Name: 112811-59-3|1-Cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid|98%
Brand: Ambeed
SKU: A142500
Price: 5.0 USD
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1
[ 50-00-0 ]
[ 10118-90-8 ]
[ 160738-57-8 ]
7-(4-[(4,7-bis-dimethylamino-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-naphthacene-2-carbonyl)-amino]-methyl}-3-methyl-piperazin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 2372 - 2375

2
[ 835920-87-1 ]
[ 112811-59-3 ]

Yield	Reaction Conditions	Operation in experiment
91.7%	With water In ethanol at 70 - 80℃; for 2h;	I.3; II.2 Stage-3 : Preparation of Gatifloxacin (Crude) The pure condensed chelate (100.0 G) prepared as above in stage-2 is suspended in 20% aq. ethanol (1000 ml), the temperature is raised and maintained at 75°C to 80°C for 2 hrs. The reaction mass is cooled, filtered to remove insolubles, distilled under vacuum to remove solvent. Fresh ethanol (200 ml) is added and solvent is removed under vacuum at temperature below 50°C. Ethanol (200 ML) is added to the residue and gradually cooled to-10°C TO-5°C. The reaction mass is mixed AT-10°C TO-5°C for 1 hr and then filtered. The wet cake is washed with ethanol (25 ml) and dried at 45°C-50°C to constant weight. The dry weight of the Gatifloxacin is 83.3 g (Yield : 91.7 %); Stage-2: Preparation of Gatifloxacin (Crude) The boron difluoride chelate derivative (100 g) prepared as above in stage-1 is suspended in acetonitrile (800 ml), 2-methyl piperazine (44 g, 1.5 mole equiv. ) is added and mixed for 15 min to obtain a clear solution. The reaction mass is maintained at 30°C- 35°C for 12 hrs. Removed the solvent by vacuum distillation. 20% Aq. ethanol (1000 ml) is added, raised the temperature and maintained at 75°C to 80°C for 2 hrs. The reaction mass is cooled, filtered to remove insolubles. The filtrate is distilled under vacuum to remove solvent completely. Fresh ethanol (250 ml) is added and distilled under vacuum at temperature below 50°C. Fresh Ethanol (250 ml) is added to the residue and gradually cooled TO-10°C TO-5°C. The reaction mass is maintained AT-10°C to-5°C for 1 hr and filtered. The wet cake is washed with ethanol (30 ML) and dried at 45°C-50°C to constant weight. The dry weight of the Gatifloxacin is 73.5 g (Yield: 65.4 %)
	With methanol at 63 - 67℃; for 5h;	1 Example 1: Preparing gatifloxacin from compound (II) 10 g (0.0339 moles, 1 equivalent) of compound (II) is placed in a flask, 30 ml of acetonitryl (3 volumes) is added and this is heated to a temperature of 76-80° C. Once reflux has been attained, and being the temperature maintained, 3.28 g (0.0203 moles, 0.6 equivalents) of hexamethyldisilazane (HMDS) is added with a compensated adding funnel. Once addition is completed, the reaction is maintained with stirring for 1 hour at a temperature of 76-80° C. Once this period has elapsed, the reaction mixture is cooled to a temperature ranging between 0 and 15° C, and 5.78 g (0.0407 moles, 1.2 equivalents) of boron trifluoride ethyletherate is added while keeping the temperature below 15° C. Once addition is completed, the temperature is allowed to rise to 15- 25° C and it is kept under these conditions for approximately 2 hours. The pH of the mixture is then adjusted to an approximate value of 9 with triethylamine (approximately 2 ml). To the resulting suspension is added a solution of 10.19 g (0.1017 moles, 3 equivalents) of 2-methylpiperazine in 28 ml of acetonitryl, while maintaining the temperature between 15 and 25° C. The resulting amber solution is kept with stirring under these conditions for approximately 3 hours. Once the reaction has been completed, the solution is distilled at low pressure until a stirrable paste is obtained. At this point 50 ml of methanol is added, the resulting suspension is raised to a temperature of 63-67'C and is kept under these conditions for approximately 5 hours. Once the reaction has been completed, the mixture is cooled to a temperature of 25-35° C in a water bath, and then at a temperature of 0-5° C in a water/ice bath for a further 1 hour. The resulting precipitate is filtered, washed with cold methanol (2 x 10 ml) and dried at 40° C in a vacuum oven to constant weight. 10.70 g of crude gatifloxacin is obtained, having a water content of 2. 95% by weight. The yield of the process is 81. 8%. The crude product is crystallised in methanol by dissolving 20 g of crude gatifloxacin in 1 1 of methanol (50 volumes) at a temperature of 63-67° C. Once all the product has been dissolved, the solution is left to cool to a temperature of 30-40° C, and then to a temperature of 0-5° C in a water/ice bath, maintaining it under these conditions for 1 hour. The resulting suspension is filtered and the solid retained is washed with 20 ml (1 volume) of cold methanol. The solid obtained is dried at 40° C in a vacuum oven to provide 18.65 g of gatifloxacin with a water content of 2. 36% by weight. The overall yield from the compound (II) is 77. 7%, with a purity exceeding 99. 8% as determined by HPLC chromatography. The content of by-product resulting from demethylation in position 8 of the ring is lower than 0. 1% as determined by HPLC chromatography.

Reference： [1]Current Patent Assignee: VIATRIS INC - WO2005/9970, 2005, A1 Location in patent: Page/Page column 9-11
[2]Current Patent Assignee: GRUPO INSUD - WO2005/47260, 2005, A1 Location in patent: Page/Page column 7-9

3
[ 109-07-9 ]
[ 112811-72-0 ]
[ 160738-57-8 ]

Yield	Reaction Conditions	Operation in experiment
81.8%		Example of preparation. Preparing form I gatifloxacin for seeding; 10 g (0.0339 moles, 1 equivalent) of 1- cyclopropyl-6, 7-difluoro-1, 4-dihydrc-8-methoxy-4-oXo-3- quinolinecarboxylic acid (CAS no.: 112811-72-0) is placed in a flask, 30 mL of acetonitryl (3 volumes) is added and the solution is heated to a temperature of 76-80 C. Once reflux has been attained, 3.28 g (0.0203 moles, 0.6 equivalents) of hexamethyldisilazane (HMDS) is added using a compensated addition funnel, maintaining the temperature. Once the addition is completed, the reaction is maintained with stirring for 1 hour at a temperature of 76-80 C. Once this period has elapsed, the reaction mixture is cooled to a temperature between 0 and 15 C, and 5.78 g (0.0407 moles, 1.2 equivalents) of boron trifluoride ethyletherate is added, keeping the temperature below 15 C. Once the addition has finished, the temperature is allowed to rise to 15-25 C and :-t is kept under these conditions for approximately 2 hour : :. The pH of the mixture is then adjusted to an approximate value of 9 with triethylamine (approximately 2 mL). To the resulting suspension : s added a solution of 10.19 g (0.1017 moles, 3 equivalents) of 2-methylpiperazine in 28 mL of acetonitryl, keeping the temperature between 15 and 25 C. The resulting amber solution is kept with stirring under these conditions for approximately 3 hours. Once the reaction has beer : completed, the mixture is distilled at low pressure unti : a stirrable paste is obtained. At this point, 50 mL of methanol is added, the resulting suspension is raised to a temperature of 63-67 C and kept under these conditions for approximately 5 hours. Once the reaction has been completed the mixture is cooled to a temperature of 25-35 C over a water bath and then to a temperature of 0-5 C over a water/ice bath for a further 1 hour. The resulting precipitate is filtered, washed with cold methanol (2 x 10 mL) and dried at 40 C in an oven in vacuo to constant weight. 10.70 g of crude gatifloxacin is obtained, with a water content of 2. 95% by weight. The yield of the process is 81.8%. The crude product obtained is used for the seeding in Example 1. The crude product is crystallised in methanol by dissolving-20 g of crude gatifloxacin in 1 1 of methanol (50 volumes) at a temperature of D3-67 C. Once all the product has been dissolved it is placed to cool to a temperature of 30-40 C, and then to a temperature of 0-5 C over a water/ice bath, maintaining it under these conditions for 1 hour. The resulting suspension is filtered and the solid retained is washed with 20 mL (1 volume) of cold methanol. The solid obtained is dried at 40 C in a vacuum oven to obtain 18.65 g of gatifloxacin with a water content of 2. 36% by weight.
66 - 84%	In dimethyl sulfoxide; at 55℃; for 24h;	Example 1: Ninety grams of L-CYCLOPROPYL-6, 7-DIFLUORO-1, 4-DIHYDRO-8-METHOXY-4-OXO-3- quinoline carboxylic acid and 64g (2.1 eq) of 2-methyl piperazine were put in suspension in 1.8 liter of DMSO under nitrogen atmosphere. The mixture was heated to 55 C during 24 hours. Subsequently, the mixture was heated to 70 C and half of the amount of DMSO was distilled-off at reduced pressure (1-5 mm Hg). At the end of the distillation, the reaction mixture was cooled to 20 C and left at this temperature overnight. The solution was then filtered under vacuum and the wet cake washed twice with n-butanol (300 ml). The collected solid was then dried under vacuum to obtain 94 g. The calculated yield, after assay, was 84%.
53.7 - 55.9%	In dimethyl sulfoxide; at 60 - 65℃; for 29 - 45h;	A mixture of 1-CYCLOPROPYL-6, 7-difluoro-1, 4-DIHYDRO-8-METHOXY-4-OXO-3- quinoline carboxylic acid (100G), 2-methylpiperazine (67.8gs) and anhydrous DMSO (300 ml) were stirred for 40-45 hrs at 60-65C. The reaction mass was then diluted with 1500 ml isopropyl alcohol. It was then stirred for 30 min at 25-30C followed by cooling at 5 to 10 C along with stirring for 2 hours. The product was obtained by filtration, which was washed with 3 x 50 ml isopropyl alcohol followed by drying at 50 to 55C for 4 hours to provide 71 g Gatifloxacin (Yield 55. 9%) Example 2: Step A: A mixture of L-CYCLOPROPYL-6, 7-difluoro-1, 4-dihydro-8-methoxy-4-oxo-3- quinoline carboxylic acid (120Kg) 2-methylpiperazine (40.8 Kg), and anhydrous DMSO (361 lit) was heated to 60-65C temperature and stirred for 2 hrs. A second lot of 2-methylpiperazine (10.2 Kg) was added, and stirred for next 1 hr, at 60-65C. followed by the addition of a third lot of 2-methylpiperazine (10.2Kg). The mixture was stirred for next 2 hrs at 60-65C. A fourth lot of 2-methylpiperazine (20.4Kg) was added to the mixture and the stirring was continued for the next 24 hrs maintaining the temperature at 60-65C followed by cooling to 25-35C. This reaction mass was added in 1802-1 isopropyl alcohol. Reaction mass was then stirred for 30 min at 25- 30C followed by cooling at 5 to 10 C along with stirring for 2 hours. Product so obtained was centrifuged, washed with 3 x 60-1 isopropyl alcohol. The wet cake of PRODUCT WAS MIXED WITH 241-LIT METHANOL AND STIRRED FOR 1 HR. , AGAIN THE PRODUCT WAS centrifuged followed by washing with 59 lit of methanol. The wet Gatifloxacin was dried at 60 to 65C for 6 hrs to yield 81. 92 Kg dry Gatifloxacin (Yield= 53.7%) HPLC Purity = 99.74% M/C=3. 42%

52.0 - 54.7%	In dimethyl sulfoxide; at 20 - 73℃; for 13.9167 - 14.3333h;	Into a reactor with a working volume of 1000 mL equipped with a thermometer, a reflux condenser and a mechanical stirrer, DMSO (480 mL), l-cyclopropyl-6,7-difluoro-l,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid (138.0 g; 0.4675 mole) and 2-methylpiperazine (94.0 g; 0.9387 mole) were put at 25C (20C-30C). The reaction mixture was stirred for 30 minutes at 25C (20C-30C). Then it was heated in 50 minutes (45-60 minutes) to the temperature of 73C. The reaction mixture was stirred at this temperature for 12 hours. After 12 hours at 73C, the reaction mixture was cooled to 25C in 45 minutes (40-50 minutes). The pH of the suspension was measured and adjusted to the pH value of 10.2 with a 15% HC1 solution (27.5 mL of 15% HC1) and the suspension was stirred for 24 hours. The pHof the suspension was periodically checked and adjusted to the desired value of 10.2 if necessary. When adjusting the pH vapours were formed, which were sucked off by underpressure and led through a trap with a solution of calcium hydroxide, which irreversibly bound fluoride ions. The product was then filtered over a filter MN 640 (black ribbon) and washed with methanol (165 mL). The product was thoroughly sucked off and the humidity was determined. Estimated yield of the dry gatifloxacin base: 52.0-54.7%.
	In dimethyl sulfoxide; at 70 - 95℃; for 2h;	EXAMPLE 3 Synthesis of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (200 mg), 2-methylpiperazine (140 mg) and anhydrous DMSO (3 ml) was stirred for 2 hours at 70 to 95 C. on an oil bath. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluding with chloroform-methanol-concentrated aqueous ammonia (20:6:1), the residue was recrystallized from methanol to give the title compound (50 mg) as white powdery crystals, mp 162 C. Analysis (%) for C19 H22 FN3 O4.1/2 H2 O; Calcd. (Found): C, 59.37 (59.95); H, 6.03 (6.01); N, 10.93 (10.81).

Reference： [1]Patent: WO2005/47262,2005,A1 .Location in patent: Page/Page column 7-8
[2]Patent: WO2004/69825,2004,A1 .Location in patent: Page 13-16
[3]Patent: WO2004/101527,2004,A1 .Location in patent: Page 6; 7
[4]Patent: WO2006/4561,2006,A1 .Location in patent: Page/Page column title page; 4; 9-10
[5]Patent: US4980470,1990,A

4
[ CAS Unavailable ]
[ 112811-59-3 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
41%	With triethylamine In DMF (N,N-dimethyl-formamide) at 20 - 55℃;	13 (R/,S)-11-Deoxy-11-[{-{2-[4-(3-carboxy-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinolin-7-yl)-2-methylpiperazin-1-yl] S Synthesis: To a stirred solution of 11-deoxy-11-(2-bromo)ethoxy)iminorifamycin S (5.0 mg, 0.006 mmol) and (R/S)-1-Cyclopropylcyclopropyl-6-fluoro-8-methoxy-7-(3-methyl-piperazin-1-yl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (gatifloxacin, 12.2 mg, 0.032 mmol) in N,N-dimethylformamide (0.4 mL) was added triethylamine (10 μL, 0.072 mmol) at room temperature. The reaction solution mixture was allowed to stir overnight at 55° C. The resultant solution was partitioned between ethyl acetate and water. The organic layer was separated, dried over sodium sulfate, concentrated in vacuo to dryness. The crude product was purified by preparative thin layer chromatography (10% MeOH/CH2Cl2) to give the title compound as an orange solid (2.8 mg, 41%). ESI MS m/z 1112.4 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 12.77 (s, 1H), 8.83 (s, 1H), 8.48 (s, 1H), 7.87 (d, J=12.4 Hz, 1H), 7.78 (s, 1H), 6.41 (dd, J=10.8, 15.6 Hz, 1H), 6.29 (d, J=10.8 Hz, 1H), 6.23 (d, J=12.0 Hz, 1H), 5.98 (dd, J=6.4, 15.2 Hz, 1H), 5.15 (dd, J=8.0, 12.0 Hz, 1H), 4.64 (d, J=9.6 Hz, 1H), 4.55-4.50 (m, 2H), 4.06-4.00 (m, 2H), 3.77 (s, 3H), 3.66-3.58 (m, 3H), 3.50-3.28 (m, 5H), 3.14 (s, 3H), 3.14-3.06 (m, 1H), 3.02-2.72 (m, 3H), 2.41-2.35 (m, 1H), 2.28 (s, 3H), 2.05 (s, 3H), 2.04 (s, 3H), 2.01 (s, 3H), 1.80-1.76 (m, 1H), 1.56-1.50 (m, 1H), 1.25-1.20 (m, 7H), 1.03 (d, J=6.8 Hz, 3H), 0.84 (d, J=7.2 Hz, 3H), 0.68 (d, J=6.4 Hz, 3H), 0.26 (c, J=7.2 Hz, 3H).

Reference： [1]Current Patent Assignee: TENNOR THERAPEUTICS LTD. - US2005/203076, 2005, A1 Location in patent: Page/Page column 19-20

5
[ 24424-99-5 ]
[ 112811-59-3 ]
[ 925684-44-2 ]

Yield	Reaction Conditions	Operation in experiment
95%	With sodium hydroxide In tetrahydrofuran; water at 20℃;
95%	With sodium hydroxide In tetrahydrofuran; water at 20℃;	B.6 The mixture of gatifloxacin (15, 335.1 mg, 0.8927 mmol), Boc2O (202 mg, 0.9163 mmol) and 1.9 mL of 1 M NaOH aqueous solution in 10 mL of THF was stirred at room temperature overnight. After the removal of the organic solvent, the residue was neutralized with saturated ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate (3*) and dried over anhydrous sodium sulfate. Removal of the solvent yielded a white solid 16 (403 mg, 95%). 1H NMR (400 MHz, CDCl3): 0.94-1.04 (m, 2H), 1.19-1.26 (m, 2H), 1.33 (d, J=6.9, 3H), 1.50 (s, 9H), 3.23-3.37 (m, 3H), 3.44-3.51 (m, 2H), 3.73 (s, 3H), 3.95-4.03 (m, 2H), 4.36 (bs, 1H), 7.89 (d, J=11.4, 1H), 8.83 (s, 1H) ppm.
68%	With sodium hydroxide In tetrahydrofuran at 20℃; Inert atmosphere;

With sodium hydroxide In tetrahydrofuran at 20℃; Inert atmosphere;

1 Synthesis of 4-(1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxamido)butanoic acid (GFX-MCT) Step 1. [0158] 200 mg of gatifloxacin sesquihydrate was dissolved in dry tetrahydrofuran solvent (5.0 ml) and 0.5 ml of 1N NaOH was added. Subsequently, 124 mg of boc-anhydride was added, and the reaction mixture was stirred under argon overnight at room temperature. The solvent was evaporated and the residue was diluted with aqueous saturated ammonium chloride solution. The resulting solution was extracted with ethyl acetate (2×20 ml). The organic layers were combined, dried over sodium sulfate and concentrated to obtain a crude product. Yield of the crude product was 68%.

Reference： [1]Location in patent: experimental part Tanaka, Kelly S.E.; Houghton, Tom J.; Kang, Ting; Dietrich, Evelyne; Delorme, Daniel; Ferreira, Sandra S.; Caron, Laurence; Viens, Frederic; Arhin, Francis F.; Sarmiento, Ingrid; Lehoux, Dario; Fadhil, Ibtihal; Laquerre, Karine; Liu, Jing; Ostiguy, Valerie; Poirier, Hugo; Moeck, Gregory; Parr Jr., Thomas R.; Rafai Far, Adel [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 20, p. 9217 - 9229] Location in patent: experimental part Houghton, Tom J.; Tanaka, Kelly S. E.; Kang, Ting; Dietrich, Evelyne; Lafontaine, Yanick; Delorme, Daniel; Ferreira, Sandra S.; Viens, Frederic; Arhin, Francis F.; Sarmiento, Ingrid; Lehoux, Dario; Fadhil, Ibtihal; Laquerre, Karine; Liu, Jing; Ostiguy, Valérie; Poirier, Hugo; Moeck, Gregory; Parr Jr., Thomas R.; Far, Adel Rafai [Journal of Medicinal Chemistry, 2008, vol. 51, # 21, p. 6955 - 6969]
[2]Current Patent Assignee: MELINTA THERAPEUTICS INC. - US2008/287396, 2008, A1 Location in patent: Page/Page column 60-61
[3]Vooturi, Sunil K.; Kadam, Rajendra S.; Kompella, Uday B. [Molecular Pharmaceutics, 2012, vol. 9, # 11, p. 3136 - 3146]
[4]Current Patent Assignee: UNIVERSITY OF COLORADO (SYSTEM) - US2013/190324, 2013, A1 Location in patent: Paragraph 0156; 0157; 0158

6
[ 22128-62-7 ]
[ 112811-59-3 ]
[ 925684-58-8 ]

Yield	Reaction Conditions	Operation in experiment
95%	With N,N,N',N'-tetramethyl-1,8-diaminonaphthalene In dichloromethane for 4h; Inert atmosphere;
95%	With N,N,N',N'-tetramethyl-1,8-diaminonaphthalene In dichloromethane at 0℃; for 4h;	B.14 A suspension of 15 (8.65 g, 22.9 mmol) and proton sponge (4.90 g, 22.9 mmol) in anhydrous CH2Cl2 (100 mL) was cooled in an ice-bath followed by the drop-wise addition of chloroformic acid chloromethyl ester (2.03 mL, 22.9 mmol). The resulting mixture was stirred at the same temperature for four hours. The reaction mixture was diluted by the addition of CH2Cl2 (300 mL) and washed with cold aqueaous HCl (5%) and saturated NaCl then dried over anhydrous sodium sulfate. After filtering off the drying agent the organics were removed under reduced pressure to give 47 as a yellow coloured solid that was used without purification (10.2 g, 95%): 1H NMR (400 MHz, CDCl3): 0.94-1.04 (m, 2H), 1.17-1.27 (m, 2H), 1.40 (d, J=6.7, 3H), 3.28-3.53 (m, 5H), 3.73 (s, 3H), 3.98-4.10 (m, 2H), 4.45 (bs, 1H), 5.85 (m, 2H), 7.92 (d, J=12.3, 1H), 8.83 (s, 1H).

Reference： [1]Location in patent: experimental part Houghton, Tom J.; Tanaka, Kelly S. E.; Kang, Ting; Dietrich, Evelyne; Lafontaine, Yanick; Delorme, Daniel; Ferreira, Sandra S.; Viens, Frederic; Arhin, Francis F.; Sarmiento, Ingrid; Lehoux, Dario; Fadhil, Ibtihal; Laquerre, Karine; Liu, Jing; Ostiguy, Valérie; Poirier, Hugo; Moeck, Gregory; Parr Jr., Thomas R.; Far, Adel Rafai [Journal of Medicinal Chemistry, 2008, vol. 51, # 21, p. 6955 - 6969]
[2]Current Patent Assignee: MELINTA THERAPEUTICS INC. - US2008/287396, 2008, A1 Location in patent: Page/Page column 69-70

7
[ 50893-53-3 ]
[ 112811-59-3 ]
[ 925684-53-3 ]

Yield	Reaction Conditions	Operation in experiment
98%	With N,N,N',N'-tetramethyl-1,8-diaminonaphthalene In chloroform at 20℃; for 5h; Inert atmosphere;
98%	With N,N,N',N'-tetramethyl-1,8-diaminonaphthalene In chloroform at 20℃; for 2h;	B.12 1-Chloroethyl chloroformate (82 μL, 0.7525 mmol) was added to a solution of gatifloxacin 15 (282.8 mg, 0.7533 mmol) and proton sponge (166.6 mg, 0.7773 mmol) in 10 mL of CHCl3. The white suspension quickly turned clear and was stirred at room temperature for another 2 h. The mixture was washed with water (3*) and dried over anhydrous sodium sulfate. Removal of the solvent yielded product 37 as a yellow solid (356.5 mg, 98%). In the cases where proton sponge was still present after water wash, the crude product was passed through a short silica gel column with the elution of 19:1 dichloromethane/methanol. 1H NMR (400 MHz, CDCl3): 0.94-1.04 (m, 2H), 1.21-1.26 (m, 2H), 1.40 (d, J=7.1, 3H), 1.85 (d, J=5.9, 3H), 3.31-3.34 (m, 2H), 3.41-3.53 (m, 4H), 3.74 (s, 3H), 3.98-4.07 (m, 2H), 4.45 (bs, 1H), 6.65 (dq, J=1.8, 5.7, 1H), 7.92 (d, J=12.0, 1H), 8.84 (s, 1H).

Reference： [1]Location in patent: experimental part Houghton, Tom J.; Tanaka, Kelly S. E.; Kang, Ting; Dietrich, Evelyne; Lafontaine, Yanick; Delorme, Daniel; Ferreira, Sandra S.; Viens, Frederic; Arhin, Francis F.; Sarmiento, Ingrid; Lehoux, Dario; Fadhil, Ibtihal; Laquerre, Karine; Liu, Jing; Ostiguy, Valérie; Poirier, Hugo; Moeck, Gregory; Parr Jr., Thomas R.; Far, Adel Rafai [Journal of Medicinal Chemistry, 2008, vol. 51, # 21, p. 6955 - 6969]
[2]Current Patent Assignee: MELINTA THERAPEUTICS INC. - US2008/287396, 2008, A1 Location in patent: Page/Page column 66-67

8
[ 925684-96-4 ]
[ 112811-59-3 ]
[ 925684-97-5 ]

Yield	Reaction Conditions	Operation in experiment
63%	With dmap; triethylamine In dichloromethane at 20℃; for 20h; Inert atmosphere;
63%	With triethylamine In dichloromethane at 20℃; for 20h;	B.37 A mixture of crude enone 119 (3.2 g, 6.7 mmol), gatifloxacin 15 (3.07 g, 8.18 mmol) DMAP (200 mg, 1.64 mmol) and triethylamine (1.4 mL, 10.0 mmol) in CH2Cl2 (200 mL) was stirred at room temperature for 20 h. The mixture was evaporated, followed by flash chromatography (gradient elution 5% methanol/CH2Cl2-10% methanol/CH2Cl2) to give 120 (3.6 g, 63%). 1H NMR (400 MHz, CDCl3) δ 0.94-1.04 (m, 2H), 1.12-1.28 (m, 5H), 1.30-1.37 (m, 12H), 2.06-2.24 (m, 4H), 2.27-2.45 (m, 1H), 2.55-3.50 (m, 10H), 3.74 (s, 3H), 3.97-4.08 (m, 3H), 4.13-4.24 (m, 8H), 6.92 (d, J=8.8, 2H), 7.86 (d, J=12.1, 1H), 7.94 (d, J=8.8, 2H), 8.80 (s, 1H).

Reference： [1]Location in patent: experimental part Houghton, Tom J.; Tanaka, Kelly S. E.; Kang, Ting; Dietrich, Evelyne; Lafontaine, Yanick; Delorme, Daniel; Ferreira, Sandra S.; Viens, Frederic; Arhin, Francis F.; Sarmiento, Ingrid; Lehoux, Dario; Fadhil, Ibtihal; Laquerre, Karine; Liu, Jing; Ostiguy, Valérie; Poirier, Hugo; Moeck, Gregory; Parr Jr., Thomas R.; Far, Adel Rafai [Journal of Medicinal Chemistry, 2008, vol. 51, # 21, p. 6955 - 6969]
[2]Current Patent Assignee: MELINTA THERAPEUTICS INC. - US2008/287396, 2008, A1 Location in patent: Page/Page column 88-89

9
[ 925685-10-5 ]
[ 112811-59-3 ]
[ 925685-11-6 ]

Yield	Reaction Conditions	Operation in experiment
34%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; Inert atmosphere; Cooling with ice;
34%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃;	B.40 A solution of 139 (400 mg, 0.836 mmol), 15 (310 mg, 0.84 mmol) and diisopropylethylamine (291 μL, 1.67 mmol) in DMF (5 mL) was cooled in an ice-bath followed by the addition of HBTU (317 mg, 0.836 mmol) in one portion. The resulting mixture was stirred while slowly warming to room temperature overnight. The reaction mixture was diluted with EtOAc (100 mL) and washed with aqueous HCl (10%), water, and saturated aqueous NaCl, followed by drying over Na2SO4. The crude beige solid was purified by silica gel chromatography (0-10% MeOH in CH2Cl2) on a Biotage flash chromatography system, resulting in 140 as a pale yellow solid (260 mg, 34%): 1H NMR (400 MHz, CDCl3) δ 0.92-0.94 (m, 2H), 1.12-1.27 (m, 14H), 1.43 (s, 3H), 1.46 (s, 3H), 2.31 (s, 3H), 2.53-5.63 (m, 1H), 2.74-2.85 (m, 3H), 3.00-3.40 (m, 5H), 3.65 (s, 3H), 3.88-4.08 (m, 6H), 4.27 (bs, 1H), 4.66 (bs, 1H), 7.07 (dd, J=3.2, 8.1, 1H), 7.60-7.65 (m, 1H), 7.75 (d, J=12.0, 1H), 7.82 (dd, J=5.2, 8.1, 1H), 8.72 (s, 1H): 31P (162 MHz, CDCl3) δ 20.07 (d, J=8.7, 1P), 33.90 (d, J=8.7, 1P).

Reference： [1]Location in patent: experimental part Houghton, Tom J.; Tanaka, Kelly S. E.; Kang, Ting; Dietrich, Evelyne; Lafontaine, Yanick; Delorme, Daniel; Ferreira, Sandra S.; Viens, Frederic; Arhin, Francis F.; Sarmiento, Ingrid; Lehoux, Dario; Fadhil, Ibtihal; Laquerre, Karine; Liu, Jing; Ostiguy, Valérie; Poirier, Hugo; Moeck, Gregory; Parr Jr., Thomas R.; Far, Adel Rafai [Journal of Medicinal Chemistry, 2008, vol. 51, # 21, p. 6955 - 6969]
[2]Current Patent Assignee: MELINTA THERAPEUTICS INC. - US2008/287396, 2008, A1 Location in patent: Page/Page column 93-95

10
[ 925685-13-8 ]
[ 112811-59-3 ]
[ 925685-14-9 ]

Yield	Reaction Conditions	Operation in experiment
34%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; Inert atmosphere; Cooling with ice;
34%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃;	B.41 A solution containing 143 (398 mg, 0.790 mmol), 15 (296 mg, 0.790 mmol) and diisopropylethylamine (275 μL, 1.58 mmol) in DMF (5 mL) was cooled in an ice-bath followed by the addition of HBTU (300 mg, 0.790 mmol) in one portion. The resulting mixture was stirred while warming to room temperature overnight. The reaction mixture was diluted with EtOAc (100 mL) and washed with aqueous HCl (10%), water, and saturated aqueous NaCl, followed by drying over Na2SO4. The crude material was purified by silica gel chromatography (0-5% MeOH in EtOAc) on a Biotage flash chromatography system resulting in 144 as a pale yellow liquid (229 g, 34%): 1H NMR (400 MHz, CDCl3) δ 0.97-1.00 (m, 2H), 1.18-1.36 (m, 14H), 1.38 (d, J=7.1, 6H), 1.54 (s, 3H), 1.56 (s, 3H), 2.63 (ddd, J=5.6, 17.2, 22.0, 2H), 2.85-2.92 (m, 3H), 3.13 (bs, 1H), 3.27-3.51 (m, 5H), 3.71 (s, 3H), 3.98-4.19 (m, 6H), 4.43 (bs, 1H), 4.83 (bs, 1H), 7.08 (dd, J=3.5, 8.1, 1H), 7.67-7.74 (m, 1H), 7.89 (d, J=12.1, 1H), 7.95 (dd, J=1.7, 13.7, 1H), 8.83 (s, 1H): 31P (162 MHz, CDCl3) δ 20.1. (d, J=9.0, 1P), 34.32 (d, J=9.0, 1P).

Reference： [1]Location in patent: experimental part Houghton, Tom J.; Tanaka, Kelly S. E.; Kang, Ting; Dietrich, Evelyne; Lafontaine, Yanick; Delorme, Daniel; Ferreira, Sandra S.; Viens, Frederic; Arhin, Francis F.; Sarmiento, Ingrid; Lehoux, Dario; Fadhil, Ibtihal; Laquerre, Karine; Liu, Jing; Ostiguy, Valérie; Poirier, Hugo; Moeck, Gregory; Parr Jr., Thomas R.; Far, Adel Rafai [Journal of Medicinal Chemistry, 2008, vol. 51, # 21, p. 6955 - 6969]
[2]Current Patent Assignee: MELINTA THERAPEUTICS INC. - US2008/287396, 2008, A1 Location in patent: Page/Page column 95-96

11
[ 925685-16-1 ]
[ 112811-59-3 ]
[ 925685-17-2 ]

Yield	Reaction Conditions	Operation in experiment
70%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃;	B.42 A solution containing 147 (163 mg, 0.322 mmol), 15 (121 mg, 0.322 mmol) and diisopropylethylamine (112 μL, 0.644 mmol) in DMF (4 mL) was cooled in an ice-bath followed by the addition of HBTU (122 mg, 0.322 mmol). The resulting mixture was stirred while warming to room temperature overnight. The reaction mixture was diluted with EtOAc (100 mL) and washed with aqueous HCl (10%), water, and saturated aqueous NaCl, followed by drying over Na2SO4. The light brown coloured liquid of 148 (194 mg, 70%) was used with out purification.

Reference： [1]Current Patent Assignee: MELINTA THERAPEUTICS INC. - US2008/287396, 2008, A1 Location in patent: Page/Page column 96-97

12
[ 925685-19-4 ]
[ 112811-59-3 ]
[ 925685-20-7 ]

Yield	Reaction Conditions	Operation in experiment
58%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃;	B.43 HBTU (229 mg, 0.603 mmol) was added to a solution containing 151 (345 mg, 0.603 mmol), 15 (226 mg, 0.603 mmol) and diisopropylethylamine (210 μL, 1.21 mmol) in DMF (5 mL) that was cooled in an ice-bath. The resulting mixture was stirred while warming to room temperature overnight. The reaction mixture was diluted with EtOAc (100 mL) and washed with aqueous HCl (10%), water, and saturated aqueous NaCl, followed by drying over Na2SO4. The light brown coloured liquid of 152 (326 mg, 58%) was used with out purification.
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; Inert atmosphere; Cooling with ice;

Reference： [1]Current Patent Assignee: MELINTA THERAPEUTICS INC. - US2008/287396, 2008, A1 Location in patent: Page/Page column 97
[2]Location in patent: experimental part Houghton, Tom J.; Tanaka, Kelly S. E.; Kang, Ting; Dietrich, Evelyne; Lafontaine, Yanick; Delorme, Daniel; Ferreira, Sandra S.; Viens, Frederic; Arhin, Francis F.; Sarmiento, Ingrid; Lehoux, Dario; Fadhil, Ibtihal; Laquerre, Karine; Liu, Jing; Ostiguy, Valérie; Poirier, Hugo; Moeck, Gregory; Parr Jr., Thomas R.; Far, Adel Rafai [Journal of Medicinal Chemistry, 2008, vol. 51, # 21, p. 6955 - 6969]

13
[ 13264-88-5 ]
[ 112811-72-0 ]
[ 160738-57-8 ]

Yield	Reaction Conditions	Operation in experiment
91%		Example 4 1-Cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid 1/2 hydrate 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), 2-methylpiperazine dihydrochloride (1.93 g), triethylamine (1.43 mL), and boron trifluoride-tetrahydrofuran complex (2.84 g) was stirred at room temperature for one hour. 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 5 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 7 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 3.55 g of the title compound (yield: 91%). 1H-NMR(400MHz,CDCl3) deltappm: 1.02-1.31(7H,m),2.92-3.53(7H,m),3.77(3H,s),3.91-4.11(1H,m),7.85(1H,d,J=12.3Hz),8.79(1H,s) Elemental analysis: Calc. C;59.37%, H;6.03%, N;10.93% Obsd. C;59.49%, H;5.77%, N;11.03%

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

14
[ 23767-30-8 ]
[ 112811-59-3 ]
[ 1335198-38-3 ]

Yield	Reaction Conditions	Operation in experiment
56%	With sodium hydrogencarbonate In N,N-dimethyl-formamide at 85 - 90℃; for 12h;	4.3. General procedure for synthesis of N-substituted piperazinyl quinolones (I-XXI) General procedure: A mixture of equimolar quantity of compound 3a-g (0.05 mmol), piperazinyl quinolone (0.05 mmol) and NaHCO3 (0.05 mmol) in DMF (10 ml), was heated under reflux at 85-90 °C for 12 h. After cooling, water was added (10 ml) and the precipitate was filtered off, washed with water and recrystallized from the mixture of DMF and H2O to give the final product.