Preparation and application of bis-fluoroquinolone thiadiazole urea N-methyl enoxacin derivatives

[0033] 1-{2-[1-Ethyl-6-fluoro-7-(4-methylpiperazin-1-yl)-[1,8]naphthyridin-4(1H)-one-3-yl]- 1,3,4-Thiadiazol-5-yl}-3-[6-fluoro-7-(4-methylpiperazin-1-yl)-8,1-(1,3-oxopropyl) -quinoline-4(1H)-ketone-3-yl]-urea (I-1), its chemical structural formula is:

[0034]

[0035] The preparation method of the bis-fluoroquinolone thiadizuron of the present embodiment is: get ofloxacin hydroxamic acid (1 ") 1.0g (2.7mmol) and suspend in 25mL acetonitrile, add carbonyldiimidazole (CDI) 0.79g (4.9mmol), stirring at normal temperature until the material dissolves. Then add N-methyl enoxacin C-3 thiadiazole amine IV intermediate 1.05g (2.7mmol), stir in a water bath at 55~60°C for 17 hours.Stand overnight, The resulting solid was collected by filtration and washed with acetonitrile. The crude product was recrystallized from a mixed solvent of DMF-ethanol to obtain a light yellow crystal (I-1), with a yield of 62%, m.p.212-214°C. 1 H NMR (400MHz, DMSO-d 6 )δ: 11.54 (brs, 1H, NH), 9.46 (s, 1H

[0037] (S)-1-{2-[1-ethyl-6-fluoro-7-(4-methylpiperazin-1-yl)-[1,8]naphthyridin-4(1H)-one-3 -yl]-1,3,4-thiadiazol-5-yl}-3-[6-fluoro-7-(4-methylpiperazin-1-yl)-8,1-(1,3- Oxygen propyl)-quinolin-4(1H)-ketone-3-yl]-urea (I-1), its chemical structural formula is:

[0038]

[0039] The preparation method of the bis-fluoroquinolone thiadizuron of this embodiment is: take levofloxacin hydroxamic acid (2″) 1.0g (2.7mmol) and suspend in 25mL acetonitrile, add carbonyldiimidazole (CDI) 0.70g (4.3mmol ), stirred at room temperature until the material was dissolved. Then, 1.05 g (2.7 mmol) of N-methyl enoxacin C-3 thiadiazole amine IV intermediate was added, and stirred in a water bath at 55-60° C. for 10 hours. Placed overnight, filtered to produce The solid was washed with acetonitrile. The crude product was recrystallized from ethanol to obtain a light yellow crystal (I-2), with a yield of 45%, m.p.223-225°C. 1 H NMR (400MHz, DMSO-d 6 )δ: 11.53 (brs, 1H, NH), 9.45 (s, 1H, NH), 9.26,

[0041] 1-{2-[1-Ethyl-6-fluoro-7-(4-methylpiperazin-1-yl)-[1,8]naphthyridin-4(1H)-one-3-yl]- 1,3,4-Thiadiazol-5-yl}-3-[6,7-difluoro-8,1-(1,3-oxopropyl)-quinolin-4(1H)-one-3 -Base]-urea (I-3), its chemical structural formula is:

[0042]

[0043] The preparation method of the bis-fluoroquinolone thiadiazole of the present embodiment is: take 1.0 g (3.4 mmol) of oxyfluorocarboxylic acid hydroxamic acid (3″) and suspend it in 25 mL of acetonitrile, add 0.82 g of carbonyldiimidazole (CDI) (5.1mmol), stirring at normal temperature until the material is dissolved. Then add N-methyl enoxacin C-3 thiadiazole amine IV intermediate 1.32g (3.4mmol), and stir in a water bath at 55~60°C for 20 hours. Place overnight, The resulting solid was collected by filtration and washed with acetonitrile. The crude product was recrystallized from a DMF-ethanol mixed solvent to obtain a light yellow crystal (I-3), with a yield of 67%, m.p.226-228°C. 1 H NMR (400MHz, DMSO-d 6 )δ: 11.53 (brs, 1H, NH),