CS269995B2 - Method of quinoline-carboxylic acid's derivatives production - Google Patents

Abstract

The present invention relates to a new and simple process for the preparation of quinoline-carboxylic acid derivatives of the general formula (I) (I) <IMG> as well as hydrates and therapeutically acceptable salts thereof. In formula (I) the meaning of the substituents is as follows: R1 represents a hydrogen atom, a linear alkyl group having 1 to 4 carbon atoms or a cyclic alkyl group having 3 to 4 carbon atoms, which may be unsubstituted or substituted by a halogen atom, a hydroxyl group or an amino group, or a CH3-NH group and R2 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.

Description

(57) The solution consists in a new and simple process for the preparation of quinolinecarboxylic acid derivatives of the general formula I in which R represents a hydrogen atom or a formyl radical, R ¹ represents a hydrogen atom, a straight-chain alkyl radical having from 4 to 4 carbon atoms or R ⁴ represents a hydrogen atom or an alkyl radical of 1 to 4 carbon atoms, as well as hydrates and pharmaceutically acceptable salts of these compounds · Process 4 C-atoms with cyclic chain, optionally substituted by hydroxyl, halogen or amino or CH 3 NH- characterized in that the compound of formula (II) in which R @ ¹ and R @ ² are as defined above or an acid addition salt thereof with piperazine in di * methylformamide and optionally to the compound of formula (III) thus obtained is introduced into the compound, wherein R 1 and R ² are as defined above, act with acid, base or preferably hydrazine, p advantage with hydrazine hydrate ·

ΛΙ 'Ώ

OHC

OS 269 999 B2

AND

The invention relates to a new simple process for the boxyl general formula I for the preparation of chanolicarboxylic acid derivatives

where

R 1 is a hydrogen atom or a C 1-4 alkyl or straight-chain or C 3 -C 4 -alkyl radical optionally substituted by a hydroxyl, halogen or amino group, or a CHyNH group -,

R represents a hydrogen atom or an alkyl radical of 1 to 4 carbon atoms;

Compounds of formula III

OHC

(XII) where

are as defined above, have so far been obtained by reaction of a quinolinecarboxylic acid derivative of the general formula XI

CS 269 994 B2

where

2

R and R are as defined above, formylpiperazine in dimethyl sulfoxide as a solvent according to Belgian Patent Publication No. 670,576. Further, the process is prepared from a derivative free of the formyl residue by formulation with 50% formic acid by the method of J. Med. Chem. gj, 1358, 1980 · This second method is of little benefit because the Austrian environment is very corrosive due to the presence of formic acid ·

A common disadvantage of the known processes is that they have to be carried out in several stages and in expensive solvents such as pyridine, dimethylsulfoxide and the like. In addition, the yields of these processes are very low.

The present invention provides a process for the preparation of a quinolinecarboxylic acid derivative of the formula I as defined above from the compounds of the formula II as well as the hydrates and salts of the compounds of the formula I by reacting the compound of the formula II or an acid addition salt thereof. The reaction is carried out by treatment with piperazine in dimethylformamide and optionally the compound of formula III thus obtained is subjected to further treatment with an acid or a base or is preferably reacted with hydrazine or preferably with hydrazine hydrate.

Of the compounds of formula I as defined above, in particular 1-ethyl-6-fluoro-7- (4-formyl) -piperazinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid has a very significant antibacterial effect. against Pasteurella multocida at an inhibitory concentration of 0.25 / Ug / ml, against various strains of Baoillus, for example Baeillus subtilis, B. licheniformis at a minimum inhibitory concentration of 0.5 to 0.75 / Ug / ml and the like at a minimum inhibitory concentration of 0.75 (Ug) ml against Shigella sonnei and Salmonella cholerae-suis. In carrying out the process according to the invention, the formylation 8 is preferably carried out by heating.

At a higher reaction temperature in the range of 120 to 153 ° C, a shorter reaction time can be achieved. The yield of the reaction can be increased by providing an acidic environment, thereby also reducing the reaction time accordingly. The acidic medium may be provided by using an acid addition salt of the compound of formula (II) or may be carried out in the presence of an acid, preferably in the presence of hydrochloric or sulfuric acid.

Further processing of the reaction mixture and isolation of the resulting product are very simple. The dimethylformamide used as solvent and reagent is removed under reduced pressure and can be reused. Water was added to the residue and the precipitate formed

CS 269 995 B2 is separated by filtration.

Compounds of formula I also include compounds of formula IV

(IV) where

2

R and R are as defined above, of significant antibacterial activity as reported by Antimicrib. Agents Chemother * 581-586, 1985 · These compounds can be obtained from compounds of formula III having a formyl group by treatment with acid, base, or preferably with hydrazine, preferably hydrazine hydrate, optionally in the presence of an acid such as acetic acid.

Of the acids, inorganic acids such as hydrochloric, sulfuric, phosphoric and the like can be used in appropriate dilutions. Alkali and alkaline earth metal hydroxides and carbonates can be used as bases. The formyl group may be removed in an organic solvent and / or in water, preferably in a mixture of water and alcohol. Most preferred is a 3: 1 mixture of isopropyl alcohol and water. The reaction is carried out at a temperature of 25 to 100 ° C, preferably at the boiling point of the reaction mixture;

The resulting product can and preferably be obtained after neutralization of excess acid or base in the reaction mixture by filtration. If desired, the product obtained can be purified by recrystallization.

E

The compounds of formula (I) may be obtained in the form of hydrates, or hydrates may be prepared from the free compounds, or the products may be released from their salts, or converted into pharmaceutically acceptable salts.

An important part of the process according to the invention is that the formyl group can be removed from the compounds of formula III by treatment with hydrazine. In this way, it was possible to carry out a new type of process whereby it is possible to obtain purer end products compared to hydrolysis.

The following examples illustrate the process according to the invention.

Example 1

5.4 g (0.02 mol) of 1-ethyl-6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 10.4 g (0.12 mol) of piperazine in solution in 120 ml dl of methyl formamide was heated at 154 ° C for a total of 6 hours. Then the solvent is removed by evaporation under reduced pressure

CS 269 995 B2 and 300 ml of water are added to the resulting residue. A precipitate formed which was collected by filtration. 4.6 g of the resultant 1-ethyl-6-fluoro-7- (4-formyl) -piperazinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid of melting point 270 DEG C. are thus obtained. After recrystallization from dimethylformamide, the melting point was increased to 285-286 ° C.

Example 2

1.0 g (0.0029 mol) of 1-ethyl-6-fluoro-7- (4-formyl) -piperazinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is suspended in 40 ml of the mixture isopropanol / water (3: 1) and 10 ml of 1 N hydrochloric acid are added. The reaction mixture is then refluxed for 5 hours. After cooling, the resulting product crystallizes in the form of the hydrochloride and can be separated by filtration, or the mixture can be neutralized by addition of 1 N sodium hydroxide solution and the precipitated product is collected by filtration. After drying, 0.58 g of 1-ethyl-6-fluoro-7-piperazinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 222 DEG C., is obtained.

Example 3

1.0 g (0.0029 mol) of 1-ethyl-6-fluoro-7- (4-formyl) -piperazin-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is suspended in 40 ml of the mixture. isopropyl alcohol / water 3: 1 and then 5 ml of 1 N aqueous sodium hydroxide solution are added. The reaction mixture is then heated to boiling for 8 hours. After cooling, the solution is neutralized with dilute hydrochloric acid solution. 0.6 g of 1-ethyl-6-fluoro-7-piperazinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 218 DEG C., is thus obtained.

Example 4

1.0 g (0.0029 mol) of 1-ethyl-6-fluoro-7- (4-formyl) -piperazinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is suspended in 50 ml of the mixture. of isopropyl alcohol and water in a ratio of 3: 1, and then 0.5 ml (0.010 mol) of 98% hydrazine hydrate and 0.6 ml (0.010 mol) of acetic acid are added. Then the reaction mixture is heated at 100 ° C for 6 hours. crystallization from the cooled solution was collected by filtration. 0.827g of the title compound 1-ethyl-6-fluoro-7-piperazinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 8 was obtained, m.p. 222 ° C.

Example 5

1.35 g (0.005 mol) of 1-ethyl-6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 2.6 g (0.03 mol) of piperazine and 1 ml of concentrated of hydrochloric acid was boiled in 30 ml of dimethylformamide for 4 hours. The solvent is then evaporated off under reduced pressure and 80 ml of water are added to the residue. The precipitated product is filtered off and washed with water. After drying, 1.42 g of 1-ethyl-6-fluoro-7- acid is obtained in 82% yield. (4-formyl) -piperazinyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p.

SUBJECT OF THE INVENTION

Claims (5)

Process for the preparation of quinolinecarboxylic acid derivatives of the general formula I CS 269 993 B2 where R represents a hydrogen atom or a formyl radical, R ¹ represents a hydrogen atom, a straight-chain alkyl radical of 1 to 4 carbon atoms, or a 3 to 4 carbon atom with a cyclic chain, optionally substituted with a halogen atom, a hydroxyl group or an amino group or a CH 3 -NH- group, R ² represents hydrogen or an alkyl radical having 1 to 4 carbon atoms, as well as hydrates of these compounds and their salts, the compounds of formula II · C00R ² R (II) wherein 1 2 R, R and R are as defined above, characterized in that the compound of formula (II) or an acid addition salt thereof is reacted in dimethylformamide with piperazine and optionally the compound of formula (III) thus obtained CS 269 994 B2 and. where R and R are as defined above, treated with an acid or base or preferably hydrazine, preferably hydrazine hydrate. 2 «A method according to claim 1, characterized in that for preparing the derivatives of quinoline carboxylic acid of formula I wherein R is hydrogen or formyl, R @ ¹ represents hydrogen, alkyl radical with a straight chain of 1 to 4 carbon atoms or C 3 -C 4 cyclic chain, optionally substituted with halogen, hydroxyl or amino, and R ² is hydrogen or C 1 -C 4 alkyl, a compound of formula II wherein R ¹ and R ² are as defined above defined, or an acid addition salt thereof is reacted with piperazine in dimethylformamide, and optionally the resulting compound of formula III, wherein R ¹ as defined above, is subjected to the action of acids or bases or, preferably hydrazine, preferably hydrazine hydrate. ’2 and R have p 3. The process of claim 1 wherein the reaction of the compound (8) with piperazine in dimethylformamide is carried out in an acidic medium. formulas II 4. A process according to claim 2 wherein the reaction of the compound with piperazine in dimethylformamide is carried out in an acid medium of the formula: II 5. de 2. The process of claim 1, wherein the reaction with an inorganic acid is a base or a compound of the formula. III uve6. de 2. The process according to claim 2, wherein the reaction with an inorganic acid is carried out by treating a compound of the formula: 3. A process according to claim 3, wherein the compound of formula III is used