SI8810668A8 - Process for producing cinnolinecarboxyclid acids - Google Patents

Description

PROCEDURE FOR THE OBTAINING OF QUINOLINE CARBOXYLIC ACIDS

Technical field

The invention is also in the field of preparative organic and pharaoutical chemistry ·

Technically a problem

The present invention relates to a novel process for the preparation of 1-cyclopropyl-7′-3upstitusiane 6-fluoro-4-oxe-1,4-dihydro-quinoline-3-carboxylic acid and its farnaceutsli acceptable salts.

The state of the art

It has been known that derivatives of L-cyclopropyl-7-eusptituisane-6fluor-4-okse-l, 4-dihydro-quinoline-3 ^_ carboxylic acid of the general formula I

COOH / I /

2.

/ where R represents piperazinyl, 4-methyl-piperazinyl or 4-ethyl-piperazinyl group / has high antibacterial activity /Eur.J.Clin.Hicrobiol.1983 »2. p. 1111 J. Ciin · Pharmacol. 1985 »25. p.82; Second Erptl.Clin. ^ Es. 1985 »

5 »p. 317 /.

Quinoline carboxylic acids of general formula 1 can be obtained by reaction of 1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid with a cyclic amine in the presence of a solvent at a temperature of X35-14O * C for 2 time)

Off. 3.033.157i German Off. 3.142.854).

Description of solution of technical problem with examples realization

According to the invention, a new process is provided for the preparation of the 1-cyclopropyl-7-substituent of 6-fluoro-4-exo-1,4-dihydro-quinoline-3-carboxylic acid of general formula I (where R has the same meaning as given above) which comprises reacting a compound of general formula II

an aliphatic acyloxy group containing from 2 to · carbon atoms and halogen-substituted assemblies or aromatic acyloxy group containing from 7 to 11 carbon atoms) with a cyclic amine of general formula III

R N NH / m / (where R 4 denotes hydrogen, methyl or ethyl) or a salt thereof and subjected to a compound of formula IV

no

A

Ί 3 (where R, R and R au same as indicated? Forward) thus obtained by hydrolysis.

The advantage of the invention of this invention is in tons, which ensures the preparation of the compound of fora 1 in a one-way manner and with high yields and with low reaction time.

Preferably, the preferred embodiment of the present invention is a boron derivative of general formula IV (wherein R, R and R as indicated above) will be converted to the desired hyaline-3-carboxylic acid of general formula 1 without isolation.

General formula IV boron derivatives into new compounds.

Bean derivatives of general formula 11 and a cyclic amine of general formula lil can optionally be reacted to inert organic solvents and acid binding agents.

n

As an inert organic solvent, the kiaelin amides (eg dimethyl foraanide, dimethyl aaetamide), ketones (eg acetone, methyl ethyl ketone) ethers (eg dioxane, tetrahydrofuran, diethyl ether) esters (eg ethyl acetate, methyl aeetate) may preferably be used. , ethyl propionate), sulfoxides (eg dimethyl sulfoxide), '+ · ....

alcohols (eg methanol, ethanol, 1-decanol, butanol) ·

Organic or inorganic bases may be used as acid binders. From the group of organic bases may be mentioned trialkyl amines (eg triethyl amine, tributyl amine), cyclic amines (eg pyridine, 1,5-diazabicyclo / 5 '4.0 / undec-5-ene, 1'-diazabicyclo / M-. JO / non - ^ - ei ^ l ^ -diazobicycles / 2.2.2 (octane), while alkaline or alkaline earth metal hydroxides or carbonates may preferably be used as inorganic bases, such as potassium carbonate, potassium bicarbonate, sodium hydroxide, calcium hydroxide, etc. or an excess of amines of the general formula lil.

The boron derivative of general formula II and the cyclic amine of general formula III can react at a temperature of from 0 to 200 ° C, depending on the solvent used. ^The echo time may vary between the sex and the destination depending on the reaction temperature. · If the reaction is carried out at elevated temperature, the reaction time may be shortened. The above reaction conditions are desirable although other reaction conditions may also be used.

borates of general formula IV '(where H, and R4 are as given above) can hydrolyze to the desired quinoline-5carboxylic acids of general formula 1, after or without isolation, under basic or acidic conditions. Compounds of general formula IV (where R is as given above) are precipitated from the reaction mixture, for example, when cooled and can be separated e.g. by filtration or centrifugation, if desired.

Transient hydrolysis may preferably be carried out by treating aqueous solutions of alkali metal hydroxides or carbonates or alkaline earth metal hydroxides. Preferably, the salt may use an aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, calcium hydroxide, potassium bicarbonate. Organic amines (eg · triethyl amine) can also be used in the degree of hydrolysis.

Acid "hydrolysis may preferably be carried out using an aqueous mineral acid solution." It may be desirable to perform hydrolysis of borates of general formula IV by heating it with an aqueous solution of hydrochloric acid, hydrochloric, sulfuric or phosphoric acid. organic acids (eg acetic acids, propionic acids, etc.) ·

Hydrolysis of compounds of general formula IV can also be carried out in an aqueous medium in the presence of an organic water miscible solvent. · For this purpose, apr «alcohols (apr · methanol, ethanol), ketones (eg acetone), ethers (apr · dioxane) can be used. , kiaelin anides (eg · formamide, dimethyl formaide), sulfoxides (e.g. dimethyl sulfoxide) or pyridine.

The quinoline-1-carboxylic acid of general formula 1 thus obtained can be isolated apr. by adjusting the pH of the aqueous solution "to a suitable value and separating the precipitated crystals, eg by filtering or centrifuging or lyophilizing the aqueous reaction mixture"

Compounds of general formula I can be converted into their pharmaceutically acceptable methods. Thus, acid addition salts are optionally built with hydrohalides, sulfonic acids. with sulfuric acid or organic acids. Preferably there are chlorides, bromides, 4-methyl-phenyl-sulfonates, methane eulffeates, maleates, fuaarates, benzoates, etc. · Compounds of general formula I form salts with alkali or alkaline earth metals the same as with other metal ions. They can also get sodium, potassium, magnesium, silver, copper, etc. ·

General formula I foods and their pharmaceutically acceptable aols can be converted into hydrates (eg, homihydrates, trihydrates, etc.) by known methods.

According to a further aspect of the invention, new compounds are provided

6.

general formula IV (who are like What is given above).

The starting materials of general formula II can be obtained e.g. by reacting 1-cyclopropyl-6-fluoro-7-chloro-4-oxo-1,1-dihydroquinoline-3-carboxylic acid (German Off. 3-1 ^ - 854) with a boron derivative (such as the compound of the general formula In fr

Λ /

B (where B, R and B? Denote hydrogen, an aliphatic? B * acyloxy group containing 2 to 6 carbon atoms optionally substituted by halogen or an aromatic acyloxy group containing 7 to 11 carbon atoms) or with fluorborate in an aqueous or organic medium.

Further details of the present invention will be found in the following examples without limiting the scope of the protection in the aforementioned examples.

Example 1

4.1 g / l-cyclopropyl "6-fluoro" 7-chloro-1,4-dihydro "4-oxo-quinoline-3-carboxyl" t-O ^, O ^and * '(bis) aceto-O / - boron and 2.8 g of piperazime anhydride are heated in 16 ml of dimethyl sulfoxide to 110 ° C with stirring. 40 ml of 3% aqueous sodium hydroxide is added to the brown solution and the reaction mixture is refluxed for 1 hour. Warm light ~ * yellow solution was filtered and the pH adjusted to 7 by addition of 1.8 ml of 96% acetic acid. The reaction mixture was cooled to room temperature and the precipitated white crystals were filtered off. washed with water and methanol and dried. The crude product is purified by boiling in 10 ml of water. 2.99 g of cyclopropyl-6-fluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid are thus obtained. The product decomposes at 255 ° C.

7.

Analysis for Formula ^C 17 ^H 18 ^FI S ° 5 ^S

Calculated: C- 61.62) 6 H- 5.48%

Found: C »$ 61.5% H- 5.50%

N- 12.68% N- 12.61%.

Example 2

Reaction of 1-cyclopropyl-6-fluoro-4-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylate-O, 0 ^{Z |} '(-bis) acetato-O / boron and N-methylpiperazine according to Example 1 afforded 1-cyclopropyl-6-fluoro-7- (4-methyl-piperazine) -1,4-dihydro-4-oxo-quinoline-3 -carboxylic acid. The product is broken down to 248-250 * 0.

Example 3

4.1 g / 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline -3-carboxylate-o-o-bis) acetato-O-boron and 3.7β N-ethyl-piperazine is heated in 16 ml of dimethyl sulfoxide to 90 ° C with stirring. Half a minute later, 40 ml of 5% aqueous sodium hydroxide solution was added and the reaction mixture was heated to reflux for 1 hour. The warm solution was filtered and the pH was adjusted to 7 ea with 96% acetic acid. The reaction mixture was cooled, the precipitated curettes were filtered! and washed with water. This gives 3.3g of 1-cyclopropyl-7- (4-ethyl-piperazinyl) -6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid. M.p .: 183-185 ° C.

Analysis for Formula ^C 19 ^H 22 ^PN 3 ° 3 ^l

Calculated: C- 63.35% H- 6.17% H- 11.69

Found: 0. 63.31 H «6.21 N- 11.70

8.

Example 4

3 »3 K / 1-Cyclopropyl-6-fluoro -? - chloro-l _t 4-dihydro-4-oxo. _ X II

-quinoline-3-carbokeylate-O, O-difluoro-boron reacts aa 3 »7 β-N-ethyl-pyrazine according to example 3 · ^ 'if ae obtains 3» 4g l-cyclopropyl-7- / 4-ethyl-l -piperazinyl / -6-fluoro- _t- 4-dihydro-4-oxo-h.inoline-3-carboxylic acid which, when mixed with the product of Example 3, does not show a decrease in melting point ·

I

Citation in NAJBDLJtl »!, l'ilUNU jiuuu rmuHvc. KNOWING THE WAY TO USE THE VALUE

FINDING

4.1 g / l-cyclopropyl6-fluoro-7-chloro-l _t 4-dihydro-4-oxo-quinoline - $ - carboxyleth-o \ o ^ <bia) ac «to-0 / -bora and 2.8 g piporazia anhydride was added in 16 ml of dimethyl sulfoxide to give 11O ° G while stirring · 40 µl of aqueous sodium hydroxide solution ae added to the brine solution and the reaction mixture was heated at reflux for 1 cone. Warm evetlo yellow solution ae filtered and adjusted to aa 7 by adding 1.8 ml 96% acetic acid · The reaction mixture was cooled to ambient temperature and the atalogenic white crystals were filtered off with water and methanol and dried. The crude product is purified by boiling in 10 ml of water. This gives 2.99 g of l-cyclopropyl-6-fluoro-7- (1-piperazinyl) -1,4-dihydro-4-oxo-quinoline-5-carboxylic acid. Product decomposes at 255 ° C *

Analysis for the formula ^ 17 ^ 13 ^^ 0 ^:

Calculated: U- 61.62% H- 5.48% tf «12.68%

Found: C «61.58% U» 5.50% N- 12.61%.

Claims (8)

Patent claims A process for the preparation of quinoline carboxyl kiaelins of general formula I (wherein B is piperazinyl, 4-methyl-piperazinyl or 4-ethyl-piperazinyl group) and their pharmaceutically acceptable salts, which comprises reacting compounds of general formula II 1? (where R and R denote halogen, an aliphatic acyloxy group containing 2 to 6 carbon atoms optionally substituted by halogen · or an aromatic avyloxy group containing 7 to 11 carbon atoms) with a piperazine derivative of general formula III n3 R ³ N NH IIIl ((where R1 denotes hydrogen, methyl or ethyl) or a salt thereof and subjecting the compound thus obtained to general formula IV / 4 / iv / ~ .Α_ (where R, R ^ i are as previously given) to acid hydrolysis after or after isolation, and if ae desires the translation of a compound of general formula I such as obtained into its ao or the release of kialein from its salt · The process of claim 1, which comprises reacting a compound of general formula II aa with a piperazine derivative of general formula III in the presence of an organic solvent, preferably an acid amide, sulfoxide, ketone, alcohol, ether or ether · 3 · The process of claim 2, which comprises using dimethyl sulfoxide as an organic solvent. The method of claim 1, which comprises reacting the compounds of general formulas II and III in the presence of an acid-binding agent. 5. The process of claim 4, which comprises the use of an amine or an excess of a compound of general formula III as an acid binding agent. 6 · The method of claim 1, wherein the hydrolysis is carried out in a kialic medium 7. The method of claim 6, wherein the reaction involves the use of an organic or inorganic acid, preferably hydrochloric, sulfuric or acetic acid. · The method of claim 1, wherein the hydrolysis is carried out in a base environment. 9. The process of claim 8, wherein the base is an alkali metal hydroxide, a calcium metal hydroxide, or an organic base, preferably an aqueous amine solution.