KR930000664B1 - Process for proparating quinolone derivatives - Google Patents

Abstract

A method for preparing 1- cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7piperazinoquinoline-3- carboxylic acid of formula (I) comprises reacting 7-chloro-1- cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid of formula (II) with piperazine in the presence of Cu or a Cu cpd. in an inert solvent. Pref. the molar ratio of the Cu cpd. to the cpd. (II) is 1-20 mol %. Cpd. (I) has a good antibacterial activity against both gram positive and gram negative bacteria.

Description

Method for preparing quinolone derivative

The present invention relates to a method for producing a quinolone derivative, in particular 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazinyl-quinoline- represented by the following structural formula (I). It relates to a method for producing 3-carboxylic acid in high yield.

In general, the quinolone derivative of formula (I) shows excellent antibacterial effect against gram negative bacteria and gram positive bacteria.

As a method for preparing the quinolone derivative represented by the structural formula (I), Korean Patent Nos. 2,468 and 23,842, Patent Publication Nos. 90-2041, US Patent Nos. 3, 142, 854 and 4,559, 341 and German Patent Nos. 3, 142 and 854 describe various manufacturing methods.

Particularly, among the methods described in Korean Patent Nos. 23468 and 23842, the preparation method of Structural Formula (I) shows that when the piperazine is introduced into the free carboxylic acid as a starting material, the reaction temperature is high and Excess amount of reactants should be used in a ratio of 5 to 10 moles of piperazine per mole of acid, and compounds reacted with piperazine at position 6 or compounds substituted at positions 6 and 7 simultaneously when reacted with 7-chloro derivatives. This side reaction can be produced. Therefore, the removal of impurities generated after the reaction is not easy, the purity is low, and the yield is low, there is an industrially uneconomical problem.

In addition, according to the method described in Korean Patent Publication No. 90-2041, the yield of the target compound was increased by using a catalyst such as iodine and tetraphenylphosphonium bromide or benzyltriammonium bromide. There was a lot of room for improvement because it was uneconomical because it had to be used and all of them used expensive catalysts.

Therefore, the present invention is a structural formula (I) of the high purity in an economical and industrial way to compensate for the disadvantages of the prior art and to further improve the yield of the target compound even when using a relatively small amount of reactants using cheaper raw materials It is an object of the present invention to provide a new method for producing a quinolone derivative represented by.

Hereinafter, the present invention will be described in detail.

In producing the 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazinoquinoline-3-carboxylic acid represented by the above structural formula (I), 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and piperazine represented by Structural Formula (II) are inert using a copper or copper compound as a catalyst It is characterized by producing a quinolone derivative by reacting in an organic solvent.

Referring to the present invention in more detail as follows.

In the method according to the present invention, in order to prepare a high yield of the target compound in a more economical manner, first, using 1 mol to 4 mol of piperazine as the compound of the formula (II), an inert organic solvent such as N, 80 ~ under nitrogen atmosphere by using copper or a copper compound as a catalyst in an organic solvent selected from N-dimethylformamide, tetrahydrofuran, dioxane, N, N-dimethylacetamide, dimethylsulfoxide pyridine, preferably pyridine When the reaction is carried out at 130 ℃ it is possible to prepare a high purity of the target compound in high yield.

Here, when reacting piperazine with the free carboxylic acid of formula (II), copper or a copper compound is added as a catalyst, thereby enhancing the reactivity of the chlorine substituent in aromatics and improving the fluoro reactivity. Yield is improved due to the reduction, that is, the order of nucleophilic reactivity in general aromatics (F> C1> Br> I) is changed to I> Br> C1> F so that the piperazine produced as a side reaction is substituted in the 6 position. It is possible to produce a compound of the above formula (I) having a high purity of 96.5% or more by inhibiting the production of the compound and the compound substituted at the 6 and 7 positions and increasing the reactivity.

According to the present invention, the copper compound used as a catalyst includes copper monovalent and copper divalent compounds including copper monomers, of which copper and copper monovalent compounds are most effective. At this time, a representative copper monovalent compound may be selected from cuprous chloride, cuprous bromide, cuprous iodide, cuprous oxide or cuprous cyanide.

Further, copper divalent compounds include copper dioxide and copper hydroxide. Copper chloride. One selected from cuprous sulfate and cupric nitrate can be used.

In addition, such a copper or copper compound catalyst used in the present invention is used in an amount of 1 to 20 mol% based on the compound of the formula (II), if the amount is too small, it is difficult to expect a catalyst addition effect Excessive use leads to the problem of separately removing the catalyst after the reaction.

As described above, according to the present invention, a copper or a copper compound is used as a catalyst. The solvent and the reaction temperature are 96.5% or more when the reaction is performed in a simple process for 2 to 4 hours under mild conditions. Under the most preferable conditions, the target compound can be prepared in high yield of 98% or more.

On the other hand, the compound of the formula (II) which is the starting material of the present invention can be prepared according to a known method (Patent No. 3314854). Further, the 1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7-piperazinyl-quinoline-3-carboxylic acid or salts thereof of the above-described structural formula (I) is suitable. It is possible to switch between the methods and this method is known in the art.

As described above, according to the present invention, it is possible to prepare a high yield of quinolone derivative economically even in a simple method under mild conditions by using a relatively small amount of reactant and using a cheap copper or copper compound as a catalyst, unlike the conventional art. will be.

Hereinafter, the present invention will be described in detail with reference to the following Examples, but the present invention is not limited by the Examples.

Example 1

20.0 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 22.0 g of piperazine and 0.5 g of cuprous chloride were added to 140 ml of a pyridine solvent. After reacting for 3 hours at 110 ° C. under nitrogen, the solvent was removed under reduced pressure, 500 ml of water was added to the residue, and the resulting solid was filtered, washed with water, and dried to yield 1-cyclopropyl-6-fluoro-1,4-di. 23.2 g (98.6%) of hydro-4-oxo-7-piperazinoquinoline-3-carboxylic acid were obtained.

Melting Point: 254 ~ 256 ℃

Example 2

In the same manner as in Example 1 except that 0.5 g of cuprous chloride was used and 0.6 g of cuprous bromide was reacted at 110 ° C. for 4 hours to yield 1-cyclopropyl-6-fluoro-1,4-dihydro-4-. 22.8 g (96.9%) of oxo-7-piperazinoquinoline-3-carboxylic acid was obtained.

Example 3

In the same manner as in Example 1 except that 0.5 g of cuprous chloride was used and 0.6 g of cuprous iodide was reacted at 120 ° C. for 3 hours to react 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo. 23.3 g (99.0%) of-7-piperazinoquinoline-3-carboxylic acid was obtained.

Example 4

In the same manner as in Example 1, except for 0.5 g of cuprous chloride, 0.4 g of cuprous oxide was used, and the mixture was reacted at 130 ° C for 4 hours for 1-cyclopropyl-6-fluoroluo-1,4-dihydro-4-oxo. 22.9 g (97.3%) of-7-piperazinoquinoline-3-carboxylic acid was obtained.

Example 5

In the same manner as in Example 1, except that 0.5 g of cuprous chloride was used and 0.5 g of copper was reacted at 80 ° C. for 3 hours to yield 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7. 23.0 g (97.6%) of -piperazinoquinoline-3-carboxylic acid was obtained.

Example 6

In the same manner as in Example 1, the reaction was carried out at 120 ° C. for 3 hours using dimethyl sulfoxide instead of pyridine as a solvent, and then 1-cyclopropyl-6fluoro-1,4-dihydro-4-oxo-7-pipera. 21.6 g (91.8%) of genyl-3-carboxylic acids were obtained.

Example 7

In the same manner as in Example 1 except that instead of pyridine as a solvent, the reaction was carried out at 110 ° C. for 4 hours using N, N-dimethylformamide to yield 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo. 21.4 g (91.0%) of -piperazinyl-3-carboxylic acid were obtained.

Comparative Example 1

135 degreeC of the mixture of 7-chloro- 1-cyclopropyl 6-fluoro- 1, 4-dihydro- 4-oxoquinoline- 3-carboxylic acid, 30.1 g of anhydrous pyrazine, and 100 ml of dimethyl sulfoxide Heated to 140 ° C. for 2 hours. The solvent is distilled off under high vacuum, the residue is suspended in water, filtered off with suction and washed with water.

For purification, the moist composition is hung with 100 ml of water, suction filtered at room temperature, washed with water and dried over CaCl ₂ in a vacuum drying cabinet at 100 ° C. 19.6 g (84.6%) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazinoquinoline-3-carboxylic acid were obtained, which decomposed at 255 ° C to 257 ° C. .

Comparative Example 2

3.4 g (12.1 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 3.13 g (36.3 mmol) of piperazine and 25 ml of pyridine 0.06 g of iodine and 0.07 g of tetraphenylphosphonium bromide were added to the mixture, the reaction was heated at 110 to 115 ° C. for 3 hours, pyridine was removed under reduced pressure, and 20 ml of water was added to the residue. The resulting solid was filtered and washed with ice water. After drying, 3.88 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazinoquinoline-3-carboxylic acid was obtained. (Yield: 96.8% mp 254-256 ℃)

Claims (3)

In preparing 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazinoquinoline-3-carboxylic acid represented by the following structural formula (I), the following structural formula (II) 7-chloro-l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and piperazine represented by) are used as a catalyst of copper or a copper compound under an inert organic solvent. Method for producing a quinolone derivative, characterized in that the reaction.

The method for preparing a quinolone derivative according to claim 1, wherein the copper or copper compound which is the catalyst is added and used in an amount of 1 to 20 mol% based on the compound of the formula (II). The copper compound according to claim 1 or 2, wherein the copper compound is a copper monovalent compound selected from cuprous chloride, cuprous bromide, cuprous iodide, cuprous oxide and cuprous cyanide, or cuprous oxide, cupric hydroxide, and cupric chloride. A method for producing a quinolone derivative, characterized in that a copper divalent compound selected from cuprous sulfate and cupric nitrate is used.