KR890002639B1 - Process for preparing quinoline derivatives - Google Patents

Abstract

The quinoline derivatives of comp. (I) have high antibacterial activitis for gram-positive bacteria, gram-negative bacteria and pseudomonas aeruginosa. In comp. (I), R-hydrogen, methyl, or ethyl; R1=hydrogen, C1-4 low alkyl, alkoxy carbonyl, or alkyl ester.

Description

Method for preparing quinoline derivative

The present invention relates to a quinoline derivative of the following general formula (I) and a method for producing a salt or a hydrate thereof having very high antibacterial activity against Gram-positive bacteria, Gram-negative bacteria, and Pseudomonas aeruginosa.

Wherein R is hydrogen, methyl or ethyl group and R 'is hydrogen, lower alkyl having 1-4 carbon atoms, alkoxy carbonyl, alkyl ester. The general formula (I) is a known compound, the preparation method of which is described in detail in German Patent Application No. 3,142,854. That is, by condensing and decarboxylating the malonic acid ester using 2,4-dichloro-5-fluoro benzoyl chloride of formula (f) as a starting material, triolso formate is reacted to form a double bond. To form a compound (K) by condensing cyclopropylamine and ring-closing with sodium hydride and replacing piperazine with chloro at position 7 of the compound (k) to give the chemical of formula (I). It is a method of manufacturing. This method is represented by the following formula.

This method requires the use of hydrofluoric acid from the structural formula (a) to obtain the structural formula (f) as a starting material, and there are industrially difficult reactions such as photoreaction, and in particular, cyclopropyl, an expensive reagent, to obtain the structural formula (k). An amine should be used, and sodium hydride should be used for waste. The method for obtaining the structural formula (f) from the structural formula (a) is as follows.

Therefore, from the structural formula (a) to the target (I), the manufacturing process is too complicated in 12 steps, so that the target is obtained with a low yield, which is uneconomical. The present invention provides a compound of formula (II) 6-fluoro-1, 4-dihydro-4-oxo-7- (1-piperazinyl), which is widely known as a starting material, in order to alleviate these disadvantages. A method of introducing methylene by adding methylene to the first vinyl group using -1-vinylquinoline-3-carboxylic acid ethyl ester to introduce a cyclopropyl group, a method having a simple process and high yield economy. That is, a feature of the present invention is a method for easily introducing a cyclopropyl group. When 1-vinylquinoline derivative of the following general formula (II) is reacted with methylene iodine and trialkyl aluminum of the general formula (III), 1-cyclopropyl quinoline Derivatives can easily obtain the target substance of the present invention.

In the above formula, R and R 'are as described above and R ″ is a lower alkyl group such as methyl, ethyl, etc. General formula (II) is a known compound as a starting material of the present invention and is a structural formula (A) which can be obtained relatively easily. Starting from Japanese Patent Application Laid-Open No. 55-33453 and J.Med. Chem. 1980.23.1358-1363, it can be produced by the method shown in the following table.

By reacting the trialkylaluminum of the general formula (III) with methylene iodine in a nonpolar solvent to the compound of the general formula (II) obtained in this manner, the compound of the general formula (I) which is the object of the present invention can be obtained in high yield. . The reaction at this time is considered to proceed through the same process.

Wherein R ″ is as described above and Q represents a quinoline derivative. The reaction is carried out in the range of -5-30 ° C., preferably at room temperature, and the reaction solvent is chloroform, methylene chloride, benzene, n-hexane. It can be carried out in a non-polar solvent such as the reaction time can be obtained in a high yield of the target product within 1-10 hours The compound of formula (I) can be prepared with a salt of organic or inorganic acid in a conventional manner and suitable Examples of the acid include hydrochloric acid, sulfuric acid, acetic acid, etc. The hydrate may be prepared according to a general method, which will be described in more detail in the following examples.

Example 1

Preparation of 3-chloro-4-fluoro-anilino methylene malonic acid diethyl ester (B)

14.6 g of 3-chloro-4-fluoro-aniline and 21.6 g of diethyl ethoxy methylene malonic acid ester are mixed and then heated at 120-130 ° C. for 2 hours. The ethanol produced during the reaction was distilled under reduced pressure and recrystallized from n-hexane. Get 28.9 g.

Yield: 91.7% m.p. 69-70 ° C

Example 2

Preparation of 7-chloro-6-fluoro-4-hydroxy quinoline-3-carboxylic acid ethyl ester (C)

300 ml of diphenyl ether was added to 31.5 g of the compound of Example 1), and the mixture was stirred under reflux for two hours. After the reaction was cooled, the resulting crystals were filtered, washed with benzene and dried to obtain 17.8 g of the target compound.

Yield: 66% m.p. 335 ° C

Example 3

Preparation of 7-chloro-6-fluoro-1-hydroxyethyl-1.4-dihydro-4-oxo quinoline-3-carboxylic acid ethyl ester (D)

5.4 g of the compound of Example 2) was mixed with 6.9 g of potassium carbonate and 100 ml of dimethyl formamide, and then maintained at 110-120 ° C. for 1 hour, and the reaction solution was lowered to 60 ° C., followed by 20 minutes of 9.4 ml of chloroethanol. After the dropwise addition, the reaction solution was heated to 110-120 ° C and stirred under heating for 5 hours. The reaction solution was distilled under reduced pressure to remove the solvent, followed by extraction with 50 ml of methylene chloride and 50 ml of water.

Yield: 86% m.p. 202 ° C

Example 4

Preparation of 7-chloro-6-fluoro-1-vinyl-1, 4-dihydro-4-oxo quinoline-3-carboxylic acid (F)

1.6 ml of pyridine and 70 ml of chloroform were mixed with 5.4 g of the compound of Example 3), cooled to 0 ° C., a mixed solution of 12.3 ml of thionyl chloride and 10 ml of chloroform was added dropwise over 30 minutes, and stirred at room temperature for 3 hours. The solvent and excess pyridine and thionyl chloride were removed by distillation under reduced pressure, water was added to the residue, and the residue was neutralized with potassium carbonate. The resulting crystals were filtered and washed with water, and 2N-NaOH and ethanol were added thereto and refluxed for 1 hour. . After cooling, the resulting crystals were neutralized with acetic acid, filtered, washed several times with water and dried to obtain 3.8 g of the target product.

Yield: 82.0% m.p. 206-207 ° C

Example 5

Preparation of 1-vinyl-6-fluoro-1-vinyl-1, 4-dihydro-4-oxo-7- (1-piperazinyl) quinoline-3-carboxylic acid (II)

20 ml of pyridine was added to 2.73 g of the compound of Example 4), and 3.5 g of piperazine was added thereto, followed by stirring under reflux for 18 hours. Dissolve by distillation under reduced pressure, 5 ml of water and 2N-NaOH were added to completely dissolve, neutralized with acetic acid to pH 6.9-7.0 and cooled to 0 ℃ filtered precipitated crystals and washed several times with ice water dimethyl crystals Recrystallization with formamide gives 1.95 g of the target compound.

Yield: 60.6% m.p.256-257 ° C

Example 6

Preparation of 1-vinyl-6-fluoro-1, 4-dihydro-4-oxo-7- (1-piperazinyl) quinoline-3-carboxylic acid ethyl ester

20 ml of anhydrous ethanol was added to 3.22 g of the compound of Example 5), followed by cooling to 0 ° C., 7.4 ml of thionyl chloride, and stirring under reflux for 3 hours, followed by cooling to remove the solvent and excess thionyl chloride under reduced pressure. The residue was dissolved in 30 ml of methylene chloride, washed with water, dried over 2 g of anhydrous sodium sulfate, and distilled under reduced pressure to obtain 3.2 g of the target compound.

Yield: 91.4% m.p. 218-219 ° C

Example 7

Preparation of 1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7- (1-piperazinyl) quinoline-3-carboxylic acid (I)

After dissolving 3.5 g of the compound of Example 6 in 30 ml of methylene chloride, air was established using nitrogen gas, 1.6 ml of methylene iodine was added using a syringe, the reaction solution was cooled to 0 ° C., and 19% of trimethyl aluminum dissolved in hexane. Take 10 ml of the solution with a syringe, add slowly, and stir for 5 hours at room temperature. Then, 30 ml of methylene chloride is added to the reaction solution, diluted with diluent, cooled to 0 ° C. and adjusted to pH 6.9-7.1 with acetic acid to precipitate crystals. The crystals were washed several times with ice water and dried to obtain 2.8 g of the target compound.

Yield: 87.0% m.p. 225-257 ° C

Elemental Analysis (C ₁₇ H ₁₈ O ₃ N ₃ F)

Theoretical value (%): C; 61.62, H; 5.48, O; 14.49, N; 12.68

Found (%): C; 61.73, H; 5.32, O; 14.33, N; 12.72

Claims (3)

The reaction of methylene iodine with trialkylaluminum of general formula (III) to a quinoline carboxylic acid derivative in which the 1-position of the general formula (II) is substituted with vinyl, and the compound of general formula (I) and derivatives thereof or Method for producing the salt or hydrate thereof.

Wherein R is a lower alkyl group such as hydrogen, methyl, ethyl, isopropyl, R 'is hydrogen, lower alkyl having 1-4 carbon atoms, alkoxycarbonyl, alkyl ester group and R' 'is methyl, ethyl group. The process according to claim 1, characterized in that the preparation of formula (I) is carried out by reacting formula (III) with methylene iodine after esterification when R in formula (II) is hydrogen. The method of claim 1, wherein the reaction temperature is carried out at -5-30 ℃ and the reaction solvent is characterized in that the non-polar solvent is carried out in chloroform, methylene chloride, benzene, n-hexane.