Synthesis method of gatifloxacin metabolite

Abstract

The invention discloses a synthesis method for gatifloxacin metabolite, belonging to the field of biological medicines. The method for synthesizing gatifloxacin metabolite in the invention is reasonable in route, good in operability and easy in product purification. According to the method, a compound I is used as a raw material and firstly reacts with isopropanolamine, then a hydroxyl group is made into active ester, the active ester is substituted by azide, and finally azide is reduced into an amino group to obtain a target molecule. The whole route of the method is reasonable in design, theabove raw materials are cheap and easy to obtain, operation is easy, the purity of the obtained gatifloxacin metabolite is high, and the synthesized target molecule provides a test sample for research of the metabolic mechanism of gatifloxacin and has important application value.

Description

technical field

[0001] The invention belongs to the field of biomedicine, in particular to a method for synthesizing gatifloxacin metabolites. Background technique

[0002] Gatifloxacin: Gatifloxacin, chemical name 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid, trade name For Tequin, Zymar, the structural formula is:

[0003]

[0004] Developed by Kyorin Pharmaceutical Co., Ltd., Japan, it is a fourth-generation quinolone antibacterial drug containing methoxy groups. It was approved by the US FDA in December 1999. It has a wider antibacterial spectrum than other fluoroquinolone antibacterial drugs in clinical practice, especially Enhanced antibacterial activity against Gram-positive bacteria and anaerobic bacteria, while reducing phototoxicity; stable in vivo, fast oral absorption, good tissue distribution, mainly used for various mild to moderate infections caused by sensitive pathogens disease.

[0005] The q...

Examples

Embodiment 1

[0026] Such as figure 1 Shown, a kind of synthetic method of gatifloxacin metabolite comprises the following steps:

[0027] Step (1): Preparation of Compound II

[0028] Dissolve 10g of raw material I and 5.3g of isopropanolamine in 50mL of dioxane, then add 6g of diisopropylethylamine, and stir at 100°C for 5 hours to obtain a light yellow solution. TLC shows that the reaction is complete. The reaction solution was directly concentrated and evaporated to dryness, and purified by chromatographic column to obtain 9 g of compound II with a yield of 79%;

[0029] Step (2): Preparation of Compound III

[0030] Dissolve 9 g of compound II in 90 mL of dry THF, add 6.5 g of methanesulfonyl chloride, 5.7 g of dry triethylamine, and react at 50°C for 2 hours. TLC shows that the reaction is complete. The reaction liquid is cooled, washed with water, and the organic phase is dried and concentrated to obtain 7 g of compound Ⅲ, MS: 451 [M+Na + ], yield 86%;

[0031] Step (3): Prepara...

Embodiment 2

[0036] Step (1): Preparation of Compound II

[0037] Dissolve 5g of raw material I and 2.5g of isopropanolamine in 25mL of DMF, then add 3g of diisopropylethylamine, and stir at 100°C for 6 hours. TLC shows that the reaction is complete, and the reaction solution is directly concentrated and evaporated to dryness. Purified to obtain 4g of compound II with a yield of 70%;

[0038] Step (2): Preparation of Compound III

[0039] Take 4g of compound II dissolved in 40mL of dry chloroform, add 4.8g of p-toluenesulfonyl chloride, 2.5g of dry triethylamine, react at 50°C for 2 hours, TLC shows that the reaction is complete, the reaction solution is cooled, washed with water, and the organic phase is dried and concentrated to obtain 3.4g Compound Ⅲ, yield 81%;

[0040] Step (3): Preparation of compound V

[0041] Dissolve 3.4g of compound III in 35mL of DMSO, add 3.4g of trimethylsilyl azide, stir overnight at 40°C, spot reaction is complete, cool the reaction solution and add wate...

technical field

[0001] The invention belongs to the field of biomedicine, in particular to a method for synthesizing gatifloxacin metabolites. Background technique

[0002] Gatifloxacin: Gatifloxacin, chemical name 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid, trade name For Tequin, Zymar, the structural formula is:

[0003]

[0004] Developed by Kyorin Pharmaceutical Co., Ltd., Japan, it is a fourth-generation quinolone antibacterial drug containing methoxy groups. It was approved by the US FDA in December 1999. It has a wider antibacterial spectrum than other fluoroquinolone antibacterial drugs in clinical practice, especially Enhanced antibacterial activity against Gram-positive bacteria and anaerobic bacteria, while reducing phototoxicity; stable in vivo, fast oral absorption, good tissue distribution, mainly used for various mild to moderate infections caused by sensitive pathogens disease.

[0005] The q...

Examples

Embodiment 1

[0026] Such as figure 1 Shown, a kind of synthetic method of gatifloxacin metabolite comprises the following steps:

[0027] Step (1): Preparation of Compound II

[0028] Dissolve 10g of raw material I and 5.3g of isopropanolamine in 50mL of dioxane, then add 6g of diisopropylethylamine, and stir at 100°C for 5 hours to obtain a light yellow solution. TLC shows that the reaction is complete. The reaction solution was directly concentrated and evaporated to dryness, and purified by chromatographic column to obtain 9 g of compound II with a yield of 79%;

[0029] Step (2): Preparation of Compound III

[0030] Dissolve 9 g of compound II in 90 mL of dry THF, add 6.5 g of methanesulfonyl chloride, 5.7 g of dry triethylamine, and react at 50°C for 2 hours. TLC shows that the reaction is complete. The reaction liquid is cooled, washed with water, and the organic phase is dried and concentrated to obtain 7 g of compound Ⅲ, MS: 451 [M+Na + ], yield 86%;

[0031] Step (3): Prepara...

Embodiment 2

[0036] Step (1): Preparation of Compound II

[0037] Dissolve 5g of raw material I and 2.5g of isopropanolamine in 25mL of DMF, then add 3g of diisopropylethylamine, and stir at 100°C for 6 hours. TLC shows that the reaction is complete, and the reaction solution is directly concentrated and evaporated to dryness. Purified to obtain 4g of compound II with a yield of 70%;

[0038] Step (2): Preparation of Compound III

[0039] Take 4g of compound II dissolved in 40mL of dry chloroform, add 4.8g of p-toluenesulfonyl chloride, 2.5g of dry triethylamine, react at 50°C for 2 hours, TLC shows that the reaction is complete, the reaction solution is cooled, washed with water, and the organic phase is dried and concentrated to obtain 3.4g Compound Ⅲ, yield 81%;

[0040] Step (3): Preparation of compound V

[0041] Dissolve 3.4g of compound III in 35mL of DMSO, add 3.4g of trimethylsilyl azide, stir overnight at 40°C, spot reaction is complete, cool the reaction solution and add wate...

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