SI8612106A8 - Process for preparation of quinoline carboxylic acids - Google Patents

Description

Ob

1. FIELD OF THE INVENTION

The invention falls within the field of organic and pharmaceutical henry and according to the International Patent Classification bears the following designations:

2. The tennis problem

A technical problem in the present invention is to provide a novel process for the preparation of 1-ethyl-6-7- (4-optionally substituted piperazino) -4-oxo-4,4-dihydro-quinoline-3-carboxylic acid derivatives of the general formula

R -

COOH (I) ° ^2-yl 5 Where H stands for hydrogen or methyl;

and pharmaceutically acceptable salts thereof.

3. Techniques

Quinoline carboxylic acid derivatives of general formula I are known to be widely treated for their high antibiotic activity for the treatment of diseases of the urinary tract and those caused by systemic bacteria (J. Pharm. Sci. 1984-, 73.

1379; kur. J. Chemother. Antibiot. 1983, 2 »pages 9 and 4-7;

J.Antimicrob. Chemother. 1984.13. Huppl, 99 «pages 107 and ii3)

Quinoline carboxylic acid of general formula I (where R is hydrogen) can be obtained by reacting 1-ethyl-6-fluoro-7-bloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and piperazine (Belgian Patent Specification Nos. 863.429 and 870.576 "Japanese Patent Specification No. 8033.54-5 and" T.Med. Chem. * 23. 1358 (1980) or by subjecting ityl-1-ethyl "6 * fluoro-7piperazino" 4-oxo-1-4 dihydro-quinoline-3-carboxylate of the formula

hydrolysis (Belgian Patent Specifications Nos. 879.106 and 890.223).

An overall disadvantage of the above procedures is that the reaction of the chlorine atom change at the 7-piperizine position is carried out under drastic reaction conditions, at a temperature of 115-1-5 ° C for 5-19 hours. optional even under pressure. Further, the reaction is not region-selective and under the indicated reaction conditions the fluorine atom at position 6 partially reacts with piperazine (J.Med.Chsm. 2J, 1358 (1980)).

Quinoline carboxylic acid of general formula I, wherein R is methyl, can be obtained by reacting 1-ethyl-6-fluoro-7-chloro 4-oxo-1,4-dihydro-quinoline.-3-carboxylic acid of general formula II

V ·; ”/ II /

with l-methyl ~ piperazine (Belgian patents Nos. 870,576 and 870,917; Laid-open phapane patent application No. 80 55,455 and J.Med. Ghem. 25. 155θ (1980) ^) or methylation of l ~ ethyl ~ 6-fluoro- 7-Piperazino-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid of formula IV. ^; .

(Belgian Patent No. 870,917 and FR-OS No. 2,424,919).

A common disadvantage of the above procedures is that the reactions are carried out under drastic conditions at a temperature between 110 and 150 ° C for 7-16 sets. Pfinos vary between 55% and 66% respectively. ^{n the} third reaction mixture is treated in a comic way.

Description of a solution to a technical problem with examples of execution

According to this invention, a novel process is provided for the preparation of compounds of formula I (wherein JR stands for halo or methyl) and their pharmaceutically acceptable salts, which comprises the reaction of compounds of general formula V

(where R · ⁴ · and iC ~ denote an amatic acyloxy group containing 2-6 carbon atoms and optionally substituted by halogen; or an aromatic acyloxy group containing 7-11 carbon atoms) with an amine of general fomula VI

I / VI / (where R has the same meaning as indicated above) or its salts so as to obtain a compound of the general formula VIT

RN

% / VII / (where R, R ^ and R ^ are as indicated above) which undergoes hydrolysis after or without isolation and if one wants the translation of a compound of general formula I thus obtained into its salt or the release thereof from its salt.

The peculiarity of the process of the present invention is that it provides the compounds of general formula I in a simple manner with very high yields in a short reaction time.

. v. .

In the general formula V R and R may be the same or different.

Borate derivatives of the general formulas V and VII are novel compounds.

According to a preferred embodiment of the method of the present invention, the borate derivative of formula VII is converted into quinoline quinoline-3carboxylic acid of general formula I without isolation.

Borate derivatives of general formula V can be reacted with an amine of the formula VI formula if desired in the presence of an inert organic solvent and an acid-binding agent.

As an inert organic solvent, the acid amide (e.g. dimethyl formamide, dimethyl acetamide), ketone (e.g. acetone, methyl ethyl ketone), ether (e.g. dioxane, tetrahydrofuran, diethyl ether), esters (e.g. ethyl acetate, methyl acetate, ethyl propionate), sulfoxide (eg dimethyl sulfoxide), alcohol (eg methanol, ethanol, l-decanol, butanol) ·

Organic or inorganic bases may be used as acid binders. From the group of organic bases, trialkyl amines (e.g. triethyl amine, tributyl amine) cyclic amines (e.g. pyridine), 1,5diazabicyclo / 5,4-, 0 / undec-5-ene may be used.

1,5-diazabicyclo / 4,3, Ο / ηοη-5-ene, 1,4diazabicyclo / 2,2,2 / octane, while hydroxides or carbonates of alkali or zenoyl alkali metals may preferably be used from inorganic bases. Suitable acid binders are potassium carbonate, potassium bicarbonate, sodium hydroxide, calcium hydroxide, etc. or an excess of amines of general formula VI.

Derivatives of boron in the general formula and amine of general formula VI may be prepared reagovati at a temperature of from 0 to 200 ° C, depending on the exploited _t of the solvent. Reaction time can vary between half an hour and 1 °. The reaction time depends on the reaction temperature · also. If the reaction is carried out at a higher temperature, the reaction time v may be shortened. The above reaction conditions are desirable values although others may also be used.

Borates of general formula VII can be hydrolyzed to the desired quinoline3 "carboxylic acids of general formula I, after or without isolation, under acidic or basic conditions. The compound of general formula VII is precipitated from the reaction mixture e.g. by cooling and can be separated e.g. by filtration or centrifugation, if desired.

The basic hydrolysis can preferably be carried out using alkali metal or alkaline earth metal hydroxide or carbonate, using an aqueous solution. It is advantageous to use an aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium bicarbonate, potassium carbonate, calcium hydroxide. ⁿ edjutim u stupnju hydrolysis takodje the benefit may be prepared and the organic amines (eg. triethylamine).

*

Acid hydrolysis can preferably be carried out using an aqueous mineral acid solution. ^And it may be desirable to carry out the hydrolysis of borates of general formula VII by heating with an aqueous solution of hydrochloric, hydrochloric, suppor, or phosphoric acid. hydrolysis can also be carried out with the aid of an organic acid (eg acetic acid, propionic acid, etc.).

Hydrolysis of compounds of general formula VII can also be carried out in an aqueous medium in the presence of a miscible organic solvent with water. For this purpose, e.g. alcohols (e.g. methanol, ethanol) ketone (e.g. acetone), ether (e.g. dioxane), acid amide (e.g. dimethyl formamide), sulfoxide (e.g. dimethyl sulfoxide) or pyridine.

The quinoline - N - carboxylic acid of general formula I thus obtained can be isolated e.g. adjusting the pH of the aqueous solution to the appropriate value and separating the crystals, e.g. filtration or centrifugation, lyophilization of the aqueous reaction mixture.

The compounds of general formula I may be converted to their pharmaceutically acceptable salts in a known manner. Suitable acid addition salts may thus be made, for example reward salts not with hydrochloric or sulfonic acids, sulfuric acid or organic acids. ^x Desirably, chlorides, bromides, aryl sulfonates, methane sulfonates, maleates, fumarates, benzoates, etc. may be formed. Compounds of general formula I form salts with alkaline earth alkali metals or other metal ions. potassium, sodium, magnesium, iron, copper, etc. may also be obtained.

^the compounds of general formula I and their pharmaceutically acceptable salts may be converted into hydrates (e.g., hemihydrates, trihydrates, etc.) by known methods.

According to a further aspect of the present invention there are provided novel compounds of the general Formula VII (wherein R, R and R are listed above).

se

The starting materials of the general formula V can be obtained by reacting 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid of formula II (Belgian patent No. 863.429) with a boron derivative (e.g. with the compound of general formula VIII)

OGOR ³

B ^ OCOR ⁴ / SCREWS /

X) COR ⁵ jx 4 5 / where R, R and R denote an alkyl group having 1-5 carbon atoms and optionally substituted by a halogen or aryl group comprising 6-10 carbon atoms / optionally in an organic environment.

^J Alja details ovog pronalska the NALZã u The following examples without ograničavanja obima zaštite u-said Examples.

Example 1

19.5 g of "ethyl ~ 6-fluox-o" 7-chloro-4-oxo-1,4-dihydro-quinoline-5carboxylic acid boron-di (propionyloxy) -anhydride and 11.9 g of piporazinn reacted in ^r / 'i. ml of dimethyl sulfoxide at 110 ° C for 1 hour. ^{The AX} reaction mixture was cooled to 9 ° C and added

116ml 6% by weight. aqueous sodium hydroxide solution

The aqueous reaction mixture was kept under low heat for one hour and the mixture was cooled to room temperature. The pH of the solution was adjusted to 7 with 96% by weight of acetic acid. The reaction mixture was allowed to crystallize in the refrigerator overnight. The following morning the precipitated crystals were filtered off, washed with water and dried in vacuo at 9O-95 ° C to constant mass. When 14, Og of 1-ethyl-6-fluoro-4-oxo-1,4-dihydro-7-piperazino-quinoline-3-carboxylic acid was obtained, 95.9% yield · Product decomposed at 221 ~ 222 ° C (from a mixture of dichloro methane and methanol).

Analysis for Formula Calculated

Found:

C = 60.18%, C a> 60.07 / S,

H »5.68%, N = 15.16% $

H, 5.74%, N = 15.18%.

folic material is obtained as follows:

A mixture of 9.5 g of boric acid and 70 g of propionic anhydride was stirred at 100 ° C for 15 minutes, after which the reaction mixture was heated to boiling point. For half an hour the temperature was lowered to 110 ° C: 29.8 g of ethyl-1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquino.lin-5-carboxylate were added. The reaction mixture, which was evaporated in a few minutes, was stirred at 110 ° C for 2 hours, cooled to room temperature and diluted with 500 ral water.

the reaction mixture was cooled and the crystals precipitated filtered. 41.5g of 1-ethyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-quinoline-5-carboxylic acid boronic-di (propionyloxy) anhydride were obtained in a yield of 97.7% . The product decomposes at 252 ° G.

Analysis for

Calculated ·.

Found:

c = 50.79%, H = 4.26%, N = 4.29%;

C - 50.94%, U = 4.15%, N = 5.41%.

Example 2

19.5 With 1-ethyl "6 * fluoro-7-chloro-4-oxo" 1,4-dihydro-quinoline-5-carboxylic acid-boron-di (propionyloxy) -anhydride and 15.56 4-methyl-piperazine was reacted -in 72 ml of dimethyl sulfoxide at 110 ° C for 2 hours. * The reaction mixture was cooled to 90 ° C and 116 ml of a 6% aqueous sodium hydroxide solution was added, The aqueous reaction mixture was kept under low heat for one hour and then cooled to room temperature. The pH of the solution was adjusted to 7 with 96% by weight of acetic acid. The reaction mixture was allowed to crystallize in the refrigerator, after 5 h the precipitated crystals were filtered, washed with water and dried at 85 ° 0 in vacuo to constant mass. 15 · g of 1-ethyl-6 ~ fluoro-7- (4-methyl? piperazino) -4-oxole, 4-dihydroquinoline-5-carboxylic acid, was obtained; (Product decomposed at 269-271 ° C from a mixture of dimethyl formamide and methanol).

Analysis for the formula ° 17 ^H 20 ^ra 3 ° 3 ^x calculated; ' C »61.25%, H ^e $ 6.054, N» 12.60%;

Found: C - $ 61.57, H = 5.91%, N «$ 12.47.

2g 1-ethyl-6-fluoro-7- (4-methyl-piperazino) -4-oxo-1,4-dihydroquinoline-5-carboxylic acid was heated in boiling water (50 ml) of anhydrous ethanol and 0, 61g was added to the boiling solution. methanesulfonic acids.

From the solution thus obtained, the crystalline precipitate begins to break in a few minutes. After 10 minutes, the reaction mixture was cooled to 0 [deg.] C. and allowed to crystallize in refrigeration over power. The next day, the precipitated crystals were filtered, washed with ethanol and dried in vacuo at 9O-95 ° G to constant weight. This gave 2.5g of 1-ethyl6-fluoro-7- (4-methyl-1-piperazino) -4-oxo-1,4-dihydro-chymoline-5-carboxylic acid methanesulfonic acid salt, yield 89.5 $. The product decomposes at 285-287 ° C.

Analysis for the formula ^c i8 ^H 29 ^ 5 ° 6 ^S

Calculated for C «50.54 $, H» 5.65%, N = $ 9.78;

found: C = $ 50.12, H * $ 5.81, N = 9.79%.

The starting material can be obtained as follows:

A mixture of 9.3 g of boric acid and 7 ° g of propionic anhydride was stirred at 100 ° C for 15 minutes after which the temperature was raised to boiling point. For half an hour the temperature was lowered to 110 ° G and 29.8 g of ethyl 1-ethyl-6-fluoro-7-chloro-4-oxole, 4-dihydro-quinoline-3-carboxylate were added. The reaction mixture, which in a few minutes goes into suspension, is heated to 11 ° C for two hours, then cooled to room temperature and diluted with $ 00ral water. The reaction mixture was cooled and the precipitated crystals were filtered. 'If 41.5 S 1-Tetyl-6 "fluoro-7-chloro 4" oxo-1,4-dichloro-quinoline-3-carboxylic acid boron-di (propionyloxy) -anhydride was obtained, yield 97.7%

Analysis for the formula C ^ gH ^ gBPClNO?

Calculated Completed:

C = 50.79%, H = 4.26%, C = 50.94%, H = 4.15%,

N = 3.29%; N = 4.15%.

.- • li

Claims (8)

Patent claims A process for the preparation of compounds of general formula I R-N / X / (where R is hydrogen. 'Or methyl) and its pharmaceutically acceptable salts, comprising 2-6 carbon atoms and optionally substituted by halogen, or an aromatic acyloxy group containing 711 carbon atoms) with an amine of the general formula VI / VI / (where R has the same purification as indicated above) or a salt thereof, and the compound thus obtained Formulas VII / VII / (wherein R, R ^ and R ² are as above) hydrolyzes the pellets either without isolation and if desired, translates the compound of formula I thus obtained into its salt or liberates the same from its salt. 2. The process of claim 1, comprising reacting a compound of general formula V aa with an amine of general formula VI in the presence of an organic solvent, preferably an acid amide, sulfoxide, ketone, alcohol, ether or ester. 5. The process of claim 2, which comprises using dimethyl sulfoxide as an organic solvent 4. The process of claim 1, wherein the compounds of the general formulas V and VI are reacted 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 the compounds of general formula VI as acidic binding agents. 13. 6. The process according to claim 1, which comprises hydrolysis in an acidic medium. The method of claim 6, wherein the reaction involves the use of an organic or inorganic acid, preferably hydrochloric acid, sulfuric acid or acetic acid. 8. The process of claim 1, wherein said hydrolysis is carried out in an alkaline medium. 9. A process according to claim 8, comprising the use of an alkali metal or alkaline earth metal hydroxide or an organic base, preferably an aqueous triethyl amine solution.