LT3084B - 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 - Google Patents

Description

1-substituted piperazine of the formula • 1

.., / 0 + 308418., I:

, / Ilrdudm '. Belongs to .organic chemistry. domain ^; ..ip --yo '' / ' _:

where R @ 2 R _x is lower alkyl, lower cycloalkyl, or 2,4 "difluorophenyl. This compound is used in medicine and has anti-inflammatory activity “It works against both Gram-positive and Gram-negative bacteria. The present invention also relates to a novel intermediate used in the process for preparing the above compound and to a process for the preparation of this intermediate.

Japanese patents no. No. 66689/1979 'and no. 33453/1980 and also in German Patent Nos. 2840910 and no. No. 3308909 discloses the substitution of a chlorine atom at the 7-position of compounds of the general formula II by synthesis with 1-alkyl-1-6-fluoro-7-halo-4-oxy-1,4-dihydroquinoline ~ 3-piperazine as an example.

25 'in German patent no. 3308909.

The closest process for the preparation of compound II is the hydrolysis of 1-alkyl-6-fluoro-7- (1-piperazinyl) -4-oxy-1,4-dihydroquinoline-3-carbonic acid alkyl ester at position 330. is described. The Belgian patent no. 890223.

Spanish patent no. 9001782 Reveals Nucleophilic // + + + + + bor ©, /., + Aluminum '+ / lr: / silicon +' + / s & lst, '35 / _. replacement / product '· was + _? - '' separated ' _: and ++, + +' immediately + -pat / was'' ⁷ ' performed by /+hiologically / '+; active +' + 'compound:,:'

....- hydrolysis' ·. - /. . .: // y 7 / \ _λ . 2.

Closest to - The compound of formula I, which is described in the Hungarian Patent No. 7,505/1987, according to

-c.

'• to. ·' // which boro che lat ini ame complex is -removed;

/ nucleophilic- / substitution at the 7-position of the halogen atom.

. The change is made at temperatures above 100 ° C. In this case, the resulting substitution product was also - not isolated and immediately subjected to hydrolysis. /, / / However, the products obtained by the above-mentioned methods contain a considerable amount of / 1:0/·.·· 'impurities, * by-products and © hydrolysis of salts, which is undesirable. .

It is an object of the present invention to provide a synthesis method which utilizes an intermediate product which has a reduced content of impurities, no by-products and no boron salts.

-77 -'hydro-i.'e - //// ^ - ////// - // -Z '·'' ¹ ' - / 7/77 /: - // --- 7 // First.s; invention //: // hopeful /// - / smug ^; /// i - ^ harrow-6 '·' flūor74 ^; a-oxy-.7 ~ Itspiperazilyl-l7dihydro / quinoline -. 3 ~ / 7carbonic acid ,, - / having the '-theme / formula' / II -, '/

'/ in which ί / ^ -' // ^; -; 'zeafesniš:? / aikilaš,:''; -. reasons:.: ^; .'ci.klaalkilas. '/ or' / 2: / J ~ diflwrfefiiįas, - /// or ///.fąrmaGly-///acceptable

- / 'acid7 / pri jungimb' / - / salt ·, / · // such as // hydrochloride: 7 or '· - lactate / / and / hydrates /' / production / 'method:, / · by / which compound, -which: general formula I

where R _x ? same'.;? as: the above mentioned and? R ₂ is' lower allyl or optionally substituted phenyl, hydrogenated? alkaline je 7; medium je / .and if desired /; the resulting JuhgiriyšHkurib / iaėhdra ^ ifprtol I is converted to a pharmaceutically acceptable ..? an acid addition salt such as hydrochloride or lactate and hydrates. Alkaline hydrolysis is carried out in aqueous or aqueous ethanol medium, for example, in the form of a shear metal / h / l hydroxide:? in solution./? such as ⁷ to 10% ?? E9H? Aifos-10% NaOH at a temperature of 50 ° C to reflux temperature, preferably at the reaction mixture užvirimo'iėmperatūra.

After?; © eels izac ij oš · '' 7 acid, '? '???: drank; :: ac t O ?: sour t imi, .gotten ?. product ; . (without additional ??? išvalymoįl / have? mažiau7 / or U '.? ^5:% ??' foendrg impurities.?.? ^/,? "

Another object of the invention is to provide a novel intermediate product, i.e.:? I-substituted-6-fluoro-4? oxy-7- (4-substituted-O '- 1-piperazinyl) -1,4'-dihydroquinoline-3-carboxylboro diacetate 7, having the general formula ·· ::'? 1, to be used as / initial ;? material in the above process for the preparation of a biological / active compound of general formula II. ?

Yet another 'object of the invention' is to obtain a novel intermediate :; product containing? ' a general formula I synthesis; in which 1-substituted-6-fluoro-7-halogen-4-oxy-1,1'-4-dihydro-cis-ioholine-3-carboxybenzoate / diacetate, of which " formula III

III

halogen at position 7, nucleophilically substituted with piperazine of formula

Wherein R _{2 is} as shown above.

The reaction is carried out in an organic solvent such as pyridine, dimethylsulfoxide, dimethylformamide, 1-methyl-2-pyrrolidone, preferably 1-methyl-2-pyrrolidone, at a temperature of 0 ° C to 40 ° C, preferably 25 ° C to 30 ° C. . At these temperatures, the reaction terminates with 1-methyl2-pyrrolidone, as in the solvent in '10 -15 hours, without formation of by-products and also without hydrolysis of the boron salts.

At reaction temperatures above 40 ° C, decomposition of the boron salt is observed which increases rapidly at elevated temperature. 3-Carboxylic acid is less reactive as a result of this cleavage since the nucleophilic substitution occurs at temperatures above 100 ° C.

(The separation of the resulting product of formula I is very simple as alcohol precipitation is carried out cleanly and does not require further purification.

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

5 / All 'reagents are commercially available or may be obtained as described in the present invention.

»/ Both methods of 'invention ..' / illustrated / following / ./reaction; j os Y: Schematic., y where X // R. and the same, 'as /. mentioned γ .10 before.

The invention is elaborated by the following examples, but the invention is by no means limited thereto. /

30, γ Deciphering / Deciphering / Deciphering Used in Examples γ:

BMR - Nuclear Magnetic.resonance

TMS-tetramethylsilane

δ - chemical shift value '5 /' m> Y.imlti ^ 3 ^ continuedSYY Υ // ΥΎ- ''

'.'Γ / · γ s' ./-' singlet- /. -ζΥ / 'ργ'

Y: //d.'-._YdubietaS..-',/ ΰ '.' Υ,. '. Ϊ.>I' ^: '/,'-.·/:-··-;''/ dd_ - doublet doublet q '· / -' quartet

m.d. - parts per million

EXAMPLE 1. 1-Cyclopropyl-6-fluoro-4-oxy-7- (4 - {[beta]).

carboethoxy-si-1-piperazinyl) -1,4 - (1 '); 1' / 1 '/ dihydroquinoline-3-carboxylboro diacetate; · Y Yy'Y '- / Y /' Y Y '/ -' Y '// //. -. '

1-Cyclopropyl-6-fluoro-4-oxy-7-chloro-1,4-dihydroquinoline-3-carboxylboro diacetate (10 g; 0.0244 mol) and 1-carboethoxypiperazine (15.44 g; 0.0977 mol) suspended in l-methyl-2-pyrrolidone (40 mL) and for 12 h.

stirred at 30 ° C. When the reaction is complete, absolute ethanol (60 mL) is added to the reaction mixture for 2 hours. stirring at room temperature. The resulting precipitate is suctioned off, washed with ethanol and dried in vacuo at 80 ° C. The filtrate is cooled to 0-5 ° C and the resulting precipitate is suctioned off, suspended in i. ..... l-methyl-; 2-pyrrolidone / ethanol mixture (2: 1) and soaked for 2 hours,

Z vacuumed and dried. The products are combined. Obtained chromatographically: Pure l-cyclopropyl-635 fluoro-4-oxy-7- (4-carboethoxy-1-piperazinyl) -1,4-dichloroacetate-3-carboxylate (10.75 §7).

83%), m.p. 235-240 ° C.

Spectroscopy data:

¹ H NMR. spectrum (CF ₃ COOH, TMS) (recorded using a 300 MHz device):

' ⁵ -' + '/ k' \ k k. ''. '' /.-/+ δ _εΗ + (cyclopropyl) = 1.29 (m, j "8Hz>2H)> k? '' - / B ;;. + / ^ + /// 5 ^^ 1, 30 (t, J = 8Hz, 3H) * k / δ ^. ^ (Cyclopropyl) = 1.52 (m, J = 8Hz, 2H)

- /// k / · /// k§ _C g ₃ = 2., '03 (s, SH), + k' // '' // '//:;./.+ _: .//' ? to _H / (piperazinyl ^; ) = 3.42 (m, 4Hj,

·. '//////// I 5 _CIJ (piperazinyl) = _3.74 (m, 4H), /'

Δ _ch (cyclopropyl) = 3.73 (m, J = 8 Hz, 1H),

-Soch ₂ ^{= 4} ' ² (q, J = 8Hz, 2H), δ _Η θ = 7.48 md (d, J = 8Hz, 1H),' k + δ _Η5 = 8> 08 (d, J = 14 , 3Hz, 1H), .B. '' // δ _Η / = 9.0 md (s. 1H). ...- /

IR spectrum:, '....., ./

1700, 1630, 1480, 1370, 1275, 1240, 1060, 960 cnrl + -, 2 / EXAMPLE. 1-et i1-6-fluoro-4-ox i-7- (4-i-1- _karboetoks: piperazinyl) -1,4-dihydroquinoline-B-carboxylate diacetate / '/ + .- // _{-': ;} B k + -.

+/- 1-Ethyl-6-fluoro-4-oxy-7-chloro-1,4-dichloro-carboxylboro diacetate (2.37 g; 0.006 mol) and 1 - N -carboethoxypiperazine (3.78). g; 0, 024 moles) · -./.;/. slurried in l-methyl-2-pyrrolidone (9.5 mL) and stirred for 9 h. At 30 ° C, complete ethanol (19 mL) was added at the end of the reaction and the reaction mixture was stirred for 2 h in a room temperature temp. Product obtained / suction, ethanol washed and vacuum dried. 80 ° C The resulting temperatūroje.- ^l'etil-:

6-Fluoro-4-oxy-7- {4-carboethoxy-1-piperazinyl) -1,4-dihydro-hydroquinoline-1-carboxylic acid diacetate {2 ₍ T g;

M.p. 235-23'8 ° C.

Spectroscopy data: b ^L H NMR Spectrum (CF ₃ COQH, .. TMS) (recorded using a device operating at 60 MHz):

S 7.to, '. j / 7 / ((..7. (/ i- 7 'j' 7 '' / ^J / / 7 S _Cil3 = _1.53 (t, J = 7Hz, 3H)), b / (7 /.

, //. / 7 {77 - ¾

-7 ^? 7 / ^; i {'- 7' · ^ '{S ^ fp? perazi ^

1 (0., 77 / (7-7 (.; (. (53 ^ ζ ^ · 7Ηζ / 2Η))> ((· / '7; · .7 ·

- (/. 7 / {b (7'7 (§ _OCH 2-5,; 0 ^^ J ^ 7iiz'i2R) 77'7 {/-/.'/ {'7 7 {· (/ ¾ § ^ = 7, 7 (d7J = ^; 6ftz (, O ^ 77 / '(// (. §H ₅ ⁼ 8/4 (d _f J = 12Hz _r lR)), () 7 δ _Η „= 9, 6 md: ((s, 1H). {(/ 7 {/ 7 '7/7 57'7' - <('''7 / /(77/7./(/ i ..//./,/; - ".. (/ 7 / '''(((.'19 _F NMR spectrum of activity. (CF-, COOH, CFC1 ₃₎ (on the The device, which _works: 60MHz dažniuj:' (/ '§ £ 7b. = -114.0 md / (dd, J = (12Hz, 6Kz).

207 7 / '-' / '' / {'-' / 7 /.·- '' / 77

IR Spectrum:

7 (7 1700, 1635, 1 (490/1375, 1285, (1240, ((1060, '970 cm'7.)

EXAMPLE 3 (1-Cyclopropyl-6-fluoro-4-oxy-7- (1'-piperazinyl) -1,4-dihydro;

- acid 1-Cyclopropyl-6-fluoro-4-hydroxy-7- (4-carboethoxy-130-piperazinyl) -1,4-dihydroquinoline-5-carboxylboro;

diacetate (10 g, 0.0188 moles) was suspended in 10% KOH (187 mL) for 1.5 h. heated / at boiling point.

/-----....... After the reaction mixture is cooled to room temperature with acetic acid (pH n £ a)

7.2-7.4. Reactions. the mixture is stirred for another 30 minutes, the precipitate is suctioned off, washed with water and dried. The resulting l-cyclopropyl-6-fluoro-4-hydroxy-7 // ⁹ (l-piperazinyl) -1,4-dihydroquinoline-3 ~ carboxylic acid (5.95 g, 96%), m.p. 258-263 ° C.

EXAMPLE 1-Cyclopropyl-6-fluoro-4-oxy-7- (1-piperidin-2-yl) -1,4-dihydroquinoline-3-carbonic acid ^t -2- ^ee hydrochloride monohydrate 1-Cyclopropyl-6-fluoro-4- oxy-7- (4-carboethoxyl-piperazinyl) -1,4-dihydroquinoline-3-carboxylboro diacetate (3 g, 0.0056 mol) suspended in 10% KOH. (56 ml) · and - 1.5 hours · Bring to the boil.

After completion of the reaction, concentrated RCl (8 mL) was added and the mixture was stirred for 30 min. heated at SOoC. The reaction mixture is then cooled to room temperature, ethanol (14 mL) is added, the mixture is stirred for another 30 min, the resulting precipitate is suctioned off, washed with water and dried to constant weight. 1-Cyclopropyl-6-fluoro-4-oxy-7- (1-piperazinyl) -1,4-dihydroquinoline-3'-carboxylic acid hydrochloride monohydrate (1.98 g, 92%), m.p. 282 ™ 288 ° C.

EXAMPLE. l-ethyl-6-fluoro-'4-hydroxy-7- (l-piperazinyl) ¹ - 1,4-dihydroquinoline-3-carboxylic acid, l-ethyl-6-fluoro-7- (4-karboetoksi -l-piperazinyl ) -1,4-Dihydroquinoline-3-carboxylboro diacetate (1.04 g, 0.002 mol) was suspended in 10% KOH (16 ml) and ethanol (12 ml) and heated for 11 hours. at the boiling point of the mixture. The mixture is then cooled to

At 15 ° C, 15% HCl, the pH is set at 7, 2-7, 4 and stirred at this temperature for a further 30 min. The resulting precipitate is suctioned off, washed with water and dried to constant weight in a vacuum dryer. At 100 ° C. The resulting l-ethyl-6 ~ fluoro 4-hydroxy-7- (1/35 - '';.>75pipeiazliii'l) l _f ^ '^ 4 diliidrochinolin-3 - carboxylic acid / /. '. HM ^: if793¾) / 'melts. : 218-221 ^. - / '// ^10' Thus, the present invention the biologically aktyvus- compound of general formula II in which a halogen atom in position 7 in the starting compounds .1pakeisto f-6-fluorophenyl-7-halo-4-hydroxy-l , 4-Dihydroquinoline5 · C-carboxylboro di acetate of general formula III .... ... '-

Wherein the nucleophilic substitution of X ~ F or Cl, R _x as previously mentioned is accomplished under milder reaction conditions while reducing the amount of substitution at the 6-position of the product.

Claims (7)

DEFINITION OF INVENTION (FROM: piperazinyl) ~ 1 4. having 1. (1-Substitution) 6-fluoro-4-oxy-7 di-hydroquinoline-3- .- (carbonic (general: formula II). II, {If i o '^ ((Rp / is a lower earth from / - / - alkyl y: // earth-h-in: ((G: pre-alkyl) or ///// '2 /. Method / according to - /; 1- -point, / b / a 's, i /: s --k / </ - r / 1 -. &,' '/ Nyt -, in that the change is executed in aqueous or ethanol / aqueous media. 2,4-difluorophenyl, method of preparation, or. ' the compound II is converted into a pharmaceutically acceptable acid (connection / (- - Salt <.; (- / ^'(fbkia: 0-kajLp (((šidrbdhį-GRID (<(' SRBA / lactate and hydrates thereof, characterized in that is carried out (Kaldge «o '(atomb (' nkie-o £ ilinš ((uplift (. (7-position © / piperazine) and hydrolysis;; be ') to duck in that the compound containing the formula · I (17 e R, same as' above '(mentioned above: and R ₂ (is: lower (alkyl' or ':: optionally' (substituted.) phenyl, is a hydro (and - optionally, the resulting compound, - which is of general formula II (is converted to a pharmaceutically acceptable acid addition salt, such as hydrochloride or lactate and hydrates. 3. A process according to claim 1, wherein the conversion is carried out at a temperature in the range of 50 ° C to the reflux temperature of the reaction mixture. 4. l 'Replaced-6 ™ f luo.r-4 ~ oxy-7- (4-pafceisto~l-pip@rax.i~ NIB 10) ~ _r ~ 4dĮhidroch.inolin 3 carboxylate diacetate having ^ general formula I wherein Rj is lower alkyl, lower cycloalkyl or 2,4-difluorophenyl, and _R? is lower alkyl or optionally substituted phenyl as a starting product in the preparation of a compound of general formula II 25 in separate form, or in these. ' 5. 1-Substituted-6-fluoro-4-oxy-7- (4-substituted-1-piperazinyl) -1,4-dihydroquinoline-3-carboxylboro diacetate of general formula I wherein R is lower alkyl, lower cycloalkyl or 2,4-difluorophenyl and ... R ₂ is a lower alkyl or optionally substituted phenyl which is subjected to 'nucleophilic substitution at the 7-position of the halogen atom, except that (! - substituted -6-fluoro-7-halo-4-oxy-1,4-dihydroquinoline-3-carboxylboro diacetate of the general formula III wherein X is F or Cl, R is the same as mentioned above is carried out on the halogen atom 7. At the position, the nucleophilic substitution of t with 1-substituted piperazine of formula coor ₂ wherein R ₂ is as defined above. 5. Process according to claim 5, characterized in that the substitution is carried out in an organic solvent such as pyridine, dimethylsulfoxide (dimethylformamide, 1-methyl-2-pyrrolidone, preferably yl-methyl-2-pyrrolidone). 7 / Process according to claim 5, characterized in that the change is carried out in a temperature range from The temperature ranges from 40 ° C to 40 ° C, preferably from 20 ° C to 30 ° C. '