Name: 127294-70-6|1-Cyclopropyl-6-fluoro-8-methoxy-7-(3-(methylamino)piperidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid|98%
Brand: Ambeed
SKU: A105718
Price: 5.0 USD
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1
3-methylaminopiperidine dihydrochloride [ No CAS ]
(PhO)3 B [ No CAS ]
[ 112811-72-0 ]
1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-(3-methylaminopiperidin-1-yl)-3-quinolinecarboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.90 g (48.8%)	With sodium hydroxide; triethylamine; In acetonitrile;	Example 7 Synthesis of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-(3-methylaminopiperidin-1-yl)-3-quinolinecarboxylic acid using (PhO)3 B A mixture of 2.95 g of <strong>[112811-72-0]1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid</strong> (10 mmol), 3.75 g of 3-methylaminopiperidine 2HCl (20 mmol), 5.80 g of (PhO)3 B (20 mmol), 4.4 g of triethylamine (43 mmol) and 20 ml of acetonitrile was refluxed with heating for 6 hours. The reaction solution was cooled to room temperature, made acid with 6N--HCl and extracted with 10 ml of ethyl acetate twice. The pH of the water layer was adjusted to 8 to 9 with 25% NaOH, and separated crystals were filtered and dried to obtain 1.90 g (48.8%) of the objective compound.

Reference： [1]Patent: US5869661,1999,A

2
3-methylaminopiperidine dihydrochloride [ No CAS ]
[ 112811-72-0 ]
1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-(3-methylaminopiperidin-1-yl)-3-quinolinecarboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%		Example 3 1-Cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-7-(3-methylaminopiperidin-1-yl)-4-oxo-3-quinolinecarboxylic acid dihydrate An acetonitrile solution (30 mL) containing <strong>[112811-72-0]1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid</strong> (3 g), 3-methylaminopiperidine dihydrochloride (2.1 g), triethylamine (1.43 mL), and boron trifluoride-tetrahydrofuran complex (2.84 g) was stirred at room temperature for 2 hours. Triethylamine (5.71 mL) was further added to the reaction mixture, followed by stirring at room temperature for 24 hours. The solvent was evaporated under reduced pressure, and methanol (30 mL) was added to the residue. The mixture was refluxed for 6 hours, and the solvent was evaporated under reduced pressure. 80% Hydrated methanol (30 mL) was added to the residue, and the pH of the product was adjusted to 8 by use of 5N aqueous sodium hydroxide solution, followed by stirring at room temperature for 16 hours. The thus-produced crystals were recovered through filtration and dried, to thereby yield 3.98 g of the title compound (yield: 92%). 1H-NMR(400MHz,DMSO-d6) deltappm: 0.90-1.31(4H,m),1.31-2.12(4H,m),2.67-3.71(5H,m),3.77(3H,s),3.98-4.09(1H,m),7.85(1H,d,J=11.1Hz),8.78(1H,s) Elemental analysis: Calc. C;56.69%, H;6.62%, N;9.74% Obsd. C;56.48%, H;6.63%, N;9.86%
	With triethylamine; In acetonitrile;	EXAMPLE 13 A mixture of <strong>[112811-72-0]1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid</strong> (2.95 g), 3-methylaminopiperidine dihydrochloride (6.69 g) and triethylamine (10 g) in acetonitrile (50 ml) was refluxed with stirring for 12 hours. The reaction mixture was concentrated in vacuum, and the residue was extracted with chloroform. The extract was washed with a saturated NaCl solution and concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform:methanol:ammoniumhydroxide=15:5:1) to give 1.28 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methylaminopiperidin-1-yl)-4-oxoquinoline-3-carboxylic acid, which was recrystallized from acetonitrile-water, colorless needles. m.p. 134-135 C.

Reference： [1]Patent: EP2130827,2009,A1 .Location in patent: Page/Page column 12
[2]Patent: US5051509,1991,A

3
[ 1016680-64-0 ]
[ 127294-70-6 ]
[ 1236145-63-3 ]

Yield	Reaction Conditions	Operation in experiment
57%	With potassium carbonate In N,N-dimethyl-formamide at 40℃;

Reference： [1]Location in patent: experimental part Feng, Lian-Shun; Liu, Ming-Liang; Wang, Bo; Chai, Yun; Hao, Xue-Qin; Meng, Shuai; Guo, Hui-Yuan [European Journal of Medicinal Chemistry, 2010, vol. 45, # 8, p. 3407 - 3412]

4
[ 4290-78-2 ]
[ 127294-70-6 ]
[ 1236145-62-2 ]

Yield	Reaction Conditions	Operation in experiment
59%	With potassium carbonate In N,N-dimethyl-formamide at 40℃; for 27.5h;

Reference： [1]Location in patent: experimental part Feng, Lian-Shun; Liu, Ming-Liang; Wang, Bo; Chai, Yun; Hao, Xue-Qin; Meng, Shuai; Guo, Hui-Yuan [European Journal of Medicinal Chemistry, 2010, vol. 45, # 8, p. 3407 - 3412]

5
[ 16773-42-5 ]
[ 127294-70-6 ]
[ 1643323-92-5 ]

Yield	Reaction Conditions	Operation in experiment
91%	With potassium hydroxide In ethanol; water for 12h; Reflux;

Reference： [1]Li, Qing; Xing, Junhao; Cheng, Haibo; Wang, Hui; Wang, Jing; Wang, Shuai; Zhou, Jinpei; Zhang, Huibin [Chemical Biology and Drug Design, 2015, vol. 85, # 1, p. 79 - 90]

6
[ 166734-83-4 ]
[ 127294-70-6 ]
[ 1643323-96-9 ]

Yield	Reaction Conditions	Operation in experiment
68%	With potassium hydroxide In ethanol; water for 12h; Reflux;

Reference： [1]Li, Qing; Xing, Junhao; Cheng, Haibo; Wang, Hui; Wang, Jing; Wang, Shuai; Zhou, Jinpei; Zhang, Huibin [Chemical Biology and Drug Design, 2015, vol. 85, # 1, p. 79 - 90]

7
[ CAS Unavailable ]
[ 127294-70-6 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	With sodium dodecyl-sulfate In aq. buffer at 20℃; for 0.25h;

Reference： [1]Qi, Yu; Zhao, Fang; Xie, Xiaomei; Xu, Xiangqian; Ma, Zhenyu [Spectroscopy Letters, 2015, vol. 48, # 5, p. 311 - 316]

8
[ CAS Unavailable ]
[ 127294-70-6 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	With sodium dodecyl-sulfate In aq. buffer at 20℃; for 0.25h;

Reference： [1]Qi, Yu; Zhao, Fang; Xie, Xiaomei; Xu, Xiangqian; Ma, Zhenyu [Spectroscopy Letters, 2015, vol. 48, # 5, p. 311 - 316]

9
[ 127294-70-6 ]
[ 2216786-17-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium hydrogencarbonate / dichloromethane / 0.33 h / Cooling with ice 1.2: Cooling with ice 2.1: triethylamine / toluene 2.2: 110 - 120 °C

Reference： [1]Current Patent Assignee: SOUTHWEST UNIVERSITY - CN107827815, 2018, A

10
[ 98-97-5 ]
[ 4635-59-0 ]
[ 127294-70-6 ]
[ 2216786-18-2 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-(3-methylaminopiperidin-1-yl)-3-quinolinecarboxylic acid With sodium hydrogencarbonate In dichloromethane for 0.333333h; Cooling with ice; Stage #2: 4-Chlorobutanoyl chloride In dichloromethane Cooling with ice; Stage #3: 2-pyrazylcarboxylic acid Further stages;	21 Example 21 Add 1 mmol of banofloxacin and 2 mL of DCM to a 100 mL round bottom flask. Cooled in the ice bath, Magnetic stirring, Add 3mmol NaHCO3, After 20 minutes, A solution of 2.5 mmol of 4-chlorobutanoyl chloride in DCM (2 mL) was added dropwise with a constant pressure dropping funnel (drip acceleration of about 1d/2s). Continue to react under the ice bath. TLC was monitored until the end of the reaction. Stop stirring, Add 15 mL of H2O and 20 mL of DCM. Adjust pH=3-4 with 1N HCl solution with stirring. If there is a solid, it will stand still. Filtering, The filter cake was washed 3 times with DCM. The filter cake is left for further purification; The filtrate was transferred to a separatory funnel. Liquid separation, The aqueous phase was extracted with DCM (15 mL×1). Combine the organic phase, Wash with saturated NaCl solution (15 mL × 1), Collect organic phase, Dry with anhydrous Na2SO4. Rotary evaporator to spin dry to obtain a crude product. Column chromatography to obtain a pure product, Vacuum drying, An intermediate is obtained.1 mmol of the above intermediate was added to a 100 mL round bottom flask. 5mL toluene, 2mmol Et3N, Stir for 20-30min, Add 2mmol of pyrazinecarboxylic acid (POA), After 10 minutes, move to 110 ° C ~ 120 ° C oil bath to reflux reaction, TLC was monitored until the reaction was complete. The reaction solution was spun dry using a rotary evaporator rotary evaporator. Add 30mL DCM and stir to dissolve. Filtering, The filter cake was washed 3 times with DCM. The filtrate was washed with 10% citric acid solution (15 mL x 1). Collect organic phase, Dry with anhydrous Na2SO4. Rotary evaporator to spin dry to obtain a crude product. Column chromatography to obtain a pure product.

Reference： [1]Current Patent Assignee: SOUTHWEST UNIVERSITY - CN107827815, 2018, A Location in patent: Paragraph 0102-0104

11
[ 79-04-9 ]
[ 127294-70-6 ]
[ 2216786-08-0 ]

Yield	Reaction Conditions	Operation in experiment
88%	With triethylamine In N,N-dimethyl-formamide at 20℃; for 24h;	Synthesis of compound 2a-g General procedure: 0.32 g (1.0 eq, 1 mmol) 1a was dissolved in 10 mL waterfreeDMF, and 150 μL (1.5 eq, 1.5 mmol) TEA and 169 μL(2.2 eq, 2.2 mmol) chloroacetyl chloride were added insequence. The solution was stirred at room temperature for24 h, After the reaction completion detected by TLC, 30 mLof deionized water was added. After filtration, the filter cakewas washed with deionized water and dried overnight in thevacuum chamber, 0.27 g of the target compound 2a wasobtained in a yield of 73%.Compound 2b-g was synthesized in the same way ascompound 2a in yields of 70-88%.
88%	With triethylamine In N,N-dimethyl-formamide at 20℃; for 24h;	Synthesis of compound 2a-g General procedure: 0.32 g (1.0 eq, 1 mmol) 1a was dissolved in 10 mL waterfreeDMF, and 150 μL (1.5 eq, 1.5 mmol) TEA and 169 μL(2.2 eq, 2.2 mmol) chloroacetyl chloride were added insequence. The solution was stirred at room temperature for24 h, After the reaction completion detected by TLC, 30 mLof deionized water was added. After filtration, the filter cakewas washed with deionized water and dried overnight in thevacuum chamber, 0.27 g of the target compound 2a wasobtained in a yield of 73%.Compound 2b-g was synthesized in the same way ascompound 2a in yields of 70-88%.
73.12%	In N,N-dimethyl-formamide at 0 - 20℃; for 24.5h;	14 Example 14 Synthesis of triazole Balofloxacin Take 0.389g of Balofloxacin, placed in a round bottom flask, add 10 mL DMF at 0 °C, stirring reaction at a constant rate for 10 min, slowly add chloroacetyl chloride 153µL, stir at 0 °C for 30 min, stir at room temperature for another 24 h, into the reaction solution add 3 times the volume of water, a large amount of insoluble matter was formed, stirred for another 1 hour, and filtered, the filter cake was dried to obtain an intermediate of 0.34 g, yield 73.12%. Weigh 0.1 g of intermediate, dissolved in 10mL acetonitrile, again added 22mg of sodium triazole, the reaction was carried out at 50 ° C for 48 h, and the reaction solution was concentrated, silica gel column chromatography and obtained new quinolone compound 0.078g, yield 58.33% (Synthetic route is shown in Figure 17)

Stage #1: 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-(3-methylaminopiperidin-1-yl)-3-quinolinecarboxylic acid With Sodium hydrogenocarbonate In dichloromethane for 0.333333h; Cooling with ice; Stage #2: chloroacetyl chloride In dichloromethane Cooling with ice;

10 Example 10 Add 1 mmol of banofloxacin and 2 mL of DCM to a 100 mL round bottom flask. Cooled in the ice bath, Magnetic stirring, Add 3mmol NaHCO3, After 20 minutes, A 2.5 mmol solution of 2-chloroacetyl chloride in DCM (2 mL) was added dropwise with a constant pressure dropping funnel (drip acceleration was about 1 d / 2 s). Continue to react under the ice bath. TLC was monitored until the end of the reaction. Stop stirring, Add H2O15mL and DCM 20mL, Adjust pH=3-4 with 1N HCl solution with stirring. If there is a solid, it will stand still. Filtering, The filter cake was washed 3 times with DCM. The filter cake is left for further purification; The filtrate was transferred to a separatory funnel. Liquid separation, The aqueous phase was extracted with DCM (15 mL×1). Combine the organic phase, Wash with saturated NaCl solution (15 mL × 1), Collect organic phase, Dry with anhydrous Na2SO4. Rotary evaporator to spin dry to obtain a crude product. Column chromatography to obtain a pure product, Vacuum drying, Get the product.

Reference： [1]Li, Weitian; Hong, Ge; Mao, Lina; Xu, Zengping; Wang, Jiawen; Wang, Wenzhi; Liu, Tianjun [Medicinal Chemistry Research, 2022, vol. 31, # 5, p. 705 - 719]
[2]Li, Weitian; Hong, Ge; Mao, Lina; Xu, Zengping; Wang, Jiawen; Wang, Wenzhi; Liu, Tianjun [Medicinal Chemistry Research, 2022, vol. 31, # 5, p. 705 - 719]
[3]Current Patent Assignee: CHINESE ACADEMY OF MEDICAL SCIENCES - CN108864043, 2018, A Location in patent: Paragraph 0042; 0078; 0079
[4]Current Patent Assignee: SOUTHWEST UNIVERSITY - CN107827815, 2018, A Location in patent: Paragraph 0074; 0075

12
[ 638-29-9 ]
[ 127294-70-6 ]
[ 2278358-26-0 ]

Yield	Reaction Conditions	Operation in experiment
41.18%	With triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 24.5h;	6 Example 6 Synthesis of valeric balofloxacin Take 0.2 g of balofloxacin, place it in a round bottom flask, add 10 mL of DMF at 0 ° C, stir the reaction for 10 min at a constant rate, slowly add 100 μL of triethylamine and 122 μL of valeryl chloride, stir at 0 ° C for 30 min, stir at room temperature for another 24 h, and react to the reaction. was added 4 volumes of water, extracted with dichloromethane, washed with water three times and concentrated organic phase was washed with cold ether, and concentrated to give the novel quinolone compound 0.10g, yield of 41.18% (see Scheme 9)

Reference： [1]Current Patent Assignee: CHINESE ACADEMY OF MEDICAL SCIENCES - CN108864043, 2018, A Location in patent: Paragraph 0034; 0062; 0063

13
[ 142-61-0 ]
[ 127294-70-6 ]
[ 2278358-27-1 ]

Yield	Reaction Conditions	Operation in experiment
47.92%	With triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 24.5h;	7 Example 7 Synthesis of hexanoyl balofloxacin Take 0.2 g of balofloxacin, place it in a round bottom flask, add 10 mL of DMF at 0 ° C, stir the reaction for 10 min at a constant rate, slowly add 100 μL of triethylamine and 132 μL of hexanoyl chloride, stir at 0 ° C for 30 min, stir at room temperature for another 24 h, and then react to the reaction solution. 2 times by volume of water was added, extracted with dichloromethane, washed three times with water, and the organic phase was concentrated, washed with cold diethyl ether, and concentrated to precipitate a precipitated product to obtain a novel quinolone compound (0.12 g, yield 47.92% (see Figure 10 for the synthetic route)

Reference： [1]Current Patent Assignee: CHINESE ACADEMY OF MEDICAL SCIENCES - CN108864043, 2018, A Location in patent: Paragraph 0035; 0064; 0065

14
[ 2528-61-2 ]
1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-(3-methylaminopiperidin-1-yl)-3-quinolinecarboxylic acid [ No CAS ]
C₂₇H₃₆FN₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34.94%	With triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 24.5h;	8 Example 8 Synthesis of heptanoyl balofloxacin Take 0.2 g of balofloxacin, place it in a round bottom flask, add 10 mL of DMF at 0 ° C, stir the reaction for 10 min at a constant rate, slowly add 100 μL of triethylamine and 142 μL of heptanoyl chloride, stir at 0 ° C for 30 min, stir at room temperature for another 24 h, and react to the reaction, three times the volume of water was added to the solution, extracted with dichloromethane, washed three times with water, and the organic phase was concentrated, washed with cold diethyl ether, and then concentrated to precipitate, to give a novel quinolone compound, 0.09 g, yield 34.94% (see Figure 11 for the synthetic route)

Reference： [1]Current Patent Assignee: CHINESE ACADEMY OF MEDICAL SCIENCES - CN108864043, 2018, A Location in patent: Paragraph 0036; 0066; 0067

15
[ 111-64-8 ]
[ 127294-70-6 ]
[ 2278358-29-3 ]

Yield	Reaction Conditions	Operation in experiment
49.09%	With triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 24.5h;	9 Example 9 Synthesis of octanoyl balofloxacin Take 0.2 g of balofloxacin, place it in a round bottom flask, add 10 mL of DMF at 0 ° C, stir the reaction for 10 min at a constant rate, slowly add 100 μL of triethylamine and 159 μL of octanoyl chloride, stir at 0 ° C for 30 min, stir at room temperature for another 24 h, and react to the reaction. 4 times by volume of water was added to the solution, extracted with dichloromethane, washed with water three times, and the organic phase was concentrated, washed with cold diethyl ether, and concentrated to give a white quinolone compound (0.13 g) (yield: 49.09%)

Reference： [1]Current Patent Assignee: CHINESE ACADEMY OF MEDICAL SCIENCES - CN108864043, 2018, A Location in patent: Paragraph 0037; 0068; 0069

16
[ 764-85-2 ]
1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-(3-methylaminopiperidin-1-yl)-3-quinolinecarboxylic acid [ No CAS ]
C₂₉H₄₀FN₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55.15%	With triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 24.5h;	Take 0.2g balofloxacin, round-bottom flask, 0 added 10mL DMF, the reaction constant stirring 10min, and 100muL of triethylamine was slowly added dropwise 190 l of nonanoyl chloride, stirred for 30min 0 , at room temperature and then stirred for 24h, to the reaction 2 volumes of water were added to the solution, extracted with dichloromethane, washed three times with water, and the organic phase was concentrated, washed with cold diethyl ether, and concentrated to give 0.15 g of a novel quinolone compound, yield 55.15% (see Figure 13 for the synthetic route)

Reference： [1]Patent: CN108864043,2018,A .Location in patent: Paragraph 0038; 0070; 0071

17
[ 112-13-0 ]
[ 127294-70-6 ]
[ 2278358-31-7 ]

Yield	Reaction Conditions	Operation in experiment
42.98%	With triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 24.5h;	11 Example 11 Synthesis of decanoyl barofloxacin Take 0.2 g of balofloxacin, place in a round bottom flask, add 10 mL of DMF at 0 ° C, and stir the reaction for 10 min at a constant rate. Slowly add 100 μL of triethylamine and 205 μL of decanoyl chloride, stirrer at 0 ° C for 30 min, stir at room temperature for 24 h. Add 3 volumes of water to the reaction solution, extracted with dichloromethane, washed with water three times, the organic phase was washed with cold diethyl ether was concentrated, and concentrated to give the novel quinolone compound 0.12g, yield of 42.98% (see Scheme 14)

Reference： [1]Current Patent Assignee: CHINESE ACADEMY OF MEDICAL SCIENCES - CN108864043, 2018, A Location in patent: Paragraph 0039; 0072; 0073

18
[ 16130-58-8 ]
[ 127294-70-6 ]
[ 2278358-32-8 ]

Yield	Reaction Conditions	Operation in experiment
0.1 g	With triethylamine In N,N-dimethyl-formamide at 20℃; for 12h;	12 Example 12 Synthesis of cyanoparoxacin derivatives 1.1 g of cyanoacetic acid was dissolved in anhydrous dichloromethane, stirred at -10 ° C for 10 min, 1.04 mL of oxalyl chloride and a catalytic amount of DMF were slowly added. After completion of the reaction, the oxalyl chloride and the solvent were removed by a rotary evaporator, and the product was added to contain 0.389 g. Add 200 μL of triethylamine to the DMF solution of balofloxacin, react at room temperature for 12 h, add 4 volumes of water to the reaction solution, extract with dichloromethane, wash three times with water, concentrate the organic phase, wash with cold ether, concentrate and precipitate. Precipitation gave 0.1 g of a novel quinolone compound in a yield of 22.10% (see Figure 15 for the synthetic route)

Reference： [1]Current Patent Assignee: CHINESE ACADEMY OF MEDICAL SCIENCES - CN108864043, 2018, A Location in patent: Paragraph 0040; 0074; 0075

19
[ 1310878-66-0 ]
[ 127294-70-6 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide for 24h;	13 Example 13 Synthesis of alanine balofloxacin Take 0·15mg boc-alanine dissolved in 5mL DMF, stir for 5min, added triethylamine 232µL and ethyl chloroformate 151µL, stir the reaction for 30 min, again added 25 mL of DMF solution containing 0.2 g of Balofloxacin, stirring reaction for 24h, into the reaction solution added 2times volumes of water, extracted with dichloromethane, washed three times with water, concentrated organic phase, add 10 mL of trifluoroacetic acid and stir the reaction for 12 h, the trifluoroacetic acid was removed under reduced pressure, wash with diethyl ether, obtained 0.2 g of a new quinolone compound, yield 69.47% (Synthetic route is shown in Figure 16)

Reference： [1]Current Patent Assignee: CHINESE ACADEMY OF MEDICAL SCIENCES - CN108864043, 2018, A Location in patent: Paragraph 0041; 0076; 0077

20
[ 4023-34-1 ]
[ 127294-70-6 ]
[ 2278358-35-1 ]

Yield	Reaction Conditions	Operation in experiment
67.57%	With triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 24.5h;	15 Example 15 Synthesis of cyclopropionyl balofloxacin Take 0.2g of Balofloxacin, placed in a round bottom flask, add 10 mL DMF at 0 °C, stirring reaction at a constant rate for 10 min, slowly add triethylamine 108µL and cyclopropionyl chloride 120µL, stir at 0 °C for 30 min, stir at room temperature for another 24 h, into the reaction solution add 4 times the volume of water, extract with dichloromethane and wash three times with water, concentrated organic phase, washed with cold ether, concentrated and then precipitated, obtained a new quinolone compound 0.15g, yield 67.57% (Synthetic route is shown in Figure 18)

Reference： [1]Current Patent Assignee: CHINESE ACADEMY OF MEDICAL SCIENCES - CN108864043, 2018, A Location in patent: Paragraph 0043; 0080; 0081

21
[ 64-18-6 ]
[ 127294-70-6 ]
[ 2278358-24-8 ]

Yield	Reaction Conditions	Operation in experiment
33%	at 20 - 110℃; for 24.17h;	4 Example 4 Synthesis of formyl balofloxacin Take 0.2g of balofloxacin, place it in a round bottom flask, add 10mL of formic acid at room temperature, stir the reaction for 10min at a constant speed, heat and reflux at 110 °C, stir for 24h, add 2 volumes of water to the reaction solution, extract with dichloromethane, wash with water three times, the organic phase was concentrated washed with cold diethyl ether, and concentrated to give the novel quinolone compound 0.07g, 33% yield (see Scheme 7)

Reference： [1]Current Patent Assignee: CHINESE ACADEMY OF MEDICAL SCIENCES - CN108864043, 2018, A Location in patent: Paragraph 0032; 0058; 0059

22
[ 2278358-20-4 ]
[ 127294-70-6 ]
[ 2278358-36-2 ]

Yield	Reaction Conditions	Operation in experiment
0.2 g	In N,N-dimethyl-formamide for 24h;	16 Example 15 Synthesis of cyclopropionyl balofloxacin Take 0.2g of Balofloxacin, placed in a round bottom flask, add 10 mL DMF at 0 °C, stirring reaction at a constant rate for 10 min, slowly add triethylamine 108µL and cyclopropionyl chloride 120µL, stir at 0 °C for 30 min, stir at room temperature for another 24 h, into the reaction solution add 4 times the volume of water, extract with dichloromethane and wash three times with water, concentrated organic phase, washed with cold ether, concentrated and then precipitated, obtained a new quinolone compound 0.15g, yield 67.57% (Synthetic route is shown in Figure 18)

Reference： [1]Current Patent Assignee: CHINESE ACADEMY OF MEDICAL SCIENCES - CN108864043, 2018, A Location in patent: Paragraph 0044; 0082; 0083

23
[ 2719-27-9 ]
[ 127294-70-6 ]
[ 2278358-37-3 ]

Yield	Reaction Conditions	Operation in experiment
85.94%	With triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 24.5h;	17 Example 17 Synthesis of cyclohexanol acyl balofloxacin Take 0.2g of balofloxacin, placed in a round bottom flask, add 10 mL DMF at 0 °C, stirring reaction at a constant rate for 10 min, slowly add triethylamine 107µL and cyclohexanoyl chloride 150µL, stir at 0 °C for 30 min, stir at room temperature for another 24 h, into the reaction solution add 4 times the volume of water, extract with dichloromethane and wash three times with water, concentrated organic phase, washed with cold ether, concentrated, obtained a new quinolone compound 0.22g, yield 85.94% (Synthetic route is shown in Figure 20)

Reference： [1]Current Patent Assignee: CHINESE ACADEMY OF MEDICAL SCIENCES - CN108864043, 2018, A Location in patent: Paragraph 0045; 0084; 0085

24
[ 64531-95-9 ]
[ 127294-70-6 ]
[ 2278358-39-5 ]

Yield	Reaction Conditions	Operation in experiment
0.18 g	In N,N-dimethyl-formamide for 24h;	19 example 19 Synthesis of pyridine-3-formyl balofloxacin Take 0.1g pyridine-3-carboxylic acid dissolved in 5mL DMF, stir for 5 min, and added 261μL of triethylamine and 170μL of ethyl chloroformate, stir the reaction for 30 min, again added 20mL of DMF solution containing 0.2 g of Balofloxacin, stirring reaction for 24h, into the reaction solution add 3 times the volume of water, extract with dichloromethane and wash three times with water, concentrated organic phase, washed with cold diethyl ether, concentrated, obtained a new quinolone compound 0.18g, yield 58.06% (Synthetic route is shown in Figure 22)

Reference： [1]Current Patent Assignee: CHINESE ACADEMY OF MEDICAL SCIENCES - CN108864043, 2018, A Location in patent: Paragraph 0047; 0088; 0089

25
[ 50-00-0 ]
[ 127294-70-6 ]
[ 2245159-01-5 ]

Yield	Reaction Conditions	Operation in experiment
82.13%	Stage #1: 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-(3-methylaminopiperidin-1-yl)-3-quinolinecarboxylic acid With formic acid at 20℃; for 0.166667h; Stage #2: formaldehyd at 100℃; for 24h;	1 Example 1 Synthesis of methyl balofloxacin Take 0.2 g of balofloxacin, place it in a round bottom flask, add 10 mL of formic acid at room temperature, stir the reaction for 10 min at a constant speed, slowly add 200 μL of formaldehyde, heat and reflux at 100 ° C, stir for 24 h, add 2 volumes of water to the reaction solution. The mixture was extracted with dichloromethane, washed with water three times, and the organic phase was concentrated, washed with cold diethyl ether, and concentrated to precipitate a precipitated product to obtain a novel quinolone compound (0.17 g, yield: 82.13% (see Figure 1 for the synthetic route and Figure 2 for the characterization)

Reference： [1]Current Patent Assignee: CHINESE ACADEMY OF MEDICAL SCIENCES - CN108864043, 2018, A Location in patent: Paragraph 0026; 0052; 0053

26
[ CAS Unavailable ]
[ 127294-70-6 ]
[ 2278358-41-9 ]

Yield	Reaction Conditions	Operation in experiment
0.21 g	In N,N-dimethyl-formamide for 24h;	21 Example 21 Synthesis of 2-tetrahydrofuranformyl balofloxacin Take 0.1g 2-tetrahydrofuran formic acid in 5mL DMF, stir for 5 min, and added 252μL of triethylamine and 164μL of ethyl chloroformate, stir the reaction for 30 min, again added 20mL of DMF solution containing 0.2 g of Balofloxacin, stirring reaction for 24h, into the reaction solution add 2 times the volume of water, extract with dichloromethane and wash three times with water, concentrated organic phase, washed with cold diethyl ether, concentrated and then Precipitate, obtained a new quinolone compound 0.21g, yield 70.02% (Synthetic route is shown in Figure 24)

Reference： [1]Current Patent Assignee: CHINESE ACADEMY OF MEDICAL SCIENCES - CN108864043, 2018, A Location in patent: Paragraph 0049; 0092; 0093

27
[ 2278358-21-5 ]
[ 127294-70-6 ]
[ 2278358-42-0 ]

Yield	Reaction Conditions	Operation in experiment
0.21 g	In N,N-dimethyl-formamide for 24h;	22 Example 22 Synthesis of pyrrole-2-formyl balofloxacin Take 0.1g pyrrole formic acid in 5mL DMF, stir for 5 min, and added 125μL of triethylamine and 94μL of ethyl chloroformate, stir the reaction for 30 min, again added 20mL of DMF solution containing 0.25 g of Balofloxacin, stirring reaction for 24h, into the reaction solution add 4 times the volume of water, extract with dichloromethane and wash three times with water, concentrated organic phase, washed with cold diethyl ether, concentrated and then Precipitate, obtained a new quinolone compound 0.21g, yield 67.74% (Synthetic route is shown in Figure 25)

Reference： [1]Current Patent Assignee: CHINESE ACADEMY OF MEDICAL SCIENCES - CN108864043, 2018, A Location in patent: Paragraph 0050; 0094; 0095

28
[ 75-36-5 ]
[ 127294-70-6 ]
[ 2278358-22-6 ]

Yield	Reaction Conditions	Operation in experiment
67.57%	With triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 24.5h;	2 Example 2 Synthesis of acetyl baloxycin Take 0.2 g of balofloxacin, place it in a round bottom flask, add 10 mL of DMF at 0 ° C, stir the reaction for 10 min at a constant rate, slowly add 208 μL of triethylamine and 141 μL of acetyl chloride, stir at 0 ° C for 30 min, stir at room temperature for another 24 h, and react to the reaction. Add 3 volumes of water to the solution, extract with dichloromethane, wash three times with water, and concentrate the organic phase, After washing with cold diethyl ether, the precipitate was precipitated to obtain 0.15 g of a novel quinolone compound, the yield was 67.57% (the synthetic route is shown in Fig. 3, and the characterization map is shown in Fig. 4).

Reference： [1]Current Patent Assignee: CHINESE ACADEMY OF MEDICAL SCIENCES - CN108864043, 2018, A Location in patent: Paragraph 0028; 0054; 0055

29
[ 79-03-8 ]
[ 127294-70-6 ]
[ 2278358-23-7 ]

Yield	Reaction Conditions	Operation in experiment
61.14%	With triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 24.5h;	3 Example 3 Synthesis of propionyl balofloxacin Take 0.2 g of balofloxacin, place it in a round bottom flask, add 10 mL of DMF at 0 ° C, stir the reaction for 10 min at a constant rate, slowly add 190 μL of triethylamine and 90 μL of propionyl chloride, stir at 0 ° C for 30 min, stir at room temperature for another 24 h, and react to the reaction. 4 times volume of water was added to the solution, extracted with dichloromethane, washed three times with water, concentrated organic phase, washed with cold diethyl ether and concentrated to give a new quinolone compound 0.14 g, yield 61.14% (the synthetic route is shown in Fig. 5, the characterization map is shown in Fig. 6)

Reference： [1]Current Patent Assignee: CHINESE ACADEMY OF MEDICAL SCIENCES - CN108864043, 2018, A Location in patent: Paragraph 0030; 0056; 0057

30
[ 2417332-18-2 ]
[ 127294-70-6 ]
[ 2417332-10-4 ]

Yield	Reaction Conditions	Operation in experiment
89%	With triethylamine In 1,4-dioxane at 20℃; stereoselective reaction;

Reference： [1]Leng, Jing; Tang, Wenjian; Fang, Wan-Yin; Zhao, Chuang; Qin, Hua-Li [Organic Letters, 2020, vol. 22, # 11, p. 4316 - 4321]

31
[ CAS Unavailable ]
[ 127294-70-6 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide at 20℃;	General protocol for the preparation of compounds 5a-e General procedure: Compound 4 (28 mg, 0.025 mmol, 1 equiv) was mixed with 2 equiv of ciprofloxacin, pazufloxacin, garenoxacin, balofloxacin, or moxifloxacin in DMF (1 mL). The mixture was stirred at room temperature for 24 h, concentrated in vacuo and then purified on a silica gel column. Compounds were eluted with DCM/MeOH (20:1 to 2:1). Compounds 5a-e were obtained as dark blue solids with purities of ≥ 95%. The identity of each hybrid was verified by HRESIMS: 5a calcd m/z for C73H83FN5O23 (M + H+) 1416.5462, found m/z 1416.5485; 5b calcd m/z for C72H80FN4O24 (M + H+) 1403.5147, found m/z 1403.5152; 5c calcd m/z for C79H85F2N4O24 (M + H+) 1511.5522, found m/z 1511.5513; 5d calcd m/z for C76H89FN5O24 (M + H+) 1474.5882, found m/z 1474.5872. The lead compound from this set, 5c, was further characterized by NMR. 1H NMR (600 MHz, DMSO-d6): δ 8.91 (s, 1H), 8.37 (d, J = 8.3 Hz, 1H), 7.79 (d, J = 6.3 Hz, 1H), 7.67 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 6.84 (m, 1H), 6.72 (t, J = 72.6 Hz, 1H), 6.54 (m, 1H), 5.90 (d, J = 11.0 Hz, 1H), 5.85 (s, 1H), 5.56 (br s, 1H), 5.32 (m, 1H), 5.26 (m, 1H), 5.14 (br s, 1H), 5.10 (s, 1H), 4.94 (t, J = 10.3 Hz, 1H), 4.78 (s, 1H), 4.73 (m, 1H), 4.50 (d, J = 6.3 Hz, 1H), 4.16 (m, 1H), 4.06 (m, 1H), 3.62 (dd, J = 8.4 Hz, 5.0 Hz, 1H), 3.54 (m, 1H), 3.51 (s, 1H), 3.42 (m, 1H), 3.28 (m, 1H), 2.81 (t, J = 8.1 Hz, 1H), 2.38 (m, 1H), 2.33 (d, J = 16.2 Hz, 1H), 2.18 (m, 1H), 2.16 (s, 3H), 2.08 (s, 3H), 2.01 (m, 1H), 1.96 (m, 1H), 1.95 (s, 3H), 1.80 (m, 1H), 1.74 (m, 1H), 1.70 (s, 3H), 1.63 (m, 1H), 1.56 (d, J = 5.26 Hz, 3H), 1.25 (m, 2H), 1.19 (m, 2H), 1.17 (d, J = 6.1 Hz, 3H), 1.08 (s, 3H), 1.05 (s, 3H), 1.03 (d, J = 6.3 Hz, 3H), 0.85 (m, 3H), 0.82 (m, 3H), 0.57 (br s, 3H); 13C NMR (150 MHz, DMSO-d6): δ 192.3, 181.7, 177.1, 175.1, 173.8, 172.0, 171.0, 169.9, 169.8, 165.2, 156.1, 155.9, 153.5, 152.5, 144.1, 143.7, 142.3, 138.2, 137.1, 136.7, 135.6, 135.4, 131.2, 130.9, 129.7, 129.6, 128.9, 128.8, 128.7, 124.3, 122.8, 122.7, 117.2, 115.5, 113.8, 113.6, 111.3, 108.3, 106.2, 104.9, 96.8, 93.9, 77.4, 77.3, 74.8, 73.8, 72.2, 72.1, 69.8, 69.4, 68.1, 60.3, 51.7, 43.4, 42.1, 41.1, 32.4, 31.3, 25.3, 24.5, 22.1, 21.0, 20.9, 20.8, 18.4, 17.3, 12.5, 11.9, 11.1, 9.57, 7.53.
	In N,N-dimethyl-formamide at 20℃;	General protocol for the preparation of compounds 5a-e General procedure: Compound 4 (28 mg, 0.025 mmol, 1 equiv) was mixed with 2 equiv of ciprofloxacin, pazufloxacin, garenoxacin, balofloxacin, or moxifloxacin in DMF (1 mL). The mixture was stirred at room temperature for 24 h, concentrated in vacuo and then purified on a silica gel column. Compounds were eluted with DCM/MeOH (20:1 to 2:1). Compounds 5a-e were obtained as dark blue solids with purities of ≥ 95%. The identity of each hybrid was verified by HRESIMS: 5a calcd m/z for C73H83FN5O23 (M + H+) 1416.5462, found m/z 1416.5485; 5b calcd m/z for C72H80FN4O24 (M + H+) 1403.5147, found m/z 1403.5152; 5c calcd m/z for C79H85F2N4O24 (M + H+) 1511.5522, found m/z 1511.5513; 5d calcd m/z for C76H89FN5O24 (M + H+) 1474.5882, found m/z 1474.5872. The lead compound from this set, 5c, was further characterized by NMR. 1H NMR (600 MHz, DMSO-d6): δ 8.91 (s, 1H), 8.37 (d, J = 8.3 Hz, 1H), 7.79 (d, J = 6.3 Hz, 1H), 7.67 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 6.84 (m, 1H), 6.72 (t, J = 72.6 Hz, 1H), 6.54 (m, 1H), 5.90 (d, J = 11.0 Hz, 1H), 5.85 (s, 1H), 5.56 (br s, 1H), 5.32 (m, 1H), 5.26 (m, 1H), 5.14 (br s, 1H), 5.10 (s, 1H), 4.94 (t, J = 10.3 Hz, 1H), 4.78 (s, 1H), 4.73 (m, 1H), 4.50 (d, J = 6.3 Hz, 1H), 4.16 (m, 1H), 4.06 (m, 1H), 3.62 (dd, J = 8.4 Hz, 5.0 Hz, 1H), 3.54 (m, 1H), 3.51 (s, 1H), 3.42 (m, 1H), 3.28 (m, 1H), 2.81 (t, J = 8.1 Hz, 1H), 2.38 (m, 1H), 2.33 (d, J = 16.2 Hz, 1H), 2.18 (m, 1H), 2.16 (s, 3H), 2.08 (s, 3H), 2.01 (m, 1H), 1.96 (m, 1H), 1.95 (s, 3H), 1.80 (m, 1H), 1.74 (m, 1H), 1.70 (s, 3H), 1.63 (m, 1H), 1.56 (d, J = 5.26 Hz, 3H), 1.25 (m, 2H), 1.19 (m, 2H), 1.17 (d, J = 6.1 Hz, 3H), 1.08 (s, 3H), 1.05 (s, 3H), 1.03 (d, J = 6.3 Hz, 3H), 0.85 (m, 3H), 0.82 (m, 3H), 0.57 (br s, 3H); 13C NMR (150 MHz, DMSO-d6): δ 192.3, 181.7, 177.1, 175.1, 173.8, 172.0, 171.0, 169.9, 169.8, 165.2, 156.1, 155.9, 153.5, 152.5, 144.1, 143.7, 142.3, 138.2, 137.1, 136.7, 135.6, 135.4, 131.2, 130.9, 129.7, 129.6, 128.9, 128.8, 128.7, 124.3, 122.8, 122.7, 117.2, 115.5, 113.8, 113.6, 111.3, 108.3, 106.2, 104.9, 96.8, 93.9, 77.4, 77.3, 74.8, 73.8, 72.2, 72.1, 69.8, 69.4, 68.1, 60.3, 51.7, 43.4, 42.1, 41.1, 32.4, 31.3, 25.3, 24.5, 22.1, 21.0, 20.9, 20.8, 18.4, 17.3, 12.5, 11.9, 11.1, 9.57, 7.53.

Reference： [1]Peek, James; Koirala, Bimal; Brady, Sean F. [Bioorganic and Medicinal Chemistry Letters, 2022, vol. 57]
[2]Peek, James; Koirala, Bimal; Brady, Sean F. [Bioorganic and Medicinal Chemistry Letters, 2022, vol. 57]

32
[ CAS Unavailable ]
[ 127294-70-6 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; O-(7-azabenzotriazol-1-yl)-n,n,n',n'-tetramethyluronium hexafluoro-phosphate In N,N-dimethyl-formamide at 25℃; for 1h;	General protocol for the preparation of compounds 2a-i General procedure: Fluoroquinolones were purchased from Sigma. Compound 1 (3 mg, 1 equiv) was dissolved in 50 µL DMF. To this was added 2 equiv each of HATU, TEA, and finally a fluoroquinolone. Reactions were performed at 25 °C and allowed to proceed for 1 h with gentle agitation. The resultant hybrids 2a-i were purified by HPLC using a 10 mm x 150 mm C18 column (Waters) using the following method: 30-95% acetonitrile:water with 0.1% formic over 30 min at a flow rate of 3.5 mL/min. All hybrids were assayed for activity at purities of 95% or greater. The identity of each hybrid was verified by HRESIMS: 2a calcd m/z for C67H80FN4021 (M + H+) 1295.5299, found m/z 1295.5277; 2b calcd m/z for C66H77FN3O22 (M + H+) 1282.4983, found m/z 1282.4960; 2c calcd m/z for C73H82F2N3O22 (M + H+) 1390.5358, found m/z 1390.5289; 2d calcd m/z for C69H84FN4O22 (M + H+) 1339.5561, found m/z 1339.5537; 2e calcd m/z for C70H77F3N5O21 (M + H+) 1380.5063, found m/z 1380.5041; 2f calcd m/z for C70H86FN4O22 (M + H+) 1353.5718, found m/z 1353.5688; 2g calcd m/z for C69H83ClFN4O21 (M + H+) 1357.5222, found m/z 1357.5175; 2h calcd m/z for C68H82FN6O22 (M + H+) 1353.5466, found m/z 1353.5435; 2i calcd m/z for C71H86FN4O22 (M + H+) 1365.5718, found m/z 1365.5652.
	With triethylamine; O-(7-azabenzotriazol-1-yl)-n,n,n',n'-tetramethyluronium hexafluoro-phosphate In N,N-dimethyl-formamide at 25℃; for 1h;	General protocol for the preparation of compounds 2a-i General procedure: Fluoroquinolones were purchased from Sigma. Compound 1 (3 mg, 1 equiv) was dissolved in 50 µL DMF. To this was added 2 equiv each of HATU, TEA, and finally a fluoroquinolone. Reactions were performed at 25 °C and allowed to proceed for 1 h with gentle agitation. The resultant hybrids 2a-i were purified by HPLC using a 10 mm x 150 mm C18 column (Waters) using the following method: 30-95% acetonitrile:water with 0.1% formic over 30 min at a flow rate of 3.5 mL/min. All hybrids were assayed for activity at purities of 95% or greater. The identity of each hybrid was verified by HRESIMS: 2a calcd m/z for C67H80FN4021 (M + H+) 1295.5299, found m/z 1295.5277; 2b calcd m/z for C66H77FN3O22 (M + H+) 1282.4983, found m/z 1282.4960; 2c calcd m/z for C73H82F2N3O22 (M + H+) 1390.5358, found m/z 1390.5289; 2d calcd m/z for C69H84FN4O22 (M + H+) 1339.5561, found m/z 1339.5537; 2e calcd m/z for C70H77F3N5O21 (M + H+) 1380.5063, found m/z 1380.5041; 2f calcd m/z for C70H86FN4O22 (M + H+) 1353.5718, found m/z 1353.5688; 2g calcd m/z for C69H83ClFN4O21 (M + H+) 1357.5222, found m/z 1357.5175; 2h calcd m/z for C68H82FN6O22 (M + H+) 1353.5466, found m/z 1353.5435; 2i calcd m/z for C71H86FN4O22 (M + H+) 1365.5718, found m/z 1365.5652.

Reference： [1]Peek, James; Koirala, Bimal; Brady, Sean F. [Bioorganic and Medicinal Chemistry Letters, 2022, vol. 57]
[2]Peek, James; Koirala, Bimal; Brady, Sean F. [Bioorganic and Medicinal Chemistry Letters, 2022, vol. 57]

33
[ 127294-70-6 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide; water monomer / 50 °C 2: trifluoroacetic acid / dichloromethane / 2 h / 20 °C

Reference： [1]Peek, James; Koirala, Bimal; Brady, Sean F. [Bioorganic and Medicinal Chemistry Letters, 2022, vol. 57]

34
[ 83948-53-2 ]
[ 127294-70-6 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In water monomer; N,N-dimethyl-formamide at 50℃;	General protocol for the preparation of compounds 6a-e General procedure: Fluoroquinolone-linker conjugates were prepared as follows. To a stirred solution of K2CO3, (2 equiv) in DMF/H2O (1:1), a fluoroquinolone (1 equiv) was added, followed by N-Boc-3-bromopropylamine (2 equiv). The reaction mixture was stirred at 50 °C for 1-3 days, at which point it was concentrated in vacuo and then diluted in H2O (5 mL). The pH was adjusted to 4-5 using aqueous 2N HCl. The solution was then extracted in DCM (2 x 10 mL). The organic fractions were washed with brine (10 mL), dried over Na2SO4, filtered, and dried under vacuum to obtain a white residue. The residue was purified by silica gel column chromatography (DCM/MeOH, 9:1) to obtain a white solid. Removal of the Boc group was subsequently completed by dissolving the intermediate in TFA/DCM (1:1, 1 mL) and stirring at room temperature for 2 h. The solvent was removed under vacuum. The solution was then neutralized with addition of 1 mL TEA followed by concentration in vacuo. Each fluoroquinolone-linker conjugate was obtained as a white solid and used directly in the synthesis of compounds 6a-e using the general procedure used to generate compounds 5a-e. The identity of each hybrid was verified by HRESIMS: 6a calcd m/z for C76H90FN6O23 (M + H+) 1473.6041, found m/z 1473.6028; 6b calcd m/z for C75H87FN5O24 (M + H+) 1460.5725, found m/z 1460.5723; 6c calcd m/z for C82H91F3N5O24 (M + H+) 1586.6006, found m/z 1586.6028; 6d calcd m/z for C79H96FN6O24 (M + H+) 1531.6461, found m/z 1531.6454.
	With potassium carbonate In water monomer; N,N-dimethyl-formamide at 50℃;	General protocol for the preparation of compounds 6a-e General procedure: Fluoroquinolone-linker conjugates were prepared as follows. To a stirred solution of K2CO3, (2 equiv) in DMF/H2O (1:1), a fluoroquinolone (1 equiv) was added, followed by N-Boc-3-bromopropylamine (2 equiv). The reaction mixture was stirred at 50 °C for 1-3 days, at which point it was concentrated in vacuo and then diluted in H2O (5 mL). The pH was adjusted to 4-5 using aqueous 2N HCl. The solution was then extracted in DCM (2 x 10 mL). The organic fractions were washed with brine (10 mL), dried over Na2SO4, filtered, and dried under vacuum to obtain a white residue. The residue was purified by silica gel column chromatography (DCM/MeOH, 9:1) to obtain a white solid. Removal of the Boc group was subsequently completed by dissolving the intermediate in TFA/DCM (1:1, 1 mL) and stirring at room temperature for 2 h. The solvent was removed under vacuum. The solution was then neutralized with addition of 1 mL TEA followed by concentration in vacuo. Each fluoroquinolone-linker conjugate was obtained as a white solid and used directly in the synthesis of compounds 6a-e using the general procedure used to generate compounds 5a-e. The identity of each hybrid was verified by HRESIMS: 6a calcd m/z for C76H90FN6O23 (M + H+) 1473.6041, found m/z 1473.6028; 6b calcd m/z for C75H87FN5O24 (M + H+) 1460.5725, found m/z 1460.5723; 6c calcd m/z for C82H91F3N5O24 (M + H+) 1586.6006, found m/z 1586.6028; 6d calcd m/z for C79H96FN6O24 (M + H+) 1531.6461, found m/z 1531.6454.

Reference： [1]Peek, James; Koirala, Bimal; Brady, Sean F. [Bioorganic and Medicinal Chemistry Letters, 2022, vol. 57]
[2]Peek, James; Koirala, Bimal; Brady, Sean F. [Bioorganic and Medicinal Chemistry Letters, 2022, vol. 57]

35
[ 127294-70-6 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: triethylamine / N,N-dimethyl-formamide / 24 h / 20 °C 2.1: potassium carbonate / acetonitrile / 0.17 h / 20 °C 2.2: 24 h / 50 °C

Reference： [1]Li, Weitian; Hong, Ge; Mao, Lina; Xu, Zengping; Wang, Jiawen; Wang, Wenzhi; Liu, Tianjun [Medicinal Chemistry Research, 2022, vol. 31, # 5, p. 705 - 719]

36
[ 127294-77-3 ]
[ CAS Unavailable ]
[ 127294-70-6 ]

Yield	Reaction Conditions	Operation in experiment
44.1%	With triethylamine In chloroform for 20h; Reflux;	1.S2; 2.S2; 3.S2 Step S2: Crude balofloxacin(1-Cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoQuinoline-3-carboxylate ·Synthesis of boron diacetate (DFQ-B complex). Operation: In a 5L three-necked flask, add 215g (1.15mol) of 3-methylaminopiperidine dihydrochloride, 400g (0.95mol) of compound (DFQ-Bcomplex), 400mL of triethylamine and 3000mL of chloroform, stir, and heat up to Reflux and react for 20h. Cooled, concentrated under reduced pressure, diluted with water, extracted with chloroform (800 mL×3), dried and concentrated to obtain 156.4 g of crude balofloxacin as a yellow solid, with a yield of 42.5%.

Reference： [1]Current Patent Assignee: HUAI TIN FREE PHARMACEUTICAL CO LTD - CN114213392, 2022, A Location in patent: Paragraph 0033; 0035; 0043-0044; 0058; 0061; 0063; 0066

37
[ 127294-70-6 ]
[ 151060-21-8 ]

Yield	Reaction Conditions	Operation in experiment
76.3%	Stage #1: 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-(3-methylaminopiperidin-1-yl)-3-quinolinecarboxylic acid In ethanol for 0.5h; Reflux; Stage #2: With water monomer at 50 - 60℃;	1.S3; 2.S3; 3.S3 Step S3: product refining. Operation: 6000 mL of ethanol was added to 150 g of balofloxacin crude product, and the mixture was heated and refluxed under stirring until the solid was completely dissolved. Slightly cool, add 10.0g activated carbon, continue to reflux for 30min, and filter while hot. The filtrate was concentrated to about 500 mL under reduced pressure at 50-60° C., 500 mL of water was added, and the mixture was cooled to room temperature with continued stirring, and crystals were precipitated. It was left overnight, filtered, and dried at 45°C to obtain 122.7 g of white crystals, yield 74.9%,

Reference： [1]Current Patent Assignee: HUAI TIN FREE PHARMACEUTICAL CO LTD - CN114213392, 2022, A Location in patent: Paragraph 0035; 0045-0046; 0058; 0062-0063; 0067

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	127294-70-6	MDL No. :	MFCD00864925
Formula :	C₂₀H₂₄FN₃O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	MGQLHRYJBWGORO-UHFFFAOYSA-N
M.W :	389.42 g/mol	Pubchem ID :	65958
Synonyms :	1. Balofloxacin

Num. heavy atoms :	28
Num. arom. heavy atoms :	10
Fraction Csp3 :	0.5
Num. rotatable bonds :	5
Num. H-bond acceptors :	6.0
Num. H-bond donors :	2.0
Molar Refractivity :	107.44
TPSA :	83.8 Å²

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-8.26 cm/s

Log Po/w (iLOGP) :	2.73
Log Po/w (XLOGP3) :	0.58
Log Po/w (WLOGP) :	2.35
Log Po/w (MLOGP) :	1.44
Log Po/w (SILICOS-IT) :	2.21
Consensus Log Po/w :	1.86

[ CAS No. 127294-70-6 ]

Quality Control of [ 127294-70-6 ]

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[ 127294-70-6 ] Synthesis Path-Downstream 1~37

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Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

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

Log S (ESOL) :	-2.55
Solubility :	1.09 mg/ml ; 0.00279 mol/l
Class :	Soluble
Log S (Ali) :	-1.91
Solubility :	4.76 mg/ml ; 0.0122 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-4.03
Solubility :	0.0366 mg/ml ; 0.000094 mol/l
Class :	Moderately soluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.58

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-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