KR920003690B1 - Process for preparation of quinoline derivatives - Google Patents

Abstract

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Description

Method for preparing quinoline derivative

The present invention relates to a new process for preparing the following compound of formula (I) having excellent antimicrobial activity.

Wherein R is hydrogen, methyl or ethyl.

The production method of the compound of the formula (I) known so far is obtained by the method of obtaining the compound of the formula (II) by the substitution reaction of the compound of the formula (II) with piperazine as in the following chemical reaction formula (Japanese) 58-74667 and the Federal Republic of Germany Patent No. 3142854 A1.

The present invention is different from the known methods so far known, by reacting a compound of formula (II) with a dialkylamine represented by formula (III) as in the following chemical reaction scheme to obtain a compound of formula (IV) in good yield Next, thionyl chloride is easily reacted to obtain a compound of formula (V), and then reacted with ammonia water to obtain a desired compound of formula (I).

Wherein X is halogen.

In the present invention, the structural formula (II) compound to be used as a starting material can be easily prepared according to the methods described in Japanese Patent Laid-Open No. 55-33453 and US Patent No. 4,398,029, Compounds of formula (III) are readily available at low cost.

The compound of formula (IV) is a novel substance and is used as an intermediate in the preparation of the compound of formula (I).

The compound of formula (V) is a novel substance and is used as an intermediate in the preparation of the compound of formula (I).

In the present invention, the structural formula (II) compound and the dialkylamine are added in an aprotic polar solvent such as dimethylformamide, dimethyl sulfoxide, acetonitrile and the like, and sodium carbonate, potassium carbonate, sodium bicarbonate, potassium hydrogen carbonate and the like. The reaction may be carried out in the presence of an acid binder such as or in an organic base such as pyridine. At this time, the reaction temperature is preferably maintained at 50 ℃ to 150 ℃ and the reaction time is preferably maintained for 1 hour to 24 hours. When the compound of formula IV is reacted with a suitable halogenating reagent, the compound of formula V can be obtained. Suitable halogenated reagents are thionyl chloride, phosphorus trichloride, and phosphorus tribromide. As solvents used in this reaction, aprotic nonpolar solvents such as dichloromethane, chloroform, benzene, and ethyl ether are suitable. In addition, the reaction proceeds well in the presence of a weak base such as pyridine, and when reacted for 1 to 5 hours at room temperature, a compound of formula (V) can be obtained in high yield.

When the compound of formula (V) is reacted with ammonia water at 25 ° C. to 90 ° C. for 2 hours to 10 hours, the desired compound of formula (I) can be obtained in high yield.

Compounds of formula (I) can produce acids and acid addition salts, such as hydrochloric acid, sulfuric acid, methanesulfonic acid, and the hydrate form of the hydrochloride is preferred, and methods for preparing these salts can be prepared by known methods well known in the art.

When explaining a specific embodiment of the present invention will be described.

Example 1

Preparation of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-bis (2-hydroxyethyl) aminoquinoline-3-carboxylic acid (IV).

20 hours by mixing 2.68 g of 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (III), 5.26 g of diethanolamine, and 30 ml of pyridine Stirring to reflux. The reaction solution was distilled under reduced pressure to remove pyridine, and 50 ml of ethanol was added thereto. The resulting crystals were cooled at 0-5 ° C. for 1 hour 30 minutes, and then filtered. After washing with a small amount of ethanol and dried at 45-68 ℃ to obtain 3.62g (96%) light yellow crystals of the target compound.

Melting Point: 237 ℃-240.2 ℃

IR (KBr, cm ^-1 ): 1720,1625

¹ H-NMR (CF ₃ CO ₂ D / CDCI ₃ / TMS, δ): 1.3 (m, 4H), 3.64-4.70 (m, 9H), 7.58-8.20 (m, 2H), 9.08 (s, 1H)

Elemental Analysis (C ₁₇ H ₁₉ O ₅ N ₂ F)

Theoretical value (%): C; 58.33, H; 5.43, N; 8.00

Found (%): C; 58.21, H; 5.52, N; 8.01

Example 2

Preparation of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-bis (2-hydroxyethyl) aminoquinoline-3-carboxylic acid (IV)

30 ml of acetonitrile with 2.68 g of 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (III), 5.26 g of diethanolamine and 3 g of potassium carbonate The mixture was stirred at reflux for 24 hours. The reaction color was neutralized with 5% HCI and the resulting crystals were cooled at 0-5 ° C. for 1 hour and then filtered. After washing with a small amount of ethanol and dried to obtain 3.25g (86%) of light yellow crystals.

Melting Point: 237 ℃-240.2 ℃

IR (KBr, cm ^-1 ): 1720,1625

¹ H-NMR (CF ₃ CO ₂ D / CDCI ₃ / TMS, δ): 1.3 (m, 4H), 3.64-4.70 (m, 9H), 7.58-8.20 (m, 2H), 9.08 (s, 1H) .

Elemental Analysis (C ₁₇ H ₁₉ O ₅ N ₂ F)

Theoretical value (%): C; 58.33, H; 5.43, N; 8.00

Found (%): C; 58.23, H; 5.51, N; 8.01

Example 3

Preparation of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-bis (2-chloroethyl) aminoquinoline-3-carboxylic acid (V).

3.26 g of Compound (IV) obtained in Example 1 was dissolved in 30 ml of dichloromethane, 3 ml of pyridine was added, and then 2.22 ml of thionyl chloride was slowly added dropwise at 0-5 ° C. over 25 minutes. The reaction solution was raised to room temperature, stirred for 4 hours, and 15 ml of water was added thereto, followed by further stirring for 30 minutes. The reaction solution was distilled under reduced pressure to remove the solvent, 50 ml of ethanol was added to the residue, the mixture was cooled to 0-5 ° C, filtered and dried to obtain 3.38 g (94%) of the title compound as yellow crystals.

Melting Point: 193.2 ℃ -195.7 ℃

IR (KBr, cm ^-1 ): 1725, 1630

¹ H-NMR (CF ₃ CO ₂ D / CDCℓ ₃ / TMS, δ): 1.40 (m, 4H), 3.37-4.36 (m, 9H), 7.55-8.30 (m, 2H), 9.10 (s, 1H)

Elemental Analysis (C ₁₇ H ₁₇ O ₃ N ₁ FCℓ ₁ )

Theoretical value (%): C; 52.28, H; 4.40, N; 7.25

Found (%): C; 52.22, H; 4.35, N; 7.24

Example 4

Preparation of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-bis (2-chloroethyl) aminoquinoline-3-carboxylic acid (V).

3.26 g of the compound of Example 1 was mixed with 30 ml of methylene chloride and 3 ml of pyridine, cooled to 0 ° C. or less, and 1.3 g of phosphorus trichloride was slowly added. The reaction solution is stirred at room temperature for 3 hours, and 15 ml of water is added thereto and distilled under reduced pressure. 60 ml of ethanol was added to the mixture, and the resultant crystals were filtered and dried to obtain 3.20 g (89%).

Melting Point: 193.2 ℃ -195.7 ℃

IR (KBr, cm ^-1 ): 1725, 1630

¹ H-NMR (CF ₃ CO ₂ D / CDCI ₃ / TMS, δ): 1.40 (m, 4H), 3.37-4.36 (m, 9H), 7.55-8.30 (m, 2H), 9.10 (s, 1H)

Elemental Analysis (C ₁₇ H ₁₇ O ₃ N ₂ FCI ₂ )

Theoretical value (%): C; 52.28, H; 4.40, N; 7.25

Found (%): C; 52.23, H; 4.34, N; 7.25

Example 5

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

To 3.30 g of Compound (V) obtained in Example 3, 30 ml of 29% aqueous ammonia was added and stirred under reflux for 5 hours. The reaction solution was distilled under reduced pressure, 40 ml of water was added, and the mixture was stirred at 0-5 ° C. for 1 hour 30 minutes. The resulting crystals were filtered to yield 2.54 (92.5%) of the target compound (I) as white crystals.

Melting Point: 255-257 ℃

IR (KBr, cm ^-1 ): 1720, 1625

¹ H-NMR (CF ₃ CO ₂ D / CDCI ₃ / TMS, δ): 1.20-1.77 (m, 4H), 3.31-4.60 (m, 9H), 7.60-8.38 (m, 2H), 9.10 (s, 1H)

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

Theoretical value (%): C; 61.63, H; 5.44, N; 12.69

Found (%): C; 61.60, H; 5.50, N; 12.64

Claims (6)

A process for preparing the compound of formula (I) by reacting the compound of formula (V) with ammonia.

Wherein X is halogen. A compound of formula (V)

Wherein X is halogen. A process for preparing a compound of formula (V) by reacting a compound of formula (IV) with a halogenating agent.

4. The method of claim 3, wherein the halogenating agent uses a halogenating agent selected from thionyl chloride, phosphorus trichloride, phosphorus tribromide, and the like. A compound of formula (IV)

A method for preparing a compound of formula (IV) by reacting a compound of formula (II) with a compound of formula (III).