Name: 115550-35-1|9-Fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-3,7-dihydro-2H-[1,3,4]oxadiazino[6,5,4-ij]quinoline-6-carboxylic acid|98+%
Brand: Ambeed
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Yield	Reaction Conditions	Operation in experiment
		60.c Preparation of 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid via the fluoroborane intermediate (c) To a solution of the above borane intermediate (5 mg) in 95% ethanol (1 ml) was added triethylamine (3 μl). After heating under reflux for 4 hours, the reaction mixture was cooled to room temperature. The precipitate which separated out was collected by filtration to give 9-fluoro-3-methyl--10-(4-methyl-1-piperazinyl)-7-oxo-2,3 -dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine-6 -carboxylic acid, mp 268°-269° C. (dec.).
		61.c Preparation of 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid via the acetoxyborane intermediate (c) The above borane intermediate (5 mg) was suspended in acetone (0.1 ml) and added conc. HCl (2.5 μl). The reaction mixture was stirred at room temperature for 30 minutes and cooled in ice bath. The precipitate which separated out was collected by filtration and the precipitate was dissolved in 95% ethanol (0.1 ml). To the solution was added triethylamine (2 μl) and the mixture was refluxed for 1 hour. After the solution was cooled to room temperature, the precipitate which separated out was collected by filtration to give 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3 -dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine -6-carboxylic acid, mp 268°-269° C. (dec.).
		7 Step 7) Preparation of 9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[3,2,1-ij][4,1,2]benzoxadiazine-6-carboxylic acid (1) STR16 Step 7) Preparation of 9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[3,2,1-ij][4,1,2]benzoxadiazine-6-carboxylic acid (1) STR16 To the dark brown reaction mixture of step 6) containing 12 340 ml of 85% formic acid (ca. 7.5 mol) were added dropwise during 5 minutes without exceeding a temperature of 50° C. In the temperature range of 40°-50° C. 75.0 ml of aqueous 36.5% formaldehyde (ca. 1.0 mol) were added over 5 minutes and the resulting brown suspension was heated to 70° C. for 30 minutes, during which time gas evolution occurred. After cooling to 5°-10° C. 300 ml of 25% aqueous ammonia (ca. 4 mol) were added and the resulting black solution was stirred for 30 minutes. To this solution 9 g of activated charcoal were added and the resulting black suspension was stirred for 15 minutes and filtered through a glass fibre filter. The filtrate was extracted with 5 portions of 1000 ml, in total 5000 ml, of methylene chloride. The combined extracts were filtered through a glass fibre filter to remove small amounts of insoluble by-products, and the dark brown filtrate was evaporated in a rotary evaporator at 50° C./20 torr to dryness to yield 107.6 g of brown crystals. The crystals were taken up in 400 ml of ethanol and the resulting slurry was stirred for 1 hour at 0°-5° C., filtered, and the filter cake was washed with 100 ml of ethanol to yield after drying at 50° C./35 torr overnight 83.7 g of crude 1 as yellow crystals. This crude material was suspended in a mixture of 835 ml of ethanol, 415 ml of toluene and 415 ml of water (deionized) and heated to reflux. From the clear yellow solution formed 835 ml of solvent mixture was distilled off, whereby the temperature rose from 74°-78° C., and a yellow precipitate was formed.

2
[ 109-01-3 ]
[ 115551-41-2 ]
[ CAS Unavailable ]
[ 115550-35-1 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine	5 Preparation of 9-fluoro-3-methyl-10-(4-methyl-I-piperazinyl)-7-oxo-2,3-dihydro-7H-pvrido[3,2,1-ij}-1,3,4-benzoxadiazine-6-carboxylic acid EXAMPLE 5 Preparation of 9-fluoro-3-methyl-10-(4-methyl-I-piperazinyl)-7-oxo-2,3-dihydro-7H-pvrido[3,2,1-ij}-1,3,4-benzoxadiazine-6-carboxylic acid A mixture of 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro -7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine-6-carboxylic acid (30 mg) obtained in Example 1, N-methylpiperazine (47 μl) and dry pyridine (3 ml) was heated at 100°-110° C. for 9 bours under nitrogen atmosphere. Pyridine was removed under reduced pressure and the residue was recrystallized from methanol to give 23 mg of 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo -2,3-dihydro-7H-pyrido[3,2,1-ij]-1,3,4-benzoxadiazine -6-carboxylic acid, mp 268°-269° C. (dec.); MS m/z 362 (M+).

Reference： [1]Current Patent Assignee: PFIZER INC - US4801584, 1989, A

3
[ 158585-86-5 ]
[ 115550-35-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; formaldehyd; formic acid In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; water	Sythesis of 9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[3,2,1-ij][4,1,2]benzoxadiazine-6-carboxylic acid (1) STR10 Sythesis of 9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[3,2,1-ij][4,1,2]benzoxadiazine-6-carboxylic acid (1) STR10 In a 2 liter steel reactor equipped with a mechanical stirrer, a thermo-meter, a descending Liebig condenser and an inert gas supply 99.0 g of potassium hydroxide (ca. 1.5 mol) were dissolved under argon and with stirring in 1000 ml of water (deionized). After addition of 204.2 g of ethyl 6,8-difluoro-1,4-dihydro-1-(N-methylformamido)-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylate (36, 0.5 mol) the suspension was heated in an oil bath until dissolution was complete. From this solution an ethanol/water mixture was distilled until the b.p. remained constant for 15 min. After replacing the descending Liebig condenser by a reflux condenser a solution of 231.0 g of potassium hydroxide (ca. 3.5 mol) in 260 ml of water (deionized) was added at 90°-95° C. over a period of 10 min, and the reaction mixture was heated in an oil bath of 135° C. during 72 hrs to reflux (reaction temperature 104° C.). The dark brown solution was cooled to 40° C., diluted with 250 ml of water (deionized) and treated over a period of ca. 30 min with 340 ml of 85% formic acid (ca. 7.5 mol) without exceeding a temperature of 50° C. In the temperature range of 40°-45° C. 75,0 ml of aqueous 36.5% formaldehyde (ca. 1.0 mol) were added over 10 min. The pink suspension was heated to 70° C. and stirred at this temperature for 30 min. After cooling to 0°-5° C. and stirring at this temperature for 30 min the suspension was filtered with vigorous so suction, the filter cake was washed with 100 ml of water (deionized, precooled to ca. 5° C.) and vigorously sucked.
	Multi-step reaction with 4 steps 1.1: sulfuric acid / 2 h / 100 °C 2.1: sodium hydroxide / dichloromethane; ethanol; water / 1 h / 20 °C 3.1: tetramethyl ammoniumhydroxide / 3 h / 100 °C 3.2: 1 h / 70 °C 4.1: ammonia / water
	Multi-step reaction with 3 steps 1.1: sulfuric acid / 2 h / 100 °C 2.1: tetramethyl ammoniumhydroxide / 8 h / 100 °C 2.2: 22 - 70 °C 3.1: ammonia / water

Multi-step reaction with 5 steps 1.1: water; sulfuric acid / 2 h / 100 °C 1.2: pH 9 2.1: sodium hydroxide / dichloromethane; ethanol; water / 1 h / 20 °C 3.1: tetramethyl ammoniumhydroxide / 4 h / 100 °C 3.2: 20 °C 4.1: tetramethyl ammoniumhydroxide / 3 h / 100 °C 4.2: 1 h / 70 °C 5.1: ammonia / water

Reference： [1]Current Patent Assignee: ZOETIS INC. - US5892040, 1999, A
[2]Current Patent Assignee: KRKA DD NOVO MESTO - WO2011/61292, 2011, A1
[3]Current Patent Assignee: KRKA DD NOVO MESTO - WO2011/61292, 2011, A1
[4]Current Patent Assignee: KRKA DD NOVO MESTO - EP2332916, 2011, A2

4
[ 109-01-3 ]
[ 115550-35-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: triethylamine / 1-methyl-pyrrolidin-2-one / 3 h / 100 °C 2.1: sulfuric acid / 2 h / 100 °C 3.1: sodium hydroxide / dichloromethane; ethanol; water / 1 h / 20 °C 4.1: tetramethyl ammoniumhydroxide / 3 h / 100 °C 4.2: 1 h / 70 °C 5.1: ammonia / water
	Multi-step reaction with 4 steps 1.1: triethylamine / 1-methyl-pyrrolidin-2-one / 3 h / 100 °C 2.1: sulfuric acid / 2 h / 100 °C 3.1: tetramethyl ammoniumhydroxide / 8 h / 100 °C 3.2: 22 - 70 °C 4.1: ammonia / water
	Multi-step reaction with 4 steps 1.1: 1 h / 100 °C 2.1: sulfuric acid / 2 h / 100 °C 3.1: tetramethyl ammoniumhydroxide / 8 h / 100 °C 3.2: 22 - 70 °C 4.1: ammonia / water

	Multi-step reaction with 5 steps 1.1: 1 h / 100 °C 2.1: sulfuric acid / 2 h / 100 °C 3.1: sodium hydroxide / dichloromethane; ethanol; water / 1 h / 20 °C 4.1: tetramethyl ammoniumhydroxide / 3 h / 100 °C 4.2: 1 h / 70 °C 5.1: ammonia / water
	Multi-step reaction with 6 steps 1.1: 1,4-diaza-bicyclo[2.2.2]octane / 3 h / 100 °C 2.1: water; sulfuric acid / 2 h / 100 °C 2.2: pH 9 3.1: sodium hydroxide / dichloromethane; ethanol; water / 1 h / 20 °C 4.1: tetramethyl ammoniumhydroxide / 4 h / 100 °C 4.2: 20 °C 5.1: tetramethyl ammoniumhydroxide / 3 h / 100 °C 5.2: 1 h / 70 °C 6.1: ammonia / water
	Multi-step reaction with 6 steps 1.1: 1 h / 100 °C 2.1: water; sulfuric acid / 2 h / 100 °C 2.2: pH 9 3.1: sodium hydroxide / dichloromethane; ethanol; water / 1 h / 20 °C 4.1: tetramethyl ammoniumhydroxide / 4 h / 100 °C 4.2: 20 °C 5.1: tetramethyl ammoniumhydroxide / 3 h / 100 °C 5.2: 1 h / 70 °C 6.1: ammonia / water
	Multi-step reaction with 3 steps 1.1: 1,3,5-trimethyl-benzene / 6 h / Reflux 2.1: N-ethyl-N,N-diisopropylamine / toluene / 1 h / Inert atmosphere; Reflux 2.2: 48 h / 60 - 65 °C 3.1: 1 h / 75 °C 3.2: 0.5 h 3.3: 1 h
	Multi-step reaction with 3 steps 1.1: 5 h / 130 - 155 °C 2.1: N-ethyl-N,N-diisopropylamine / toluene / 1 h / Inert atmosphere; Reflux 2.2: 48 h / 60 - 65 °C 3.1: 1 h / 75 °C 3.2: 0.5 h 3.3: 1 h

Reference： [1]Current Patent Assignee: KRKA DD NOVO MESTO - WO2011/61292, 2011, A1
[2]Current Patent Assignee: KRKA DD NOVO MESTO - WO2011/61292, 2011, A1
[3]Current Patent Assignee: KRKA DD NOVO MESTO - WO2011/61292, 2011, A1
[4]Current Patent Assignee: KRKA DD NOVO MESTO - WO2011/61292, 2011, A1
[5]Current Patent Assignee: KRKA DD NOVO MESTO - EP2332916, 2011, A2
[6]Current Patent Assignee: KRKA DD NOVO MESTO - EP2332916, 2011, A2
[7]Current Patent Assignee: SOUTHEAST UNIVERSITY; WISDOM PHARMACEUTICAL - CN107383058, 2017, A
[8]Current Patent Assignee: SOUTHEAST UNIVERSITY; WISDOM PHARMACEUTICAL - CN107383058, 2017, A

Yield	Reaction Conditions	Operation in experiment
	In ethanol; water; toluene at 74 - 79℃;	11 Example 11 Crystallization from ethanol/toluene/water 2:1:18.4g of crude marbofloxacin was suspended in a mixture of 83 ml of ethanol, 41ml of toluene and 41 ml of water and heated to reflux. From the clear yellow solution formed 83 ml of solvent mixture was distilled off, whereby the temperature rose from 74 to about 79°C, and a yellow pre¬ cipitate was formed. The suspension was cooled to 20° - 25°C, stirred for 1 hour, filtered, and the filter cake was washed with 3 portions of 6 ml of ethanol to yield after drying in vacuum dryer the product in more than 95% yield .
	Stage #1: marbofloxacin With acetic acid In water Stage #2: With potassium hydroxide In water at 20℃; for 1h;	23 Example 23 Purification of Marbofloxacin; Marbofloxacin was dissolved in 20 parts by weight of water by addition of acetic acid. Marbofloxacin was completely dissolved at pH of 5.3. Active charcoal was added and the mixture was stirred overnight. The mixture was then filtered using activated charcoal filter. The pH of the filtrate was adjusted to 7.2 by use of KOH, the obtained suspension was stirred for 1 hour at room temperature and then the precipitated product was recovered. Marbofloxacin with a purity of 99,9% (HPLC area) was obtained. HPLC analysis was performed on a pentafluorophenyl propyl (PFP) column (type Luna PFP, 150 x 4.6mm, 3µm, Phenomenex, USA); detector: UV315 nm; flow rate: 0.8 ml/min; injection volume: 5 µl; mobile phase: A: 0.02M NaH2PO4xH2O+0,1% TEA, pH2.5; B: acetonitrile : methanol = 5:95 (v/v) ; gradient: 0'=10B, 25'=100B, 30'= 100B, 32'=10B. The HPLC chromatogram of marbofloxacin prior to purification is shown in Figure 1, the HPLC chromatogram after purification is shown in Figure 2. As evident from the chromatograms all products with retention time above 24min were successfully eliminated.

6
[ 100276-65-1 ]
[ 115550-35-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: sulfuric acid / acetonitrile / 21 h / 100 °C 2.1: triethylamine / ethanol / 19 h / 100 °C 3.1: sodium hydroxide / dichloromethane; ethanol; water / 1 h / 20 °C 4.1: tetramethyl ammoniumhydroxide / 3 h / 100 °C 4.2: 1 h / 70 °C 5.1: ammonia / water
	Multi-step reaction with 4 steps 1.1: triethylamine / 1-methyl-pyrrolidin-2-one / 3 h / 100 °C 2.1: sulfuric acid / 2 h / 100 °C 3.1: tetramethyl ammoniumhydroxide / 8 h / 100 °C 3.2: 22 - 70 °C 4.1: ammonia / water
	Multi-step reaction with 4 steps 1.1: sulfuric acid / acetonitrile / 21 h / 100 °C 2.1: triethylamine / ethanol / 19 h / 100 °C 3.1: tetramethyl ammoniumhydroxide / 8 h / 100 °C 3.2: 22 - 70 °C 4.1: ammonia / water

	Multi-step reaction with 4 steps 1.1: 1 h / 100 °C 2.1: sulfuric acid / 2 h / 100 °C 3.1: tetramethyl ammoniumhydroxide / 8 h / 100 °C 3.2: 22 - 70 °C 4.1: ammonia / water
	Multi-step reaction with 5 steps 1.1: triethylamine / 1-methyl-pyrrolidin-2-one / 3 h / 100 °C 2.1: sulfuric acid / 2 h / 100 °C 3.1: sodium hydroxide / dichloromethane; ethanol; water / 1 h / 20 °C 4.1: tetramethyl ammoniumhydroxide / 3 h / 100 °C 4.2: 1 h / 70 °C 5.1: ammonia / water
	Multi-step reaction with 5 steps 1.1: 1 h / 100 °C 2.1: sulfuric acid / 2 h / 100 °C 3.1: sodium hydroxide / dichloromethane; ethanol; water / 1 h / 20 °C 4.1: tetramethyl ammoniumhydroxide / 3 h / 100 °C 4.2: 1 h / 70 °C 5.1: ammonia / water
	Multi-step reaction with 6 steps 1.1: water; sulfuric acid / acetonitrile / 21 h / 100 °C 2.1: triethylamine / ethanol / 19 h / 100 °C 3.1: sodium hydroxide / dichloromethane; ethanol; water / 1 h / 20 °C 4.1: tetramethyl ammoniumhydroxide / 4 h / 100 °C 4.2: 20 °C 5.1: tetramethyl ammoniumhydroxide / 3 h / 100 °C 5.2: 1 h / 70 °C 6.1: ammonia / water
	Multi-step reaction with 6 steps 1.1: 1,4-diaza-bicyclo[2.2.2]octane / 3 h / 100 °C 2.1: water; sulfuric acid / 2 h / 100 °C 2.2: pH 9 3.1: sodium hydroxide / dichloromethane; ethanol; water / 1 h / 20 °C 4.1: tetramethyl ammoniumhydroxide / 4 h / 100 °C 4.2: 20 °C 5.1: tetramethyl ammoniumhydroxide / 3 h / 100 °C 5.2: 1 h / 70 °C 6.1: ammonia / water
	Multi-step reaction with 6 steps 1.1: 1 h / 100 °C 2.1: water; sulfuric acid / 2 h / 100 °C 2.2: pH 9 3.1: sodium hydroxide / dichloromethane; ethanol; water / 1 h / 20 °C 4.1: tetramethyl ammoniumhydroxide / 4 h / 100 °C 4.2: 20 °C 5.1: tetramethyl ammoniumhydroxide / 3 h / 100 °C 5.2: 1 h / 70 °C 6.1: ammonia / water

Reference： [1]Current Patent Assignee: KRKA DD NOVO MESTO - WO2011/61292, 2011, A1
[2]Current Patent Assignee: KRKA DD NOVO MESTO - WO2011/61292, 2011, A1
[3]Current Patent Assignee: KRKA DD NOVO MESTO - WO2011/61292, 2011, A1
[4]Current Patent Assignee: KRKA DD NOVO MESTO - WO2011/61292, 2011, A1
[5]Current Patent Assignee: KRKA DD NOVO MESTO - WO2011/61292, 2011, A1
[6]Current Patent Assignee: KRKA DD NOVO MESTO - WO2011/61292, 2011, A1
[7]Current Patent Assignee: KRKA DD NOVO MESTO - EP2332916, 2011, A2
[8]Current Patent Assignee: KRKA DD NOVO MESTO - EP2332916, 2011, A2
[9]Current Patent Assignee: KRKA DD NOVO MESTO - EP2332916, 2011, A2

7
[ 158585-87-6 ]
[ 115550-35-1 ]

Yield	Reaction Conditions	Operation in experiment
71%	With ammonia In water	6 Example 69-fluoro-3-methyl-10- (4-methylpiperazin-l -yl ) - '-oxo-3, 7-1.140g of 6 , 8-difluoro-1- (methylamino ) -7- ( 4-methyl- piperazin-l-yl ) -4-oxo-l, 4-dihydroquinoline-3-carboxylic acid (3.00mmol) was mixed with 2.72g of Me4NOH.5H20 ( 15. Olmmol ) and stirred at 100°C for 8 hours. Ammonium salt melts and dark brown oil is formed during the reac¬ tion. Reaction mixture was cooled to room temperature and 3.0 mL of HCOOH was added followed by addition of 0.5 mL of 37% aq. solution of HCHO (6.0mmol) and the flask was cooled on the water bath at 22 °C. Precipitate was immedi¬ ately formed. The flask was warmed to 70°C, during which precipitate was dissolved and stirred for 30 min (after stirring for at 70°C for 5min precipitate formed again) . Reaction flask was cooled to room temperature and 20mL of H20 was added to the reaction mixture and left in a re¬ frigerator for 16h. Precipitate was filtered under re¬ duced pressure and washed with cold ethanol (lOmL) . After drying 1.022g of greyish powder was obtained (75%) . with a purity of 97.11% (HPLC) .Crude reaction product was mixed with 0.9mL of 25% NH3 aqueous solution and crystallised in a mixture of 20mL of EtOH and 6mL CHCI3. 0.771g of yellow powder was obtained (71%) with a purity of 99.50% as determined by HPLC.
	With ammonia In water	6 Example 6 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-3,7-dihydro-2H-[1,3,4]oxadiazino[6,5,4-ij]quinoline-6-carboxylic acid; [Show Image] 1.140g of 6,8-difluoro-1-(methylamino)-7-(4-methyl-piperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (3.00mmol) was mixed with 2.72g of Me4NOH.5H2O (15.01mmol) and stirred at 100°C for 8 hours. Ammonium salt melts and dark brown oil is formed during the reaction. Reaction mixture was cooled to room temperature and 3.0 mL of HCOOH was added followed by addition of 0.5 mL of 37% aq. solution of HCHO (6.0mmol) and the flask was cooled on the water bath at 22°C. Precipitate was immediately formed. The flask was warmed to 70°C, during which precipitate was dissolved and stirred for 30 min (after stirring for at 70°C for 5min precipitate formed again). Reaction flask was cooled to room temperature and 20mL of H2O was added to the reaction mixture and left in a refrigerator for 16h. Precipitate was filtered under reduced pressure and washed with cold ethanol (10mL). After drying 1.022g of greyish powder was obtained (75%). with a purity of 97.11% (HPLC). Crude reaction product was mixed with 0.9mL of 25% NH3 aqueous solution and crystallised in a mixture of 20mL of EtOH and 6mL CHCl3. 0.771g of yellow powder was obtained (71%) with a purity of 99.50% as determined by HPLC.

Reference： [1]Current Patent Assignee: KRKA DD NOVO MESTO - WO2011/61292, 2011, A1 Location in patent: Page/Page column 32
[2]Current Patent Assignee: KRKA DD NOVO MESTO - EP2332916, 2011, A2 Location in patent: Page/Page column 18-19

8
[ 100276-37-7 ]
[ 115550-35-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sodium hydroxide / dichloromethane; ethanol; water / 1 h / 20 °C 2.1: tetramethyl ammoniumhydroxide / 3 h / 100 °C 2.2: 1 h / 70 °C 3.1: ammonia / water
	Multi-step reaction with 2 steps 1.1: tetramethyl ammoniumhydroxide / 8 h / 100 °C 1.2: 22 - 70 °C 2.1: ammonia / water
	Multi-step reaction with 4 steps 1.1: sodium hydroxide / dichloromethane; ethanol; water / 1 h / 20 °C 2.1: tetramethyl ammoniumhydroxide / 4 h / 100 °C 2.2: 20 °C 3.1: tetramethyl ammoniumhydroxide / 3 h / 100 °C 3.2: 1 h / 70 °C 4.1: ammonia / water

Reference： [1]Current Patent Assignee: KRKA DD NOVO MESTO - WO2011/61292, 2011, A1
[2]Current Patent Assignee: KRKA DD NOVO MESTO - WO2011/61292, 2011, A1
[3]Current Patent Assignee: KRKA DD NOVO MESTO - EP2332916, 2011, A2

9
[ CAS Unavailable ]
[ 115550-35-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: tetramethyl ammoniumhydroxide / 3 h / 100 °C 1.2: 1 h / 70 °C 2.1: ammonia / water
	Multi-step reaction with 3 steps 1.1: tetramethyl ammoniumhydroxide / 4 h / 100 °C 1.2: 20 °C 2.1: tetramethyl ammoniumhydroxide / 3 h / 100 °C 2.2: 1 h / 70 °C 3.1: ammonia / water

Reference： [1]Current Patent Assignee: KRKA DD NOVO MESTO - WO2011/61292, 2011, A1
[2]Current Patent Assignee: KRKA DD NOVO MESTO - EP2332916, 2011, A2

10
[ 100276-67-3 ]
[ 115550-35-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: triethylamine / ethanol / 19 h / 100 °C 2.1: sodium hydroxide / dichloromethane; ethanol; water / 1 h / 20 °C 3.1: tetramethyl ammoniumhydroxide / 3 h / 100 °C 3.2: 1 h / 70 °C 4.1: ammonia / water
	Multi-step reaction with 3 steps 1.1: triethylamine / ethanol / 19 h / 100 °C 2.1: tetramethyl ammoniumhydroxide / 8 h / 100 °C 2.2: 22 - 70 °C 3.1: ammonia / water
	Multi-step reaction with 5 steps 1.1: triethylamine / ethanol / 19 h / 100 °C 2.1: sodium hydroxide / dichloromethane; ethanol; water / 1 h / 20 °C 3.1: tetramethyl ammoniumhydroxide / 4 h / 100 °C 3.2: 20 °C 4.1: tetramethyl ammoniumhydroxide / 3 h / 100 °C 4.2: 1 h / 70 °C 5.1: ammonia / water

Reference： [1]Current Patent Assignee: KRKA DD NOVO MESTO - WO2011/61292, 2011, A1
[2]Current Patent Assignee: KRKA DD NOVO MESTO - WO2011/61292, 2011, A1
[3]Current Patent Assignee: KRKA DD NOVO MESTO - EP2332916, 2011, A2

11
[ 117380-92-4 ]
[ 115550-35-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: tetramethyl ammoniumhydroxide / 3 h / 100 °C 1.2: 1 h / 70 °C 2.1: ammonia / water

Reference： [1]Current Patent Assignee: KRKA DD NOVO MESTO - EP2332916, 2011, A2

12
[ 115550-35-1 ]
[ 1606995-33-8 ]

Yield	Reaction Conditions	Operation in experiment
85%	With calcium(II) nitrate tetrahydrate; triethylamine In ethanol; water at 60℃; for 3h;	3 Example 3 3 mmol of H-Marbo was dissolved in a mixed solvent of 80 mL of water / ethanol (wherethe volume ratio ofwater to ethanolwas 1: 1) to give a suspension; 3 mmol of triethylamine was added dropwise to amixture ofH-MarboIn the suspension, the solution gradually becomes clear.1 mmol of Ca (NO3)2· 4H2O was dissolved in 10 mL ofwater, and the mixture was added dropwise to the above aqueous solution, and the mixture was stirred at 60 ° C for 3 hours.After the completion of the reaction, the aqueous solution wasclear and no precipitate was precipitated.The reaction solution was concentrated by evaporation to about 20 mL under reduced pressure to remove most of the solvent,and then 100 mL of ethanol was added to precipitate the product,and the mixture was sufficiently cooled to precipitate a large amount of the precipitate.Filtered,the precipitate successively with a small amount of cold water, washed with ethanol, dried blower 40 deg.] C under normal pressure for 3 hours to give a fine whitecrystals, yield: 85%).

Reference： [1]Current Patent Assignee: GUANGXI NORMAL UNIVERSITY - CN103755730, 2016, B Location in patent: Paragraph 0033-0034

13
[ CAS Unavailable ]
[ 115550-35-1 ]
[ 1610600-70-8 ]

Yield	Reaction Conditions	Operation in experiment
85%	With triethylamine In water at 40℃; for 7h;	4 Example 4: Synthesis of Marbo-Eu (III) Chelate by Solution Method Take 4mmol of H-Marbo dissolved in 40mL of water, was suspended; take 4mmol of triethylamine dissolved in 20mL of water, added to the H-Marbo suspension, the solution becomes clear, indicating that Marbo has been transformed into salt form.Then, 1 mmol of Eu (NO3) 3 .6H2O was dissolved in 10 mL of water, added dropwise to the above aqueous solution, and mixed for reaction at 40 ° C for 7 hours.After the reaction was completed, a light yellow clear solution.The reaction mixture was concentrated to about 20 mL by evaporation under reduced pressure to remove most of the solvent. Then, 200 mL of ethanol was added to precipitate the product, which was sufficiently cooled to precipitate a large amount of light yellow precipitate.The precipitate was filtered, washed with cold water, ethanol and dried in vacuo to give a pale yellow solid.The product by infrared spectroscopy, EFIFTIR and X-ray single crystal diffraction analyzes were carried out to determine the target chelate [Eu (Marbo-3) (Marbo-H +)] (yield: 85%).

Reference： [1]Current Patent Assignee: GUANGXI NORMAL UNIVERSITY - CN103804393, 2017, B Location in patent: Paragraph 0039; 0040

14
[ CAS Unavailable ]
[ 115550-35-1 ]
[ 1610600-71-9 ]

Yield	Reaction Conditions	Operation in experiment
75%	With triethylamine In ethanol; water at 50℃; for 5h;	5 Example 5: Synthesis of Marbo-Lu (III) Chelate by Solution Method Take 4mmol of H-Marbo dissolved in 80mL of ethanol, was suspended; take 4mmol of triethylamine dissolved in 10mL of water, added to the H-Marbo suspension, the solution gradually becomes clear, indicating that Marbo has been transformed into Salt form.Then, 1 mmol of Lu (NO3) 3 · H2O was dissolved in 10 mL of water, added dropwise to the above aqueous solution, and mixed and reacted at 50 ° C for 5 hours.After the reaction, a certain amount of precipitation, the reaction solution was light yellow.After the reaction solution was sufficiently cooled, a larger amount of a pale yellow precipitate precipitated.The precipitate was filtered, washed with cold water, ethanol and dried in vacuo to give a light yellow solid.The product was characterized by IR, electrospray ionization mass spectrometry and single crystal X-ray diffraction analysis, and was identified as the target chelate[LuIII (Marbo) 3 (Marbo-H +)] (yield: 75%).

Reference： [1]Current Patent Assignee: GUANGXI NORMAL UNIVERSITY - CN103804393, 2017, B Location in patent: Paragraph 0041; 0042

15
[ CAS Unavailable ]
[ 115550-35-1 ]
[ 1610600-72-0 ]

Yield	Reaction Conditions	Operation in experiment
80%	With triethylamine In water at 60℃; for 3h;	6 Example 6: Synthesis of Marbo-Tb (III) Chelate by Solution Method Take 4 mmol of H-Marbo dissolved in 10 mL of water as a suspension; take 4 mmol of triethylamine and add dropwise to the suspension of H-Marbo and the solution gradually becomes clear, indicating that Marbo has been converted to salt form.Then, 1 mmol of Tb (NO3) 3 .6H2O was dissolved in 10 mL of water, added dropwise to the above aqueous solution, and mixed and reacted at 60°C for 3 hours. After the reaction was completed, a light yellow clear solution. The reaction solution was concentrated to about 20 mL by evaporation under reduced pressure to remove most of the solvent, and then the product was precipitated by mixing with 150 mL of ethanol. After cooling sufficiently, a large amount of light yellow precipitate was precipitated.The precipitate was filtered, washed with cold water, ethanol and dried in vacuo to give a light yellow solid.The structure was determined by FTIR, ESI-MS and X-ray single crystal diffraction analysis, and identified as the target chelate[TbIII (Marbo-3) (Marbo-H +)] (yield: 80%).

Reference： [1]Current Patent Assignee: GUANGXI NORMAL UNIVERSITY - CN103804393, 2017, B Location in patent: Paragraph 0043; 0044

16
[ CAS Unavailable ]
[ 115550-35-1 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
70%	In water at 30℃; for 7h;	7 Example 7: Synthesis of Marbo-Dy (III) Chelate by Solution Method Take 4mmol of H-Marbo dissolved in 100mL of water, was suspended; take 4mmol of triethylamine dissolved in 10mL of water, added to the H-Marbo suspension, the solution gradually becomes clear, indicating that Marbo has been transformed into salt form.Then, 1 mmol of Dy (NO3) 3.6H2O was dissolved in 10 mL of water, added dropwise to the above aqueous solution, and mixed for reaction at 30 ° C for 7 hours. After the reaction was completed, it was light yellow and transparentSolution.The reaction solution was concentrated to about 20 mL by evaporation under reduced pressure to remove most of the solvent, and then 100 mL ethanol was added to mix to precipitate the product. After cooling sufficiently, a large amount of light yellow precipitate precipitated.The precipitate was filtered, washed with cold water, ethanol and dried in vacuo to give a light yellow solid.The structure was determined by IR, electrospray ionization mass spectrometry and X-ray single crystal diffraction analysis, and identified as the target chelate[Dy III (Marbo 3 (Marbo-H +)] (yield: 70%).

Reference： [1]Current Patent Assignee: GUANGXI NORMAL UNIVERSITY - CN103804393, 2017, B Location in patent: Paragraph 0045; 0046

17
[ CAS Unavailable ]
[ 115550-35-1 ]
[ 1610600-74-2 ]

Yield	Reaction Conditions	Operation in experiment
90%	With triethylamine In water at 70℃; for 1h;	8 Example 8: Synthesis of Marbo-Yb (III) Chelate by Solution Method Take 4mmol of H-Marbo dissolved in 50mL of water, was suspended; take 4mmol of triethylamine dissolved in 10mL of water, added to the H-Marbo suspension, the solution gradually becomes clear, indicating that Marbo has been transformed into salt form.Then 1 mmol of Yb (NO3) 3 .6H2O was dissolved in 10 mL of water, added dropwise to the above aqueous solution, and mixed and reacted at 70°C for 1 hour. After the reaction was completed, it was light yellow and transparentSolution.The reaction mixture was concentrated to about 20 mL by evaporation under reduced pressure to remove most of the solvent. Then, 200 mL of ethanol was added to precipitate the product, which was sufficiently cooled to precipitate a large amount of light yellow precipitate.The precipitate was filtered, washed with cold water, ethanol and dried in vacuo to give a light yellow solid. The product by infrared spectroscopy, EFIFTIR and X-ray single crystal diffraction analysis were carried out to determine the target chelate[Yb III (Marbo) 3 (Marbo-H +)] (yield: 90%).

Reference： [1]Current Patent Assignee: GUANGXI NORMAL UNIVERSITY - CN103804393, 2017, B Location in patent: Paragraph 0047; 0048

18
[ CAS Unavailable ]
[ 115550-35-1 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
78%	With triethylamine In water at 60℃; for 6h;	9 Example 9: Synthesis of Marbo-Y (III) Chelate by Solution Method Take 4mmol of H-Marbo dissolved in 50mL of water, was suspended; take 4mmol of triethylamine dissolved in 10mL of water, added to the H-Marbo suspension, the solution gradually becomes clear, indicating that Marbo has been transformed into salt form.Then, 1 mmol of Y (NO3) 3 .6H2O was dissolved in 10 mL of water, added dropwise to the above aqueous solution, and mixed and reacted at 60°C for 6 hours. After the reaction was completed, it was light yellow and transparentSolution.The reaction mixture was concentrated to about 20 mL by evaporation under reduced pressure to remove most of the solvent. Then, 200 mL of ethanol was added to precipitate the product, which was sufficiently cooled to precipitate a large amount of light yellow precipitate. The precipitate was filtered, washed with cold water, ethanol and dried in vacuo to give a light yellow solid.The structure was determined by IR, electrospray ionization mass spectrometry and X-ray single crystal diffraction analysis, and identified as the target chelate[Marcel 3 (Marbo-H +)] (yield: 78%).

Reference： [1]Current Patent Assignee: GUANGXI NORMAL UNIVERSITY - CN103804393, 2017, B Location in patent: Paragraph 0049; 0050

19
[ CAS Unavailable ]
[ 115550-35-1 ]
[ 1610600-76-4 ]

Yield	Reaction Conditions	Operation in experiment
85%	With triethylamine In methanol; water at 70℃; for 1h;	10 Example 10: Synthesis of Marbo-Ho (III) Chelate by Solution Method Take 4mmol of H-Marbo dissolved in 80mL of methanol, was suspended; take 4mmol of triethylamine dissolved in 10mL of water, added to the H-Marbo suspension, the solution gradually becomes clear, indicating that Marbo has been transformed into Salt form.Then, 1 mmol of Ho (NO3) 3 .6H2O was dissolved in 10 mL of water, added dropwise to the above aqueous solution, and mixed and reacted at 70°C for 1 hour. After the reaction was completed, it was light yellow and transparentSolution.The reaction mixture was concentrated to about 20 mL by evaporation under reduced pressure to remove most of the solvent. Then, 200 mL of ethanol was added to precipitate the product, which was sufficiently cooled to precipitate a large amount of light yellow precipitate. The precipitate was filtered, washed with cold water, ethanol and dried in vacuo to give a light yellow solid.The structure was determined by IR, electrospray ionization mass spectrometry and X-ray single crystal diffraction analysis, and identified as the target chelate[Ho III (Marbo-3) (Marbo-H +)] (yield: 85%).

Reference： [1]Current Patent Assignee: GUANGXI NORMAL UNIVERSITY - CN103804393, 2017, B Location in patent: Paragraph 0051; 0052

20
[ CAS Unavailable ]
[ 115550-35-1 ]
[ 1610600-77-5 ]

Yield	Reaction Conditions	Operation in experiment
72%	With triethylamine In water at 55℃; for 6h;	11 Example 11: Synthesis of Marbo-Gd (III) Chelate by Solution Method Take 4mmol of H-Marbo dissolved in 50mL of water, was suspended; take 4mmol of triethylamine dissolved in 10mL of water, added to the H-Marbo suspension, the solution gradually becomes clear, indicating that Marbo has been transformed into salt form.Then, 1 mmol of Gd (NO3) 3 .6H2O was dissolved in 10 mL of water, added dropwise to the above aqueous solution, and mixed for reaction at 55 ° C for 6 hours. After the reaction was completed, it was light yellow and transparentSolution.The reaction mixture was concentrated to about 20 mL by evaporation under reduced pressure to remove most of the solvent. Then, 200 mL of ethanol was added to precipitate the product, which was sufficiently cooled to precipitate a large amount of light yellow precipitate.The precipitate was filtered, washed with cold water, ethanol and dried in vacuo to give a light yellow solid. The product by infrared spectroscopy, EFIFTIR and X-ray single crystal diffraction analysis were carried out to determine the target chelate[GdIII (Marbo) 3 (Marbo-H +)] (yield: 72%).

Reference： [1]Current Patent Assignee: GUANGXI NORMAL UNIVERSITY - CN103804393, 2017, B Location in patent: Paragraph 0053; 0054

21
[ CAS Unavailable ]
[ 115550-35-1 ]
[ 1610600-78-6 ]

Yield	Reaction Conditions	Operation in experiment
85%	With triethylamine In water at 45℃; for 7h;	12 Example 12: Synthesis of Marbo-Tm (III) Chelate by Solution Method Take 4mmol of H-Marbo dissolved in 50mL of water, was suspended; take 4mmol of triethylamine dissolved in 10mL of water, added to the H-Marbo suspension, the solution gradually becomes clear, indicating that Marbo has been transformed into salt form.Then, 1 mmol of Tm (NO3) 3 .6H2O was dissolved in 10 mL of water, added dropwise to the above aqueous solution, and mixed and reacted at 45°C for 7 hours. After the reaction was completed, it was light yellow and transparentSolution.The reaction mixture was concentrated to about 20 mL by evaporation under reduced pressure to remove most of the solvent. Then, 200 mL of ethanol was added to precipitate the product, which was sufficiently cooled to precipitate a large amount of light yellow precipitate.The precipitate was filtered, washed with cold water, ethanol and dried in vacuo to give a light yellow solid. The product by infrared spectroscopy, EFIFTIR and X-ray single crystal diffraction analysis were carried out to determine the target chelate[TmIII (Marbo) 3 (Marbo-H +)] (yield: 85%).

Reference： [1]Current Patent Assignee: GUANGXI NORMAL UNIVERSITY - CN103804393, 2017, B Location in patent: Paragraph 0055; 0056

22
[ CAS Unavailable ]
[ 115550-35-1 ]
[ 1610600-67-3 ]

Yield	Reaction Conditions	Operation in experiment
85%	With triethylamine In methanol; water at 60℃; for 2h;	1 Example 1: Synthesis of Marbo-Er (III) Chelate by Solution Method Take 4mmol of H-Marbo dissolved in 50mL of methanol, was suspended; take 4mmol of triethylamine dissolved in 10mL of water, added to the H-Marbo suspension, the solution gradually becomes clear, indicating that Marbo has been transformed into Salt form.Then, 1 mmol of Er (NO3) 3 · 5H2O was dissolved in 10 mL of water, added dropwise to the above solution, and mixed and reacted at 60 ° C for 2 hours. After the reaction, as a light yellow solution, a certain amount of precipitation generated.The reaction solution was concentrated to about 20 mL by evaporation under reduced pressure to remove most of the solvent, and then 100 mL of ethanol was added for mixing. After cooling sufficiently, a large amount of light yellow precipitate precipitated.The precipitate was filtered, washed with cold water, ethanol and dried in vacuo to give a pale yellow solid.Products by infrared spectroscopy, electricitySpray mass spectrometry and single crystal X-ray diffraction analysis of the structure determination, identified as the target chelate[ErIII (Marbo) 3 (Marbo-H +)] (yield: 85%).

Reference： [1]Current Patent Assignee: GUANGXI NORMAL UNIVERSITY - CN103804393, 2017, B Location in patent: Paragraph 0033; 0034

23
[ CAS Unavailable ]
[ 115550-35-1 ]
[ 1610600-68-4 ]

Yield	Reaction Conditions	Operation in experiment
80%	With triethylamine In water at 20℃; for 12h;	2 Example 2: Synthesis of Marbo-Nd (III) Chelate by Solution Method Take 4mmol of H-Marbo dissolved in 160mL of water, was suspended; take 4mmol of triethylamine dissolved in 20mL of water, added to the H-Marbo suspension, the solution becomes clear, indicating that Marbo has been transformed into salt form.Then, 1 mmol of NdCl3 · 6H2O was dissolved in 20 mL of water, added dropwise to the above aqueous solution, and mixed and reacted for 12 hours at room temperature.After the reaction, the aqueous solution is clear.The reaction mixture was concentrated to about 20 mL by evaporation under reduced pressure to remove most of the solvent, and then 200 mL of ethanol was added to precipitate the product. After cooling sufficiently, a large amount of light green precipitate was precipitated.The precipitate was filtered, washed with cold water, ethanol and dried in vacuo to give a pale green solid.The structure was determined by IR, electrospray ionization mass spectrometry and X-ray single crystal diffraction analysis, and identified as the target chelate[Nd (Marbo) 3 (Marbo-H +)] (yield: 80%).

Reference： [1]Current Patent Assignee: GUANGXI NORMAL UNIVERSITY - CN103804393, 2017, B Location in patent: Paragraph 0035; 0036

24
[ CAS Unavailable ]
[ 115550-35-1 ]
[ 1610600-69-5 ]

Yield	Reaction Conditions	Operation in experiment
90%	With triethylamine In ethanol; water at 20℃; for 10h;	3 Example 3: Synthesis of Marbo-La (III) Chelate by Solution Method Take 4mmol of H-Marbo dissolved in 50mL water / ethanol mixed solvent (in which the volume ratio of water to ethanol is 3: 1), as a suspension; take 4mmol of triethylamine, was added dropwise to H-Marbo In the suspension, the solution gradually became clear, indicating that Marbo has been converted to a salt form.Then 1mmol of LaCl3 · 6H2O was dissolved in 20mL of water, added dropwise to the above aqueous solution, the reaction mixture at room temperature 10hour. After the reaction, a large amount of white precipitate formed.Filtration, precipitation successively with cold water, ethanol washDistilled in vacuo to give a white solid.The product was characterized by infrared spectroscopy, electrospray ionization mass spectrometry and X-ray single crystalThe diffraction analysis was conducted to determine the structure as a target chelate [Mar III 3 (Marbo-H +)] (yield: 90%).

Reference： [1]Current Patent Assignee: GUANGXI NORMAL UNIVERSITY - CN103804393, 2017, B Location in patent: Paragraph 0037; 0038

25
[ 50-00-0 ]
[ 64-18-6 ]
[ 2162920-12-7 ]
[ 115550-35-1 ]

Yield	Reaction Conditions	Operation in experiment
4.72 g	Stage #1: formaldehyd; formic acid; (6,8-difluoro-7-(4-methylpiperazin-1-yl)-4-oxo-3-(2,2,2-trichloroacetyl)quinolin-1(4H)-yl)carbamic acid tert-butyl ester at 75℃; for 1h; Stage #2: With ammonium hydroxide for 0.5h; Stage #3: With pyrographite for 1h;	7 Example 7: Preparation of Marbofloxacin A 100 mL reaction flask was charged with 1-amino-6-fluoro-8-hydroxy-7- (4-methylpiperazin-1-yl)4-dihydroquinoline-3-carboxylic acid (Formula VIII, 6.0 g), 85% formic acid (30 mL) and 36.5% aqueous formaldehyde (6.0 mL).After adding the system carefully and slowly heated to about 75 for 1 hour.Then the system was cooled to below 10 ,Carefully added 25% aqueous ammonia (25 mL)Stirred for 0.5 hours.Then add activated carbon (1g) to the system, stir for 1 hour and then filter,The filtrate was extracted twice with methylene chloride (2 × 100 mL).The combined organic phases are dried over anhydrous sodium sulphate, filtered and the organic phase is taken to high vacuumThe solvent was removed under reduced pressure to give the strobilurin (5.4 g).The crude product was added to H2O (50 mL)Slowly add formic acid to adjust pHTo 3.2 (pH meter test),Stand for 4 hours,filter,The filtrate was added dropwise aqueous sodium bicarbonate to adjust the pH to 6.2 (pH meter test),A large number of solid precipitation, ice salt bath cooling system to about 0 , stirring for 1 hour, filtered,After the product was dried ribendazole(4.72 g)

Reference： [1]Current Patent Assignee: SOUTHEAST UNIVERSITY; WISDOM PHARMACEUTICAL - CN107383058, 2017, A Location in patent: Paragraph 0026

26
[ 114214-66-3 ]
[ 115550-35-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: acetonitrile / 4 h / 88 °C 2.1: acetic acid; hydrogen bromide / 24 h / Reflux 3.1: 2.37 h / 45 - 60 °C 3.2: pH 9.3

Reference： [1]Current Patent Assignee: ZHEJIANG GUOBANG PHARMACEUTICAL - CN107522718, 2017, A

27
[ 50-00-0 ]
[ 117380-92-4 ]
[ 115550-35-1 ]

Yield	Reaction Conditions	Operation in experiment
75%	Stage #1: formaldehyd; 6-fluoro-8-hydroxy-1-(methylamino) 7-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid at 45 - 60℃; for 2.367h; Stage #2: With sodium carbonate In water	15 Example 15 Take the feed liquid of Example 13, and control the feed liquid temperature at 45°C.Add 37% formaldehyde 15.9g(0.1955 mol),Drip finish in 22 minutes.After the drop is warmed to 60°C,Stir and stir for 2 hours. Cool down to 2°C and incubate for 4 hours. Filter to obtain the wet product of the Malbofloxacin Hydrobromide.The obtained hydrobromide hydrobromide wet product, add water 200g, and then add sodium carbonate to adjust the alkali, after all the dissolved, the measured pH was 9.3, plus activated charcoal decolorization filtration, filtration was completed, and then use glacial acetic acid to reverse the pH =7.4. Transferred, cooled to 20 °C, filtered, rinsed with 20 g of ethanol,Depo-floxacin. The wet product was dried and weighed to obtain 18.1 g of product (calculated from compound 9, yield 75%, chromatographic content 99.9%).

Reference： [1]Current Patent Assignee: ZHEJIANG GUOBANG PHARMACEUTICAL - CN107522718, 2017, A Location in patent: Paragraph 0065; 0066; 0067; 0068; 0069; 0070; 0071-0073

28
[ 112811-66-2 ]
[ 115550-35-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: triethylamine / 1 h / 47 - 89 °C 2.1: sulfuric acid / methanol / 1.27 h / 0 - 58 °C 3.1: sodium carbonate / toluene / 4 h / 35 - 82 °C 4.1: acetonitrile / 4 h / 88 °C 5.1: acetic acid; hydrogen bromide / 24 h / Reflux 6.1: 2.37 h / 45 - 60 °C 6.2: pH 9.3

Reference： [1]Current Patent Assignee: ZHEJIANG GUOBANG PHARMACEUTICAL - CN107522718, 2017, A

29
[ CAS Unavailable ]
[ 115550-35-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: sulfuric acid / methanol / 1.27 h / 0 - 58 °C 2.1: sodium carbonate / toluene / 4 h / 35 - 82 °C 3.1: acetonitrile / 4 h / 88 °C 4.1: acetic acid; hydrogen bromide / 24 h / Reflux 5.1: 2.37 h / 45 - 60 °C 5.2: pH 9.3

Reference： [1]Current Patent Assignee: ZHEJIANG GUOBANG PHARMACEUTICAL - CN107522718, 2017, A

30
[ 2170897-32-0 ]
[ 115550-35-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: sodium carbonate / toluene / 4 h / 35 - 82 °C 2.1: acetonitrile / 4 h / 88 °C 3.1: acetic acid; hydrogen bromide / 24 h / Reflux 4.1: 2.37 h / 45 - 60 °C 4.2: pH 9.3

Reference： [1]Current Patent Assignee: ZHEJIANG GUOBANG PHARMACEUTICAL - CN107522718, 2017, A

31
[ 115550-35-1 ]
[ 1606995-33-8 ]

Yield	Reaction Conditions	Operation in experiment
85%	With calcium(II) nitrate tetrahydrate; triethylamine In methanol; water at 70℃; for 10h;	2.2.1. Synthesis of the Ca(II) complex of marbofloxacin, (MB-Ca) The complex was prepared by mixing Ca(NO3)3·4H2O (0.05 mmol) in water (12 mL) and marbofloxacin (0.10 mmol) in methanol (2 mL) in the ratio 1:2, along with the same equivalent of triethylamine (Et3N,0.10 mmol), to give a light yellow transparent solution. The reaction mixture was stirred and refluxed for 10 h at 70°C, and then it was stopped and cooled down to room temperature. The mixture was allowed to stand overnight to achieve white crystallites. They were filtered as the corresponding product, and washed twice by cold methanol-water (1:1) solvent. The product was dried in a vacuum dryer at r.t. (Yield: 85%). Then the filtrated colorless and transparent solution was continually kept for slow evaporation at room temperature, till the colorless bulk single crystals suitable for X-ray diffraction analysis were harvested after a week. IR (KBr, cm-1): 3429 ν(OeH), 2932 ν(AreH),2859 2806 ν(CeH), 1621 ν(C=O), 1590 νas(COO-), 1532 1462 ν(C=C), 1407 νs(COO-), 1291 ν(CeN), 1154 1052 1010 ν(CeH), 876,819 δ(CeH), 679 σ(CeH) (Fig. S1, ESI). Calc. for[CaC51H57F3N12O13]: C, 53.59; H, 5.03; N, 14.70. Found: C, 54.39; H,5.09; N, 14.86%. ESI-MS (+m/z) Calc.: 363.1469 [MB+H]+, 404.1734 [MB+H+CH3CN]+, 557.1217 [Ca(MB-H)+2DMSO]+,635.1356 [Ca(MB-H)+3DMSO]+, 725.2859 [2 MB+H]+. Found:363.1488 [MB+H]+, 404.0521 [MB+H+CH3CN]+, 557.1254 [Ca(MB-H)+2DMSO]+, 635.1394 [Ca(MB-H)+3DMSO]+,725.2906 [2 MB+H]+ (Fig. S2, ESI). UV-Vis (in aqueous solution at 35 °C): εmax=5.233×104 M-1·cm-1 (291 nm) (Fig. S3, ESI).

Reference： [1]Xie, Yan-Jie; Yu, Meng-Xin; Yang, Qi-Zhen; Liu, Yan-Cheng; Liu, Rui-Xue; Dong, Jia-Xin; Wu, Xiao-Ye; Guo, Rui-Feng; Pan, Yu-Xing; Chen, Zhen-Feng; Liang, Hong [Journal of Inorganic Biochemistry, 2020, vol. 203]

32
[ 115550-35-1 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
85%	With magnesium(II) nitrate hexahydrate; water; triethylamine In acetone at 80℃; for 72h;	2.2 Synthesis of MB-Mg MB (0.05mmol, 0.0181g) and Mg(NO3)2·6H2O (0.10mmol, 0.0256g) were added into a one-end closed thick Pyrex glass tube (25cm). 0.5mL acetone and 0.1mL H2O were added consequently. A few drops of triethylamine was further added to adjust the pH value of the reaction solution, and the mixture was then frozen by liquid nitrogen. Then the glass tube was sealed under the condition of vacuum by fusing its open end. Then the reactants inside were reacted in an oven at 80°C for 3days, and then slowly cooled down to room temperature. Colorless block crystals were then harvested in the glass tube (yield: 85%). IR (KBr cm-1): (-OH) 3356 (m), (Ar-H) 2836 (m), (-NH) 2927 (m), (OC=O) 1622 (vs), (C=O) 1593(vs), (C=C) 1539 1480 (s), (OC=O) 1388 (vs). ESI-MS m/z: 541.1428 [Mg(MB-H)+2DMSO]+, 619.1561 [Mg(MB-H)+3DMSO]+.

Reference： [1]Cui, He; Li, Hong-Chang; Liu, Li-Min; Liu, Yan-Cheng; Tang, Zi-Tian; Wu, Lin-Hua; Xu, Qing-Min [Inorganica Chimica Acta, 2021, vol. 516]

33
[ 50-00-0 ]
[ 64-18-6 ]
[ CAS Unavailable ]
[ CAS Unavailable ]
[ 115550-35-1 ]

Yield	Reaction Conditions	Operation in experiment
218 g	Stage #1: formaldehyd; formic acid; C₁₆H₁₈FN₄O₄^(1-)K⁽¹⁺⁾ at 65℃; Stage #2: C₁₇H₁₈FN₄O₄^(1-)K⁽¹⁺⁾*2CH₂O₂ With water; potassium hydroxide In dichloromethane	9 Embodiment 9: Preparation of Marbofloxacin Add 240g of the compound represented by formula (I), 150g of N-methylpiperazine, and 88g of granular sodium hydroxide to the autoclave, and start stirring the hot water to raise the temperature.The inner temperature was 125°C and the reaction was incubated for 80 minutes.After the heat preservation is completed, recover under reduced pressure to obtain the compound shown in formula (II), then add 125 g of potassium hydroxide and 550 g of tri-n-propylamine, and turn on the stirring oil bath to raise the temperature.The inner temperature was 150°C and the reaction was kept for 4 hours.After the heat preservation is completed, add the water layer, adjust the pH of the water layer to 5.0 with formic acid, then add 120g of formaldehyde solution dropwise, keep the temperature at 65°C for 1.5h, then lower the temperature to 0°C and keep it for 1h, filter and dry to obtain the compound shown in formula (IV) , add 150g of dichloromethane, 50g of alcohol, 100g of water, adjust the pH to 9-10 with potassium hydroxide, let stand and separate the layers, extract the water layer with 50g of dichloromethane, combine the dichloromethane layers, recover and dry to obtain the formula (V) shows 218g of the compound with a purity of 99.5%, namely marbofloxacin.

Reference： [1]Current Patent Assignee: ZHEJIANG GUOBANG PHARMACEUTICAL - CN115557966, 2023, A Location in patent: Paragraph 0048-0049

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	115550-35-1	MDL No. :	MFCD00864820
Formula :	C₁₇H₁₉FN₄O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BPFYOAJNDMUVBL-UHFFFAOYSA-N
M.W :	362.36	Pubchem ID :	60651
Synonyms :		Chemical Name :	9-Fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-3,7-dihydro-2H-[1,3,4]oxadiazino[6,5,4-ij]quinoline-6-carboxylic acid

Num. heavy atoms :	26
Num. arom. heavy atoms :	10
Fraction Csp3 :	0.41
Num. rotatable bonds :	2
Num. H-bond acceptors :	6.0
Num. H-bond donors :	1.0
Molar Refractivity :	103.84
TPSA :	78.25 Å²

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-8.86 cm/s

Log Po/w (iLOGP) :	2.15
Log Po/w (XLOGP3) :	-0.49
Log Po/w (WLOGP) :	-0.21
Log Po/w (MLOGP) :	1.45
Log Po/w (SILICOS-IT) :	0.36
Consensus Log Po/w :	0.65

[ CAS No. 115550-35-1 ] {[proInfo.proName]}

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[ 115550-35-1 ] Synthesis Path-Downstream 1~33

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Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Log S (ESOL) :	-1.93
Solubility :	4.25 mg/ml ; 0.0117 mol/l
Class :	Very soluble
Log S (Ali) :	-0.69
Solubility :	74.7 mg/ml ; 0.206 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.29
Solubility :	1.85 mg/ml ; 0.00509 mol/l
Class :	Soluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.37

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling