Pyrrolidine pyrazolyl oxo-quinoline carboxylic acid compound
A compound and drug technology, applied in the field of tetrahydropyrrolopyrazolyl oxoquinoline carboxylic acid compounds and their preparation, can solve the problems of enhanced efflux system and decreased outer membrane permeability, and achieve strong activity Effect
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Embodiment 1
[0021] The preparation of embodiment 1,2-hydroxyethyl-3-aminotetrahydropyrrole [3,4-c] pyrazole hydrochloride (II)
[0022] Under nitrogen protection, a mixture of 1-tert-butoxycarbonyl-3-cyano-4-pyrrolidone (1.05g, 5.0mmol), 98% hydroxyethyl (0.42g, 5.5mmol) and ethanol (20ml) was stirred at room temperature for reaction 12h. After the reaction was complete, the solvent was evaporated to dryness, and the resulting residue was dissolved in ethyl acetate (20 ml), washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the concentrated residue was dissolved in methanol (10 ml), and dry HCl gas was passed through, followed by TLC until the reaction was complete. The precipitated solid was filtered and vacuum-dried to obtain 0.33 g of off-white solid (yield 27.4%). 1 H-NMR (400MHz, DMSO-d 6 )δ ppm : 3.64-3.67 (2H, m, pyrrolidine), 3.97-3.98 (2H, m, pyrrolidine), 4.08 (2H, br, N CH 2 CH 2 OH), 4.17 (2H, m, NCH 2 CH 2 OH), MS (ESI, m / z): ...
Embodiment 2
[0023] Example 2, 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate-O 3 , O 4 - Preparation of boron diacetate (III)
[0024] A mixture of boric acid (1.50 g, 24.2 mmol) and acetic anhydride (8 mL, 80.0 mmol) was heated to 110° C. and stirred for 1.5 h. The reaction temperature was lowered to 50-60°C, and 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxo-quinoline-3- Ethyl carboxylate (4.55g, 14.1mmol) was heated to 110°C, and the stirring was continued. The reaction progress was tracked by TLC, and the reaction was completed in 6 hours. Cool down to room temperature, slowly pour the reaction solution into well-stirred ice water (200mL), continue to stir for 0.5h and filter, wash the filter cake with water, rinse with an appropriate amount of ethanol, and dry to obtain a white powdery solid (5.21g , 90.1%). 1 H NMR (500MHz, CDCl 3 )δ ppm : 1.20-1.45 (4H, m, 2×cyclopropylCH 2 ), 2.03 (6H, s, 2×COCH 3 ), 4.40-4.42 (1H, m, cyclopropylCH), ...
Embodiment 3
[0025] Example 3, 1-cyclopropyl-6-fluoro-7-(2-hydroxyethyl-3-aminopyrazol[3,4-c]tetrahydropyrrolyl)-8-methoxy-1,4 -The preparation of dihydro-4-oxoquinoline-3-carboxylic acid (I)
[0026] Under nitrogen protection, a mixture of 2-hydroxyethyl-3-aminotetrahydropyrrole[3,4-c]pyrazole hydrochloride (0.36g, 1.5mmol), acetonitrile (10mL) and triethylamine (1.0mL) After stirring at room temperature for 10 min, add 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate-O 3 , O 4 -Boron diacetate (0.41g, 1.0mmol), continue to stir for 1h and then heat the reaction at 40°C. TLC traces the reaction progress, and the reaction is completed in 36h. After separation on a silica gel column under reduced pressure, it was evaporated to dryness under reduced pressure, and the resulting brownish-yellow solid was dissolved in 7% aqueous sodium hydroxide solution (10 mL), stirred at 40°C, followed by TLC, and the reaction was completed in 30 minutes. Cool down to room tem...
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