KR900004878B1 - Process for preparing of quinoline derivatives - Google Patents

Abstract

Quinolone derivs. of formula (I) are prepd. by the cyclization of a cpd. of formula (II) in the presence of metal hydrides and organic solvents. In the formulas, R1 is halogen or substd. amino gp. e.g. pyrrolydinyl, imidazolyl, piperidinyl, piperazinyl, pyridyl etc.; R2= C1-3 alkyl; X= halogen. (I) are useful as potent antibacterials.

Description

Method for preparing quinolone derivative

The present invention relates to a new and advanced method for preparing a quinolone derivative represented by the following general formula (I) and salts thereof, and is a powerful antimicrobial agent having a bactericidal effect on bacteria.

R in general formula (I) represents a cyclic substituted amino group which may contain a halogen atom, a monosubstituted amino group, a disubstituted amino group, or another hetero atom. Cyclic substituted amino groups refer to 4- to 7-membered cyclic compounds, for example azetidinyl, pyrrolidinyl, imidazolidine, piperidinyl, morpholinyl, piperazinyl, pyridyl, imidazolyl and homo pipera Genyl is included.

As a known method for preparing a quinolone derivative of general formula (I), various methods are described in German Patent No. 31485, European Patent No. 113092, 113093 and the like.

The preparation method according to the above document starts 3-fluoro-4,6-dichlorobenzoic acid as a starting material, which is not easily purchased or synthesized, and is prepared even by 2,4-dichloro-5-methyl. It can be obtained from the aniline through at least four steps, and its composition requires the use of fluoric acid, and therefore requires a special device or design. The manufacturing methods of other patents also have disadvantages that the process is too long and the yield is extremely low.

The inventors of the present invention have developed a new and advanced quinolone derivative of general formula (I), which is more than expected, which has been endeavoring to improve the above-mentioned disadvantages. The present invention does not require a difficult reaction process and is economical unlike the known method. It is made by the method.

Nitrobenzoyl-3-cyclopropylamino acrylate represented by the general formula (II) used as the starting material of the present invention is a novel substance which the present inventors have applied for the same patent (Patent Application No. 88-7341: 88.6.17) Nitrobenzoyl-3-cyclopropylamino acrylate and its preparation method are described in detail in the preparation thereof. In other words, the compound of formula (II) is prepared by heating and refluxing a nitrobenzoyl ester compound and an alkylorthoformate in a solvent to prepare nitrobenzoyl-3-alkoxyacrylate and reacting it with cyclopropylamine. Nitrobenzoyl-3-cyclopropylamino acrylate can be prepared.

In general formula (II), R represents an aliphatic hydrocarbon, methyl, ethyl, or a propyl group, and X represents a chloro, fluorine, or bromo group as a halogen element.

According to the preparation method of the present invention, nitrobenzoyl-3-cyclopropylamino acrylate of the general formula (II) is prepared in a metal hydride such as potassium or sodium and organic solvents such as dioxane, methylene chloride, ether and tetrahydrofuran. When heated to reflux for 1 to 3 hours at, cyclization occurs to obtain oxo quinoline-3-carboxylate of general formula (III).

R and X in general formula (III) are the same as R and X of general formula (II). On the other hand, when preparing the oxoquinoline-3-carboxylic acid of the general formula (IV) from the oxoquinoline-3-carboxylate of general formula (III), it is 1-3 hours in aqueous alkali solution, such as sodium hydroxide, potassium hydroxide, etc. Obtained by heating under reflux and then acidifying with a strong acid such as sulfuric acid or hydrochloric acid.

X in general formula (IV) is the same as X of general formula (II).

Finally, in preparing the quinolone derivative of general formula (I), compounds such as piperazine and morpholine, dimethyl sulfoxide, pyridine, dimethylformamide, and sulfolane in the oxoquinoline-3-carboxylic acid of general formula (IV) When heated to 100 ° C to 259 ° C in a polar solvent such as N-methylpyrrolidone, a quinolone derivative of the general formula (I) is obtained. Of course, the quinolone derivatives of the present invention can produce acids and acid addition salts such as hydrochloric acid, sulfuric acid, methanesulfonic acid, and can also produce corresponding carboxylic acid salts such as sodium, potassium and the like.

The product can be separated and purified by conventional techniques such as evaporation, filtration, extraction, recrystallization and combinations thereof. If the product contains by-products, it can be further purified by recrystallization.

As an example, a process for preparing a quinolone derivative of general formula (I) from general formula (II) is shown below as a general formula to help understand the present invention.

The following examples will illustrate the invention in more detail, but the invention is not so limited. Percentages and percentages are by weight unless otherwise indicated.

Example 1

Ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (III, X = fluoro)

40 ml of dioxane was added to 0.33 g (8 mmol) of 60% sodium hydride and cooled to 0 ° C., followed by ethyl (4,5-difluoro-2-nitrobenzoyl) -3-cyclopropylamino acrylate (II). 2.8g (8mmol), X = fluoro, R = ethyl) is added. The reaction solution was stirred at room temperature for 30 minutes and then heated to reflux for 1 hour. After distillation under reduced pressure to blow off the dioxane solvent, 150 ml of methylene chloride was added to the residue. The organic solvent is washed with 1N hydrochloric acid solution, saturated bicarbonate water and saturated brine in that order and dried over magnesium sulfate. After filtration of magnesium sulfate, the filtrate was distilled under reduced pressure, and the remaining residue was recrystallized from ethanol to obtain 2.15 g (89%) of a solid product.

m.p: 226-227 ° C

nmr (CF ₃ COOD) ppm: 9.53 (1H, S), 8.43-8.76 (2H, m), 4.59-4.95 (2H, q), 4.05-4.15 (1H, m), 1.40-1.83 (7H.m)

IR (KBr): 1715, 1610, 1480cm ^-1

Example 2

Ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (III, X = fluoro)

40 ml of methylene chloride was added to 0.33 g (8 mmol) of 60% sodium hydride, and cooled to 0 ° C., followed by ethyl (4,5-difluoro-2-nitrobenzoyl) -3-cyclopropylamino acrylate (II). 2.8g (8mmol), X = fluoro, R = ethyl) is added. The reaction solution was stirred at room temperature for 30 minutes and then heated to reflux for 1 hour. Again 150 ml of methylene chloride are added. The organic solvent is washed with 1N hydrochloric acid solution, saturated bicarbonate water and saturated brine in that order and dried over magnesium sulfate. After filtration of magnesium sulfate, the filtrate was distilled under reduced pressure and the remaining residue was recrystallized from ethanol to obtain 2.14 g of a solid product.

m.p: 226-227 ° C

Example 3

Ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (III, X = fluoro)

40 ml of tetrahydrofuran was added to 0.33 g (8 mmol) of 60% sodium hydride and cooled to 0 ° C., followed by ethyl (4,5-difluoro-2-nitrobenzoyl) -3-cyclopropylamino acrylate ( II, X = fluoro, R = ethyl) 2.8 g (8 mmol) was added. The reaction solution was stirred at room temperature for 30 minutes and then heated to reflux for 1 hour. After distillation under reduced pressure to blow off the solvent, 150 ml of methylene chloride was added to the residue. The organic solvent is washed with 1N hydrochloric acid solution, saturated bicarbonate water and saturated brine in that order and dried over magnesium sulfate. After filtration of magnesium sulfate, the filtrate was distilled under reduced pressure and the remaining residue was recrystallized from ethanol to obtain 2.15 g of a solid product.

m.p: 226-227 ° C

Example 4

Ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (III, X = fluoro)

To 2.1 g (7.2 mmol) of ethyl ester of Formula (V) prepared in Example 1, 15 ml of 2N potassium hydroxy aqueous solution was added and heated to reflux for 3 hours. 10% hydrochloric acid solution is added to the reaction to adjust the pH to 1 to form crystals. Filtration of the solid and recrystallization from dimethylformamide gave 1.85 g (97% yield) of solid.

m.p: 285-287 ° C

nmr (CF ₃ COOD) ppm: 9.60 (1H, S), 8.49-8.78 (2H, m), 4.0-4.50 (1H, m), 1.43-1.91 (4H, m)

IR (KBr): 1720, 1610, 1490cm ^-1

Analysis of C ₁₃ H ₉ NO ₃ F ₂

Calculated: C; 58.57, H; 3.42, N; 5.28

Found: C; 58.90, H; 3.39, N; 5.20

Example 5

Ethyl 1-cyclopropyl-7-chloro-6-fluoro-4-oxoquinoline-3-carboxylate (III, X = chloro)

Reaction of ethyl (4-chloro-5-fluoro-2-nitrobenzoyl) -3-cycloamino acrylate in a similar manner to Example 1 yields a solid product in 80% yield.

Example 6

Ethyl 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (IV, X = chloro)

Reaction with ethyl X = chloro) in a similar manner to Example 2 gave a solid in 86% yield.

m.p: 240-242 ° C

nmr (CF ₃ COOD) ppm: 9.39 (1H, S), 8.67-8.83 (1H, d), 8.23-8.43 (1H, d), 3.96-4.34 (1H, m), 1.39-1.86 (4H, m)

Example 7

1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -quinoline-carboxylic acid (I, R = piperazinyl)

N-methyl in 0.5 g (1.9 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinolyl-3-carboxylic acid (IV, X = fluoro) 3 ml of pyrrolidone and 0.8 g (9.4 mmol) of perrazine are added and stirred at 135 ° C to 140 ° C for 1 hour. 10 ml of water is poured into the residue and stirred to form crystals. Filtration and drying gave 0.44 g (70% yield) of the solid product.

m.p: 257 ° C

nmr (CF ₃ COOD): 9.35 (1H, S), 8.29-8.35 (1H, d), 7.94-7.98 (1H, d), 4.13 (1H, m), 3.83-4.02 (8H, m), 1.48- 1.73 (4 H, m)

Example 8

1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-8- (1-piperazinyl) -quinoline-3-carboxylic acid (I, R = pyrerazinyl)

When 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (IV, X = chloro) was reacted in a similar manner to Example 4), 60 Solids are produced in% yield.

Claims (7)

First step and general preparation of oxoquinoline-3-carboxylate of general formula (III) by cyclization of nitrobenzoyl-3-cyclopropylamino acrylate of general formula (II) in the presence of a metal hydride and an organic solvent A second step of preparing oxoquinoline-3-carboxylic acid of general formula (IV) by reacting oxoquinoline-3-carboxylate of formula (III) in an aqueous alkali solution and oxoquinoline-3 of general formula (IV) A process for producing a quinolone derivative of general formula (I), wherein the carboxylic acid is reacted with piperazine or morpholine in the presence of a polar solvent to produce a quinolone derivative of general formula (I).

In general formula (I), R represents piperazinyl, in general formula (II), R represents ethyl, X represents chloro and fluoro, and in general formula (III), R Represents ethyl, X represents chloro, fluoro, and in general formula (IV), X represents chloro, fluoro. The method for producing a quinolone derivative of general formula (I) according to claim 1, wherein sodium hydride and potassium hydride are used as the metal hydride. The process for producing a quinolone derivative of general formula (I) according to claim 1, wherein the organic solvent is selected from dioxane, methylene chloride, ethyl ether and tetrahydrofuran. In the first step of claim 1, the method for producing a quinolone derivative of the general formula (I), characterized in that heated to reflux for 1 to 3 hours under the reaction conditions. The method for producing a quinolone derivative of general formula (I) according to claim 2, wherein the aqueous alkali solution is selected from sodium hydroxide and potassium hydroxide for reaction. The third process of claim 1, wherein the polar solvent is selected from dimethyl sulfoxide, pyridine, dimethylformamide, sulfolane, N-methyl pyrrolidone and reacted. . In the third step of claim 1, the reaction temperature is a method for producing a quinolone derivative of the general formula (I), characterized in that it is maintained at 100 ℃ to 250 ℃.