HU200175B - Process for producing quinolinecarboxylic acid derivatives - 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 CR 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

The present invention relates to a novel process for the preparation of 1- (optionally substituted with halogen) ethyl-7-substituted 4-oxo-1,4-dihydroquinoline-3-carboxylic acids and their pharmaceutically acceptable acid addition salts. It is known that the 7-substituted quinolinecarboxylic acids of the formula (I) wherein R ⁴ is oiperazinyl or 4-methylpiperazinyl R, R ² and R ³ are the same or different, hydrogen or halo have antibacterial activity (J. Med. Chem. 1986,29,445; Drugs Fut. 1984.2,246,23rd Intersci. Conf. Antimicrob. Agents Chemother. 1983, Abstr. 658, 7th Int Symp. Fut. Trends Chemother. 1986,86). .

Compounds of formula I can be prepared by reaction of 6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid with cyclic amines (Belgian Patent No. 887,574, British Patent 2,057,444, U.S. Patent No. 537,813). Australian Patent Specification 106,4489).

In the first step, an appropriately substituted derivative of the 6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester is prepared, the ester group is hydrolyzed and the resulting intermediate is reacted with the appropriate amine. (For example, the first two steps in the preparation of 1- (2-fluoroethyl) -6,8-difluoro-1,4-dihydro-7- (4-methyl-1-piperazinyl) quinoline-3-carboxylic acid hydrochloride salt 393%, reaction time 123 hours, final step 663% reaction time 6 hours.

According to the present invention, 1 (optionally substituted with halo) -ethyl-7-substituted-1,4-dihydroquinoline-3-carboxylic acids of formula (I), wherein R ¹ , R ² , R ³ and R ⁴ are as defined above, may be prepared by the borate of formula (II) using a very short reaction time in high yield derivative (that is a halogen atom. or C2_6 alkanoyloxy group wherein the report of R, ^R, R, and R ³ present in the structure as defined above) and By hydrolysis of a borate derivative of formula IV (wherein R ¹ , R, R ³ and R ⁴ are as defined above) formed by the reaction of cyclic amines of formula (III) or salts thereof (wherein R ^{5 is} hydrogen or methyl). In a preferred embodiment of the process, the borate derivatives (IV) (wherein R 1, R ³ and R ⁴ are as defined above) are converted without isolation into the quinoline-3-carboxylic acids (I). The intermediates of formula (IV) are novel compounds

The borate derivatives of general formula (II) are optionally reacted with cyclic amines of general formula (M) in the presence of an inert woven solvent and an acid acceptor.

Suitable organic solvents include acid amides such as dimethylformamide, dimethylacetamide, ketones such as acetone, methyl ethyl ketone, ethers such as dioxane, tetrahydrofuran, diethyl ether, esters such as ethyl acetate, methyl acetate, ethyl propionate, sulfoxides, dimethyl sulfoxide, alcohols such as methanol, ethanol, 1-deans, butanol, halogenated organic solvents such as chloroform, dichloroethane

Organic and inorganic bases may be used as acid binders. Organic bases include trialkylamines such as triethylamine, tributylamine, cyclic amines such as pyridine-1,5-diazabicyclo [5.4.0decene 5, 13-thiazabicyclo [43.0] non-5-ene, 1,4-diazabicyclo [2331octane, inorganic bases include hydroxides and carbonates of alkali metals and alkaline earth metals. Thus, potassium carbonate, potassium bicarbonate, sodium hydroxide, calcium hydroxide can be used as the acid acceptor.

The skin derivatives (Π) and the amines (IH), depending on the solvent used, are reacted at a temperature of 10-200 ° C for a reaction time of 0.1 to 10 hours. The reaction time used depends on the reaction temperature chosen. Increasing the reaction temperature allows a shorter reaction time. If desired, circumstances other than those described above may be employed.

The borates (TV) (where R ¹ , R ² , R ³ and R ⁴ are as defined above) may be hydrolyzed, if desired, under acidic or basic conditions to the quinoline-3-carboxylic acid derivatives of formula (I). wherein R *, R ² , R ^{3 and} R ^{4 are} as defined above). Depending on the solvent, for example, the compound of formula (IV) is separated from the reaction mixture by cooling, which may then be recovered by filtration or centrifugation or optionally by evaporation.

Hydrolysis under basic conditions preferably includes hydroxides or carbonates of alkali metals and aqueous solutions of hydroxides of alkaline earth metals. In a particularly preferred embodiment of the process, the hydrolysis of the compounds of the formula (TV) is carried out by heating with an aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium bicarbonate, potassium carbonate, calcium hydroxide. If desired, the hydrolysis may be carried out using organic bases such as triethylamine.

For hydrolysis under acidic conditions, an aqueous solution of mineral acids is preferred. In a particularly preferred embodiment of the process, the hydrolysis of the borates of formula (IV) is carried out by heating with an aqueous solution of hydrochloric, hydrobromic, sulfuric or phosphoric acid. If desired, the hydrolysis may also be carried out using organic acids such as acetic acid, propionic acid.

If desired, hydrolysis of the compounds of formula IV in an aqueous medium is carried out in the presence of a water-miscible organic solvent. Organic solvents include alcohols such as methanol, ethanol, ketones such as acetone, ethers such as dioxane, acid amides such as formamide, dimethylformamide monomido sulfoxides such as dimethyl sulfoxide, and pyridine.

The resulting quinoline-3-carboxylic acids of formula (1) may be isolated, for example, by adjusting the pH of the aqueous solution, then separating the precipitated crystals, for example by centrifugation or filtration, or by lyophilizing the aqueous reaction mixture.

If desired, the quinoline-3-carboxylic acids of formula (I) wherein R @ ¹ , R @ ³ and R @ ⁴ are as defined above are known per se.

-2HU 200175 Β can be converted into pharmaceutically acceptable acid addition salts. It is preferable to form acid addition salts such as hydrogen halides, sulfonic acids, sulfuric acids, organic acids to form chlorides, bromidocarbonyl 4-methylphenyl sulfonates, methanesulfonates, maleates, fumarates, benzoates.

If desired, hydrates of the compounds of formula (I) or pharmaceutically acceptable acid addition salts thereof may be prepared in known manner.

Exemplary quinpline derivatives of formula (Π) (wherein R, R ¹ , R, and R ³ are as defined above) include, for example, 1-ethyl-6,7,8-trifluoro-4-oxo-1,4-dihydro- quinoline-3-carboxylic acid (British Patent No. 2,057,440) and various skin derivatives, such as skin derivatives of formula (V) wherein R is a C 2-6 alkanoyloxy group or fluoroboric acid in aqueous or by reaction in an organic medium.

The invention is further illustrated by the following non-limiting Examples.

Examples

Example 1

1.59 g of (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-5-carboxylate) -β-difluoro-boron are reacted with 1.29 g of piperazine. ml of dimethylsulfoxide at 100 ° C for 3 hours.

Subsequently, 12.6 ml of a 6% aqueous solution of sodium hydroxide were added to the reaction mixture, and after heating to reflux for 2 hours, the mixture was warm filtered, adjusted to pH 7 with 96% acetic acid and diluted with 15 ml of water. The crystalline mass thus obtained was cooled overnight. The precipitated crystals are filtered off, washed with water and dried.

1.61 g of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-piperazinoquinoline-3-carboxylic acid are obtained, m.p. 234-236 ° C.

Analysis calculated for C16 H17 F2 N3 O3: C, 56.9; H, 5.07; N, 12.45. Found: C, 56.75; H, 5.02; N, 12.48.

Example 2

1.99 g of (1-ethyl-6,7,8-hjfluoro-1,4-dihydro-4-oxoquinoline-3-carboxylato) -N-diacetato boron are reacted with 1 x 29 g of piperazine in 8 ml of Dimethylsulfoxide at 110 DEG C. for 2 hours 20 ml of a 3% aqueous solution of sodium hydroxide are then added and the mixture is refluxed for 1 hour. The reaction mixture is filtered and 90% acetic acid is added to pH 7. The precipitated crystals, after dilution with 10 ml of water and cooling, were filtered and dried to give 1.59 g of ocher yellow 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-piperazinoquinoline-3-carboxylic acid. mp 234 ° C.

Analysis calculated for C16 H17 F2 N3 O3: C, 56.90; H, 5.07; N, 12.45. Found: C, 57.03; H, 5.11; N, 12.51.

Example 3

1.06 g of (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate), (dipropionato-boron) were reacted with 0.64 g of piperazine. as in Example 2 in 4 ml of dimethylsulfoxide.

6.3 ml of a 6% aqueous solution of sodium hydroxide are then added and the mixture is refluxed for one hour. After filtration, the pH was adjusted to 7 with 96% acetic acid, water (10 mL) was added and the mixture was cooled overnight. The activated crystals are filtered off, washed with water and dried. 0.74 g of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid is obtained, m.p.

232-236'C-are.

Analysis: Calculated for C16H17F2N3O3: C, 56.90; H, 5.07; N, 12.45. Found: C, 56.85; H, 5.00; N, 12.39.

Example 4

1.06 g of (l-ethyl-he, 7,8 »Trifluoromethyl-l, 4-dihydro-4-oxoquinoline-3-carboxylato-O ^{3, 04)} difluoroacetic boron compound 1 13 g of methyl piperazine in 8 mL of dimethyl sulfoxide as in Example 1. Work up gives 1.54 g of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (1-methylpiperazino) -quinoline-3-carboxylic acid, m.p. 237-240 ° C.

Analysis calculated for C17 H19 F2 N3 O3: C, 58.10; H, 5.45; N, 11.91. Found: C, 58.00; H, 5.46; N, 11.95.

Example 5

1.99 g of (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylato- ^1.04 ) -diacetato-b-k-compound 1 µg of 1-methyl Piperazine was reacted as in Example 2.

130 g of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (1-methylpiperazino) -quinoline-3-carboxylic acid are obtained, m.p. 238-240 ° C.

H, 5.45; N, 11.91. Found: C, 58.19; K, 5.53; N, 11.87.

Example 6

1.06 g of (l-ethyl-6,7-trifluoro-l $, dihidnM 4-oxoquinoline-3-carboxylato-fi ^{3, 04)} bet dipropionate boron compound reacted with 0.75 g of 1-methyl -piperazine as in Example 3.

0.79 g of 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7- (1-methylpiperazino) -quinoline-3-carboxylic acid is obtained, m.p. 239-240 ° C.

Analysis calculated for C 17 H 19 F 2 N 3 O 3: C, 58.10; H, 5.45; N, 11.91. Found: C, 57.95; H, 537; N, 11.90.

Example 7

337 g of (1- (2-fluoroethyl) -6,7,8,8-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate,? methyl piperazine in 20 ml of dimethyl sulfoxide at 80-90 ° C for 2 hours, then 50 ml of a 3% aqueous solution of sodium hydroxide are added to the reaction mixture and hydrolyzed by heating to spin for 2 hours. The pH was adjusted to 7 with 20% acetic acid, water (20 mL) was added and the resulting crystalline suspension was cooled for 5 hours at 5 DEG C. The crystal was filtered off, washed with water and dried (2.88 g, 78%). 1- (2-Fluoroethyl) -6,8-difluoro-1,4-dihydro-7- (4-methyl-1-piperazinyl) quinoline-3-carboxylic acid is obtained, from which hydrochloric acid is formed. 'C.

-3HU 200175 Β

Found: C, 50.33; H, 4.68; N, 10.45 Found: C, 50.33; H, 4.72; N, 10.36.

Example 8

4.17 g of (1- (2-fluoroethyl) -6,7,8,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylato-Q. ³ , ⁰⁴ ) diacetato boron are reacted with g of 1-methylpiperazine in 20 ml of dimethylsulfoxide as in Example 7.

3.0 g of 1- (2-fluoroethyl) -6,8-difluoro-1,4-dihydro-7- (4-methyl-1-piperazinyl) quinoline-3-carboxylic acid are obtained.

Analysis: Calculated for C17H19F3N3O3: C, 55.28; H, 4.91; N, 11.38. Found: C, 55.34; H, 4.88; N, 11.44.

Example 9

4.45 g of (1- (2-fluoro (X-ethyl) -6,7,8-ylflucr-1,4-dihydro-4-oxoquinoline-3-carboxylate- ³ ,) -dipropionato boron are reacted with 2.6 g of with anhydrous piperazine in 20 mL of dimethyl sulfoxide as in Example 7. After work-up, 2.48 g (74%) of 1- (2-fluoroethyl) -6,98-difluoro-1,4-dihydro-7-piperazinyl-quinoline -3-carboxylic acid is obtained, m.p. 229230C.

H, 4.53; N, 11.83 Found: C, 54.14; H, 4.48; N, 11.84.

Example 10

4.53 g of (1, 2, 2, 2-trifluoroethyl, 7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline-3-carboxylato- ³ , ³ , ⁴ ) ^-diacetato boron compound was treated with 3.0 g of 1-methylpiperazine in 20 ml of dimethyl sulfoxide as in Example 7. There was obtained 2.88 g (71.1%) of 0- (2.2.2-trifluoroethyl) -6,8-difluoro-1,4-dihydro-7- (4-methyl-1-piperazinyl) -quinoline-3-carboxylic acid. . M.p .: 199-102 ° C.

Analysis calculated for C17 H16 F5 N3 O3: C, 50.38; H, 3.98; N, 10.37. Found: C, 50.44; H, 3.88; N, 10.44.

Preparation of starting materials

Example 11

3.17 g of ethyl [1- (2-fluoroethyl) -6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate] in 15 ml of 50% w / w aqueous hydrogen fluoroboric acid solution was stirred at 80-90 ° C for 2 hours. After half an hour, the crystalline precipitate begins to form from the crude solution, and after the reaction time, a cake suspension is obtained. The crystal was filtered off and washed with water, methanol. After drying, 3.27 g (97%) of (1- [2-fluoroethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate], 1,1'-difluoro-boron are obtained. m.p. 280 ° C.

Analysis: Calculated for C12H6BF6NO3: C, 42.77; H, 1.79; N, 4.16. Found: C, 42.52; H, 1.82; N, 4.25.

Example 12 To a mixture of g of boric acid and 0.1 g of zinc chloride was added 50 ml of acetic anhydride and the suspension was stirred. During dissolution, the temperature rises to 78 ° C and then begins to decrease. After stirring for another half hour at 110 ° C, 31.7 g of ethyl [1- (2-fluoroethyl) 6.7.8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate] in 100 ml of 96 A warm solution of 1% acetic acid in water was added dropwise and the reaction mixture was stirred at 110 ° C for an additional 1.5 hours. After cooling, 600 ml of water was added. The crystal was filtered off, washed with water, methanol. After drying, 40.7 g (97.6%) of (1- / 2-fluoroethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate- ³ , ⁰⁴ ) -diaceto- yields a boron compound having a decomposition point of 259-260 ° C.

Analysis: Calculated for C16H12BF4NO7: C, 46.07; H, 2.90; N, 3.36. Found: C, 46.12; H, 2.82; N, 3.25.

Example 13 A mixture of g of boric acid and 69 g of propionic anhydride was stirred for 30 minutes at 95-100 ° C. 31.7 Getyl [1- (2-fluoroethyl) -6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate] is dissolved in 120 ml of propionic acid and added to the above solution while heating of the reaction mixture was continued. The red solution was stirred for an additional 2.5 hours at 110 ° C. It is then cooled and 1.51 water is added. The activated crystal is filtered off and washed with water, methanol. After drying, 43.1 g (96.8%) (l- / 2-FLUCK '- ethyl-6,7,8-trifluoro-l, 4-dihydro-4-oxoquinoline-3-carboxylato-y, ⁰⁴⁾ dipropionate boron compound. Decomposition 211-222 ° C.

Analysis: Calculated for C18H17BF4NO7: C, 48.57; H, 3.62; N, 3.14. Found: C, 48.62; H, 3.62; N, 3.25.

Example 14 To a mixture of g of boric acid and 0.1 g of zinc chloride was added 50 ml of acetic anhydride and the suspension was stirred. During dissolution, the temperature rises to 78 ° C and then begins to decrease. After stirring for another half hour at 110 'C, 35.3 g of ethyl [1- (2,2.2-trifluoroethyl) -6,7,8-trifluoro-1,4-dihydro-4-oxoquinolinecarboxylate] 100 A warm solution of 96 ml of 96% acetic acid in water was added dropwise and the reaction mixture was stirred at 110 ° C for an additional 1.5 (khan). After cooling, 600 ml of water were added. The crystal was filtered off, washed with water, methanol. 43.4 g (95.0%) of 1- (2,2,2-trifluoroethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate), m.p. of diacetate boron, m.p. 243-244 ° C.

Analysis for C 1 H 10 BFeNO; Calculated: C, 42.42; H, 2.22. N, 3.09. Found: C, 42.33; H, 2.12; N, 3.05.

Example 15

To a mixture of 1.85 g of boric acid and 20 mg of zinc chloride are added 10 ml of acetic anhydride and the suspension, in which dissolution begins immediately, is stirred. The reaction mixture rises to 80 ° C at a temperature and then begins to decrease. After stirring for another hour at 110 ° C, ethyl (1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate) (6.0 g) was added (20 ml). A warm solution of 1% acetic acid is added dropwise. The reaction mixture was stirred for 2 hours at 110 ° C, then cooled to room temperature and 150 ml of water were added and the resulting suspension was stirred for 3 hours under cooling. The activated crystals are filtered off with suction, washed with water and a little methanol. After drying

7.7 g of (1-ethyl-6,6-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylate), ^w ) -diacetato boron are obtained, which decomposes at 211 ° C.

-4EN 200175 Β

Analysis: Calculated for C16H13BF3NO7: C, 48.15; H, 3.28; N, 3.52. Found: C, 48.12; H, 3.28; N, 3.54.

Claims (7)

PATENT CLAIMS A process for the preparation of a compound of formula I and pharmaceutically acceptable acid addition salts thereof R ⁴ is piperazinyl or 4-methylpiperazinyl, R ¹ , R ¹ and R ^{3 are the} same or different, hydrogen or halogen, characterized in that a compound of formula (ΠΙ) R is halogen or C 2-6 alkanoyloxy and R ¹ , R, R ³ are as defined above, by reaction with a piperazine derivative of formula (ΙΠ) or a salt thereof, wherein ^R5 in hydrogen or methyl group, and the resulting compound represented by the formula (VI) formulas. ,. . R, R, R, R and R are as defined above, with or without isolation, and the resulting compound of formula (1) is, if desired, converted into the pharmaceutically acceptable acid addition salt thereof or liberated from the salt thereof. 2. A process according to claim 1 wherein the compounds of formula II and III wherein R, R ¹ , R, R ³ and R ⁵ are The reaction of claim 1 in the presence of an organic solvent, preferably an acid amide, sulfoxide, ketone, alcohol, ether or ester. 3. The process according to claim 2, wherein the organic solvent is dimethyl sulfoxide. 4. A process according to claim 1 wherein the compounds of formula (H) and (III) wherein R, R, R, R ³ and R ⁵ are The compound of claim 1 is reacted in the presence of an acid acceptor. 5. A process according to claim 4, wherein the acid acceptor is an amine or an excess of a compound of formula (III). The process according to claim 1, wherein the hydrolysis is carried out in an alkaline medium. 7. The process according to claim 6, wherein the alkali is an aqueous solution of an alkali hydroxide, an alkaline earth metal hydroxide or an organic base, preferably triethylamine.