro-oxy-yl-piperazinyl-D-M-dihydroquinoline-S-carboxylic acid of the formula I COOH in which R is CH ₂ CH ₃ , cyclopropyl, CH ₂ CH ₂ OH, CH ₂ OCH ₂ CH ₂ CH, characterized in that a 1-substituted e-fluoro-oxo-yK-carbethoxy-1-piperazinylMAdihydrochinolin-S- Carbonsäuid or their ethyl esters of the general formula II