DD271114A5 - PROCESS FOR THE PREPARATION OF CHINOLINCARBONSAEUREDERIVATES - Google Patents

Abstract

The invention relates to a novel process for the preparation of quinolinecarboxylic acid derivatives of the general formula I in which R 1 is phenyl optionally substituted by 1 or 2 halogen atoms or a group of the general formula CH 2 C R 6 R 7 R 8 (in which R 6, R 7 and R 8 represent hydrogen or halogen) R 2 is piperazinyl or R4 is hydrogen or fluorine) and pharmaceutically acceptable salts thereof. The compounds of general formula I are known as antibacterial agents. The advantage of the process of the invention is that it provides the desired compounds of the general formula I in a simple manner in high yield and in a short reaction time. Formula (I)

Description

17 834 55

-1-

Ancestors for the preparation of quinolinecarboxylic acid derivatives Field of application of the invention:

The invention relates to a novel process for the preparation of l-substituted-7- (wehlwelee substituted piperazine) -6-fluoro-8- (optionally fluoreub8tituierten) _-4-oxo-l-f 4-S-dihydrochinolln carboneäurederlvaten the general formula I

COOH

(I)

27 ί 1 14

I - 2 -

j and their pharmaceutically acceptable salts.

In the general formula I stands

R is phenyl which is optionally substituted by 1 or 2 halogen atoms or is a group of the general formula --CH ₂ CR ⁶ R ⁷ R ⁸ (wherein R ^6, R ⁷ and R ^{8 are} hydrogen or halogen);

2 R for piperazinyl or 4-methylpiperazinyl;

R ^{3 is} hydrogen or fluorine, i characteristic of the known state of the art

Ee is known that a group of 7-substituted-carboxyl derivatives of general formula I (wherein R is piperazinyl-4-methylpiperazinyl, R is a group of general formula - CH ₂ CR ⁶ R ⁷ R ⁸ (wherein R ⁶ , R ⁷ and R ^{8 is} hydrogen or halogen.

; and R ^{3 is} fluorine) has a high antibacterial potency (Ό, Med. Chem. 1986, 29, 445; Drugs of Fut.: 1984, 9, 246; 23. Intersci. Conf. Antimlcrob. Agents Chemother. , 1983 »Abet. 628, 7th Int. Symp. Fut. Trends Chemother · 1986,

: 86). These compounds can be prepared by reacting 6,7,8-trifluoro-oxo-1-dihydroquinoline-S-carboxylic acid and cyclic amines (Belgian PS 887874 "GB-PS 2057444" Austrian PS 537813 and EP-PS 1064489).

Another group of 7-eubetitulertem quinoline-3-carboxylic acids of the general formula I (in which R is phenyl optionally substituted by 1 or 2 halogen atoms is piperezinyl or 4-methylpiperazinyl and R ^{3 is} hydrogen offset) also has a high antibacterial activity ( Chem., 1984, Abst., 72-78, Antimicrob., Agente Chemother, 1987, 619, Antimicrob. Agents Chemother., 1986, 192-208) These compounds may be prepared by the addition of l-substituted tetrahydrofuran. Phenyl-e-fluoro ^ -chloro ^ -oxo-li ^ -dihydroquinoline-3-carboxylic acid and cyclic amines for 20 hours in the presence of a solvent at a temperature of 100 j

- 3 - j

⁰ C are produced (EU-PS 131839, Ό, Mod., 1985, 1558, 0. Mod. Com. 1987, 504).

Object of the invention:

The aim of the invention makes it possible to simplify the preparation of the compounds mentioned above.

Explanation of the essence of the invention:

According to the invention a novel process for the preparation of the Chlnolln-S-carboneäurederivate of the general formula I (wherein R is optionally substituted with 1 or 2 halogen atoms substituted phenyl or a group of the formula -CH CR ₀ R ⁷ R ⁸

6 7 8 (in which R, R and R represent hydrogen or halogen), '

R ^{2 is} piperazinyl, 4-methyl-piperazinyl and R ^{3 is} hydrogen or fluorine) and pharmaceutically acceptable salts thereof, which comprises reacting a compound of general formula II

(II)

(wherein R is halogen, an acyloxy aliphatic group having 2 to 6 carbon atoms or an aromatic acyloxy group having 7 to 11 carbon atoms, R is fluorine or chlorine

R and R are as defined above) with an Am in the general formula III

27 M 14 ]

irH HH (> Iii)

(in which R is hydrogen or methyl) or their salt and the compound thus obtained of the general formula IV

(IV)

12 3

(Wori have 'R ₁ R, R and R have the meaning explained above) \ is hydrolyzed by ι'der without isolation and if desired ,; the thus obtained compound of the general formula I in her! Salt is converted or the compound is released from its salt.

The advantage of the process according to the invention is that j

that it \ the preparation of the compounds of the general research

I mel in a simple way with very high yield and in; a short reaction time allowed *

The boron derivatives of general formula IV are new compounds. :

According to a preferred Aueführungeform of erfindungegemäßen; Process becomes the Borderivat of the general formula IV without J

Isolation into the desired quinoline-3-carboxylic acid of all- i

• I '

27 ί ί f4

ί - 5 -

! converted to formula I.

The boron derivatives of general formula II can be reacted with the amine of general formula III. if desired, in the presence of an inert organic solvent and an edurebindenden agent to be implemented *

As the inert organic solvent, there may preferably be used an acid amide (ζ, B, dimethylformamide, dimethylacetamide), a ketone (eg, acetone, methyl ethyl ketone), an ether (e.g., dioxane, tetrahydrofuran, diethyl ether), an ester (e.g. Ethyl acetate, methyl acetate, ethyl propionate), a sulfoxide (e.g., "dimethyl" sulfoxide), an alcohol (e.g., methanol, ethanol, 1-decanol, butanol).

As the acid-binding agent, an organic or inorganic base can be used. For the group of organic bases, trialkylamines (eg, triethylamine, tri-butylamine), Icyclic amines (e.g., pyridine, I, ö-diazabicyclo / Sj ^ O / undec-; 5-ene, 1, S -Lazablcyclo / A. 3.O / -non-5-ene, 1-diazabicyclo / a ^ .a / octane), and in the inorganic bases, hydroxides or carbonates of alkali or alkaline earth metals may preferably be used. Thus, as acidic agents, advantageously potassium carbonate, potassium hydrogencarbonate, sodium hydroxide, calcium hydroxide, etc., or an excess of the amine of general formula III are suitable.

Da Borderivat the general formula II and the amine of general formula III can be implemented at a temperature between 0 and 200 ⁰ C depending on the solvent used. The reaction time can be between half an hour and 10 hours. The reaction time also depends on the reaction temperature. When the reaction is carried out at an elevated temperature, the reaction time can be shortened. The above reaction conditions are preferred values, other conditions may also be used.

27 11 f 4

The compounds of general formula IV can be hydrolyzed after or without isolation under acidic or basic conditions to give the desired quinoline-3-carboxylic acids * The compound of general formula IV precipitates z. B. on cooling from the reaction mixture and can, if desired z, B. be separated by filtration or centrifuging ·

The basic hydrolysis may preferably be carried out by heating with the aid of a hydroxides or carbonates of an alkali metal or an alkaline earth metal hydroxide, the aqueous solution is used. Preferably, an aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, calcium hydroxide may be used. Organic amines (ζ B. triethylamine) can also be used in the hydrolysis step.

The acid hydrolysis can preferably be carried out by using an aqueous mineral acid · A compound of _the: general formula IV may preferably be hydrolyzed by heating with an aqueous solution of hydrochloric acid, hydrogen bromide, sulfuric acid or phosphoric acid. The hydrolysis can also be carried out with the aid of an organic acid (for example acetic acid, propionic acid etc.).

The hydrolysis of the compounds of general formula IV can also be carried out in an aqueous medium in the presence of a water-miscible organic solvent. For this purpose, for example, alcohols (eg, methanol, ethanol), a ketone (e.g., * acetone), an ether (e.g., dioxane), an acid amide (e.g., dimethylformamide), a sulfoxide (e.g. , B. dimethyl sulfoxide) or pyrldin in question.

The thus obtained Chlnolin-3-carboxylic acid of general formula I may, for. B. by adjusting the pH of the aqueous solution to a suitable value and separation of the precipitated crystals z. B. by filtration or centrifugation or by .... Lyophllisieren dee aqueous reaction mixtures are isolated ·

I -7- j

j i

ί The compounds of general formula I 'known manner into their pharmaceutically acceptable salts ·' can be converted to a loading · These may preferably acid addition are formed ealze, z. B. with Halogenwaeseretoffen. Salts formed from sulfonic acids, sulfuric acid or organic acids. Chlorides, bromides, arylsulfonates, methanesulfonates, maleates, fumarates, benzoates, etc. may preferably be formed. The compounds of the general formula I form salts with alkali or alkaline earth metals and also with other metal ions. Accordingly, the sodium, potassium, magnesium, silver, copper salts, etc. can be prepared.

The compounds of general formula I and their pharmaceutically acceptable salts may be converted by known methods of calibration \ into hydrates (for example, hemihydrates, trihydrates, etc..): Are.

According to another aspect of the invention, new

12 3

compounds of general formula IV (wherein R, R, R and R di have the meaning explained above) are provided.

The starting material of the general formula II can be replaced by Substitution of 1-phenyl-e-fluoro-1-chloro-1-oxo-1-dihydro-quinoline-3-carboxylic acid (EU Pat. No. 131,839) or 1-ethyl-e1.-trifluoro-1-oxo-1,4-one dihydroquinoline-3-carboxylic acid (GB-PS 2,057,440) with a Borderivat, z. B. with a compound of the general formula V ^ *;

(wherein R is halogen or an aliphatic acyloxy group having 2 to 6 carbon atoms or an aromatic acyloxy group having 7 to 11 carbon atoms) or fluoroborate in aqueous or organic medium. i

Further details of the present invention oind in the fol-; However, the scope of the j

2 7 Π.1 4

Ι - θ -

Do not restrict examples.

e Auefohrunsampleet

Example 1

1.59 g _(l-ethyl-6-t 7,8-trifluoro l, 4-dlhydro-4-oxo ".chinolin-3: carboxylate 0, 0) are -dlf.1uorbor for 3 hours at 100 ⁰ C reacted with 1.29 g of piperazine in θ ml of dimethyl sulfoxide. Ee is added to a 6% aqueous solution of 12.6 ml of sodium hydroxide; geeetzt for 2 hours by heating hydrolyeiert · _The: Reaktionegemiech is filtered, the pH is adjusted to 7 with 96% acetic acid, and the Gemiech is with If? The crystalline reaction mixture is cooled overnight and the precipitated crystals are filtered, washed with water and dried. Thus, 1.61 g of 1-ethyl-oxy-difluoro-1-dihydro-1-oxo-piperazino-quinoline-3-carboxylic acid are obtained.

The melting point is 234-236 ⁰ C.

Analysis for the formula C ₁₆ HL ₇ FgN ₃ O ₃ :

Calculated: C «56.90% H «5,07%N = 12.45%

Found; C »56.75% H »5,02%N »12,48%

Example 2

1.99 g (l-ethyl-e ^ e-trifluoro-l ^ -dihydro ^ -oxo-quinoline-S-carboxylate 0, 0) -bie (diacetate-O) boron are for 2 hours at 110 ⁰ C. reacted with 1.29 g of piperazine in 8 ml of dimethyl sulfoxide. A 3% aqueous solution of 20 ml of 3% sodium hydroxide is added. The Reaktionsegemisoh is boiled for one hour under reflux, then filtered and the pH is adjusted to 7 with 36% acetic acid. After cooling and dilution with 10 ml of water, the precipitated crystals are filtered and dried. Thus, 1.59 g ocher-colored l-ethyl-6,8-difluoro-l, 4-dlhydro-4-oxo-7-piperβzino- ;. quinoline-3-ocarboxylic acid. The melting point is

• 1 i

27ί ί f4

the formula C, • % - 9 - 5, 07 % N / A 12 < i 234 ⁰ C. C - 56,90 % 5, 11 % N / A 12 ι Analysis for C a 57.03 7 ¹ W 45 % : Calculated: H a 51 % Found: H " Example 3

According to Example 2, 1.06 g of (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-0, 0) -bis (propionate-0) -boron reacted with 0.64 g of piperine in 4 ml of dimethylsulfoxide. A 6% aqueous solution of 6.3 ml of sodium hydroxide is suspended and the reaction mixture is refluxed for one hour. After filtration, the pH is adjusted to 7 with 96% acetic acid, 10 ml of water are added and the reaction mixture is cooled overnight. The precipitated crystals are filtered, washed with water and dried. This gives 0.74 g of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid. The melting point is 232-236 ⁰ C.

Analysis for the Fo • mel ^C 16 ^H 17 F ₂ N 3 ° 3 ^: 07 % N / A 12 • 45 % Calculated: C a 56 90 % H B 5, OO % N - 12 39 % Found: C a 56 85 % H a 5, Example 4

According to Example 1, 1.59 g (l-ethyl-6,7,8-trifluoro-l, 4- \ dihydro-4-oxo-quinoline-3-carboxylate-0, 0) -difluor-boron with 1.5 g 1-methylpiperazine in 8 ml Dimethylsulfoxld reacted. In order to ! 1.54 g of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (1-methylpiperazino) -quinoline-3-ocarbonic acid are obtained. The melting point is ü37-240 ⁰ C.

27 ί if 4 - ίο -

Analysis for the formula C ₄₇ H ₄₀ F ₉ N, 0 ,:

ι Calculated: C a 58 10 % H - 5, 45 % N / A 11 91 % Found: i C a 58 OO % H «5, 46 % N / A 11 95 % Example 5 '·

In accordance with Example 2, 1.99 g (1-ethyl-6,7,8-trifluoro-1,1,4-dihydro-1-oxo-quinoline-S-carboxylate-O, O) -bie (aceto-O) - boron reacted with 1.5 g of 1-methylpiperazine. Thus, 1.5 g of 1-ethyl-6,8-dlfluoro-l, 4-dihydro-4-oxo-7- (l-methylplperazino) - ¹ quinoline-3-carboxylic acid obtained. The melting point is j 238-240 ⁰ C.

Analysis for the formula

Calculated: , C - 58 10 % H a 5, 45 % N / A 11th 91 % Found: C a 58 19 % H a 5, 53 % N » 11 87 % Example 6

According to Example 3, 1.06 g (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate-0, 0) -bls (propionate-0) -] boron is reacted with 0.75 g of 1-methylpiperazine. Thus, 0.79 g of 1-ethyl-6,8-difluoro-1, 4-dihydro-4-oxo-7- (1-methylpiperazino) -i quinoline-3-carboxylic acid is obtained. The melting point is 239-240 ⁰ C., ' ]

Analysis for the formula ^c i7 ^H ig

Calculated: C »58.10 % H» 5.45 % N β 11.91 % Found: C «57.95 % Ha 5.37 % Ne 11.90 % \

Example 7 ;

0.46 g of 1- (4'-fluorophenyl) -6-fluoro-7-chloro-1,4-dihydro-4-oxo; quinoline-3-carboxylate-O, O) -bis (aceto) -O) -boron become an i

27 1 f 14

- li - j

i j

For ¹ hour at 110 ⁰ C with 0.6 g of N-methylpiperazine in 5 mx Di

_; implemented methyl sulfoxide. 10 ml of 5% aqueous Natriumhydrogencarbonatlöeung be added, the reaction mixture is refluxed for 2 'hours, then the pH is adjusted to 7 with 96% acetic acid. The reaction mixture will! cooled and the precipitated crystals are filtered and washed with cold water. Thus 3.54 g l- (4-fluoro be phenylJ-e ^ fn-methylpiperazinylJ-l ^ ^ -dihydro- oxo-quinoline-3-carboneäure won * -fluoro- ·>. The Ochmelzpunkt is 282 to 264 ⁰ C The carboxylic acid thus obtained is dissolved by heating in a weak solution of hydrochloric acid, the solution is evaporated in vacuo, and the resulting hydrogen chloride is prepared from 1- (4'-fluorophosyl) -6-fluoro-7- (N-methylpiperazinyl) -1, 4- dihydro-4-oxo-chlnolin-3-carbon8äure. The product decomposed at temperatures over 270 ⁰ C.

Analysis for the formula: ^C 2i ^H ig ^F 2 ^N 3 ° 3 ^:

! Calculated: C * 63.15 % H = 4.97 % Ne 10.52 %

«Found: C - 63,27 % H = 4,89 % N« 10,35 %

Claims (6)

! claims 11. A process for the preparation of compounds of the general formula I I (I) (wherein R _{1 is} phenyl optionally substituted by 1 or 2 halogen atoms, or a group of the general formula CH ₂ CR ⁶ R ⁷ R ⁸ (wherein R ⁶ , R ⁷ and R ^{8 are} hydrogen or halogen); R for piperazinyl or 4-Methylpiperaziny1 etehtj R ^{3 stands} for Waeeeretoff or fluorine) and their pharmaceutically acceptable salts, characterized in that a compound of general formula II (II) (wherein R is halogen or an aliphatic ^ acyloxy group having 2 to 6 carbon atoms or an aromatic acyloxy group having 7 to 11 carbon atoms, R is fluorine or chlorine        -. , , , , j - 13 -; is a Piperazlnderlvat the general formula III (III) (wherein R is hydrogen or methyl) or their salt
is reacted and the thus obtained compound of general formula IV (IV) (C 12 3 (who wherein R, R, R and R have the meaning explained above) after or j is hydrolyzed without isolation and if the compound of general formula thus obtained is converted to its \ Salt I is required, "or the compound is released from its salt. i * 2. The method according to claim I _1, characterized in that a ί compound of general formula II in the presence of an orga-> lower solvent, preferably an acid amide, SuIf-; oxides, ketones, alcohols, ethers or esters with an am in the! general formula III is implemented · 3. The method according to claim 2, characterized in that ale ' organic solvents Oimethyleulfoxid is used, | Verfahren » Method according to claim 1, characterized in that the
Umeetzung of the compounds of the general formulas II and III ι - 14 - ; in the presence of an acid-binding agent ©. 5. The method according to claim 4, characterized in that an amine or an excess of the compound of general formula VI ale acid binding agents is used. ! 6. The method according to claim 1, characterized in that the; Hydrolyee takes place in an acid medium ; Process according to claim 6, characterized in that the reaction is carried out in an organic or inorganic acid, preferably hydrochloric acid, sulfuric acid or acetic acid; he follows" 8. The method according to claim 1, characterized in that the ι hydrolysis is carried out in an alkaline medium. 9. The method according to claim 8, characterized in that an alkali metal hydroxide, an alkaline earth metal hydroxide or a ; organic base, preferably an aqueous triethylamine solution.