* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Example 1 Preparation of 1-cyclopropyl-7-[(S,S)-2,8-diazabicyclo[4.3.0]non-8-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. (III) Dimethylsulfoxide (600 ml), 50 g of 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid (IV) and 25.70 ml of [S,S]-2,8-diazabicyclo [4.3.0] nonane (V) were stirred at 65 - 70 °C for 6 - 8 hours. Completion of the reaction was monitored by HPLC. The reaction mass was cooled to 25-30 °C, 100 ml of water was added and stirred for 2 hours. The solid was filtered off with suction, washed with 100 ml water and dried under vacuum at 75°C, affording 61.0 g of the title compound. Yield: 89.7 percent Purity: 98 percent (HPLC) Chiral impurity (R,R isomer content): 3 - 5 percent
66%
With triethylamine In N,N-dimethyl-formamide; acetonitrile at 0 - 78℃; for 11 h; Reflux
1 -cyclopropyl-^-difiuoro-δ-methoxy^-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid (100g, 0.338 mole) and triethylamine were taken in mixture of acetonitrile (300 ml) and dimethylformamide (80 ml) . To it was added (S,S)-2,8-diazabicyclo [4.3.0] nonane (47g, 0.373 mole) and refluxed at 72- 78°C for 10 hours at reflux. The reaction mixture was cooled to room temperature, and further to 0-5°C maintained for 1 hr, filtered and washed with acetonitrile (50 ml) to get the desired product.Dry wt: 89.7g, Yield: 66percent.
Stage #1: With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 20 - 85℃; for 36 h; Inert atmosphere Stage #2: With hydrogenchloride In water at 15℃; for 1 h; Inert atmosphere
Under nitrogen protection, 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid 10.0 g (0·0339 mοl) and (S,S) -2,8-diazabicyclo[4,3,0] nonane 5 .13g(0.0406mol)were added to 70 mL acetonitrile, it was stirred at 20 ° C~30 ° C and 1,8-diazabicyclo[5·4·0]undec-7-ene 7.74 g (0.0508 mol) was added, it was stirred at 75 ° C~85 ° C for 36 h. Concentrated in vacuo (temperature 45 ° C ~ 65 ° C, pressure -0 · 08MPa ~ -0.1MPa) to remove most of the solvent, it was then dissolved in chloroform, the mass concentration is 2percent aqueous acetic acid solution (the mass concentration refers to the mass of acetic acid as a percentage of the total mass of the aqueous acetic acid solution), the mass concentration was 10percent saline (the mass concentration refers to the mass of sodium chloride as a percentage of the total mass of brine were sequentially added, respectively, then the mixture was stirred, allowed to stand, and the aqueous layer was separated. The organic layer was concentrated in vacuo (temperature 35 ° C ~ 55 ° C, pressure -0.08MPa ~ -0.1MPa) to remove most of the solvent, ethyl acetate was added, and the mixture was cooled to 10 ° C to 20 ° C and stirred for 2 hours to 3 hours. Centrifugation, rinsed three times with ethyl acetate, dried in vacuo (vacuum degree -0.01MPa~-0.1MPa, temperature 45~55°C) dried for 14 to 18 hours, to obtain 4.01g of moxifloxacin , yield 29.5percent.HPLC purity 93.54percent. Under nitrogen protection, add 4.0 g of moxifloxacin to 2.5 mL of water and 10 mL of methanol.Stir at 170 ° C for 1 hour, filter, and cool to 35 ° C.The pH was adjusted to 1.4 to 1.8 by the addition of 6N hydrochloric acid. Cool to 15 ° C and stir for 1 hour.It was filtered, washed with water, and stirred at 15 ° C for 1 hour in a solution of water 5 mL and concentrated hydrochloric acid.Filtered, washed with water, vacuum dried (vacuum degree - 0.01 MPa ~ -0.1 MPa, temperature 45 ~ 55 ° C) for 16 hours, to obtain 3.3 g of moxifloxacin hydrochloride,Yield 75.6percent (total yield 22.3percent, based on 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid ). The HPLC purity was 99.23percent, and the maximum single impurity was 0.47percent.
Reference：
[1] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2014, vol. 121, p. 254 - 258
[2] Patent: CN109096276, 2018, A, . Location in patent: Paragraph 0090-0093
With hydrogenchloride In methanol; water at 65℃; for 15 h;
Reaction: In a 250 mL round bottom flask, add 10 g of the compound of formula 2 and 100 mL of anhydrous methanol, stir and mix slowly, then add 13.3 mL of 36percent hydrochloric acid slowly. The addition is complete; the system is heated to 65° C., and the reaction is stirred at this temperature. 15h; Post-treatment: After the reaction is over, the system is cooled to 10° C., and the crystals are stirred for 2 h. The system is filtered under reduced pressure. The filter cake is washed with 20 mL of anhydrous methanol, and then vacuum-dried at 60° C. for 8 h to obtain 8.86 g of formula 3. The compound shown, yield: 96.83percent;
Reference：
[1] Patent: CN107778308, 2018, A, . Location in patent: Paragraph 0067; 0068; 0069
[2] Asian Journal of Chemistry, 2013, vol. 25, # 11, p. 6079 - 6082
[3] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 5, p. 2558 - 2569
[4] Patent: US4997943, 1991, A,
[5] Patent: WO2004/14893, 2004, A2, . Location in patent: Page 75; 76
[6] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 19, p. 5948 - 5951
[7] Patent: US4980470, 1990, A,
6
[ 112811-70-8 ]
[ 112811-72-0 ]
Reference：
[1] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2014, vol. 121, p. 254 - 258
[2] Patent: US4980470, 1990, A,
7
[ 154093-72-8 ]
[ 77-78-1 ]
[ 141290-02-0 ]
[ 112811-72-0 ]
Reference：
[1] Patent: WO2006/4561, 2006, A1, . Location in patent: Page/Page column title page; 4; 12-13
8
[ 141290-02-0 ]
[ 112811-72-0 ]
Reference：
[1] Patent: WO2006/4561, 2006, A1, . Location in patent: Page/Page column title page; 4; 12-13
9
[ 112811-64-0 ]
[ 112811-72-0 ]
Reference：
[1] Patent: US4980470, 1990, A,
10
[ 112811-63-9 ]
[ 112811-72-0 ]
Reference：
[1] Patent: US4980470, 1990, A,
11
[ 112811-67-3 ]
[ 112811-72-0 ]
Reference：
[1] Patent: US4980470, 1990, A,
12
[ 13332-24-6 ]
[ 112811-72-0 ]
Reference：
[1] Patent: US4980470, 1990, A,
13
[ 112811-65-1 ]
[ 112811-72-0 ]
Reference：
[1] Patent: US4980470, 1990, A,
14
[ 112811-66-2 ]
[ 112811-72-0 ]
Reference：
[1] Patent: US4980470, 1990, A,
15
[ 112811-68-4 ]
[ 112811-72-0 ]
Reference：
[1] Patent: US4980470, 1990, A,
16
[ 122375-85-3 ]
[ 112811-72-0 ]
Reference：
[1] Patent: US4980470, 1990, A,
17
[ 112811-72-0 ]
[ 154093-72-8 ]
Yield
Reaction Conditions
Operation in experiment
90%
With hydrogenchloride; calcium chloride In water; dimethyl sulfoxide at -5 - 25℃; for 3.5 h;
A volume of approximately 500 mL of DMSO filtrate after the step of nucleophilic substitution was put into a 1000 mL reactor and, under stirring, CaCl2 (approximately 33 g) was added. The mixture was cooled under stirring to 0-5°C (-5°C-25°C) in 30 minutes. The pH was adjusted to the value of 4 with a 15percent HC1 aqueous solution and it was stirred for 3 hours under maintaining the temperature between 0 nad 5°C. The precipitated product was filtered, thoroughly washed with acetone and dried. Dry 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-hydroxy-4-oxo-3-quinoline carboxylic acid (approximately 35 g) with a purity over 90percent was isolated.
7-[3S-amino-5S-methylpiperidinyl]-1-cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-4-oxo-3-quinolinecarboxylic acid hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
[1-CYCLOPROPYL-1,] 4-dihydro-6,7-difluoro-8-methoxy-4-oxo-quinoline-3-carboxylic acid (Precursor A) (0.059 g, 0.200 mmol), (5 (S) -methyl-piperidin-3 (S) -yl)-carbamic acid tert-butyl ester (Precursor [M) _ (0.] 048 g, 0.210 mmol) and triethylamine (0.075 [ML)] are dissolved in N- methyl-pyrrolidone (2 mL). The reaction mixture is stirred at [80C] for 5 hours, then is poured on an ice/water mixture. The pH is lowered to 2 with diluted [HC1] and the resulting precipitate is filtered. The solid is then suspended in ethanol and 6N [HC1] is added. After 18 hours at room temperature, the desired final product is collected by filtration.
trimethylsilyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sulfuric acid; In water; acetonitrile; at 76 - 80℃; for 1h;Product distribution / selectivity;
Example 1 Obtaining Moxifloxacin In a four-mouth 500 ml flask with refrigerant, thermometer, mechanical stirring and nitrogen bubbler with the outlet connected to a washing flask with a solution of H2SO4 is placed 50 g (0.1694 moles, 1 eq) of the compound II, and 150 ml of acetonitryl (3 volumes), and it is heated to T = 76-80 C (reflux). Once reflux has been reached, and maintaining T = 76-80 C, a compensated addition funnel is used to add 19.14 g (0.1186 moles, 0.7 eq) of hexamethyldisilazane. Once the addition has been completed, the reaction is maintained with stirring at T = 76-80 C for 1 hour. Once that period has elapsed the reaction mixture is cooled to T = 0-15 C and 28.85 g (0.2033 moles, 1.2 eq) of boron trifluoride etherate is added, maintaining T<15 C. Once the addition has been completed, it is maintained at T = 0-15C until the starting product has disappeared (approximately 2 hours) and it is then adjusted to pH = 8-9 with triethylamine (approximately 30 ml). To the resulting suspension is added a solution of 32.07 g (0.2541 moles, 1.5 eq) of (S,S)-2,8-diazabicyclo[4.3.0]nonane and 25.71 g of triethylamine (0.2541 moles, 1.5 eq) in 150 ml of acetonitryl, maintaining T = 15-25 C. The resulting amber solution is maintained with stirring under those conditions until the starting product has disappeared (approximately 5-6 hours). Once the reaction is completed it is distilled until a stirrable paste is obtained, 250 ml of methanol is added, the resulting solution is brought to T = 63-67 C (reflux) and is maintained under those conditions until the boron compound (VIII) has disappeared (approximately 5-6 hours). The reaction completed, the methanol is distilled at low pressure, and to the resulting concentrate is added 250 ml of water. The resulting suspension is taken to pH = 12.0 with NaOH 30% and, later to pH=8.0-8.2 with HCl 35% and is extracted with methylene chloride (3 x 125 ml). The combined organic extracts are dried over anhydrous MgSO4 and are concentrated to dryness, obtaining 60.72 g of base Moxifloxacin. Yield: 89.3%. Example 2: Obtaining Moxifloxacin In a four-mouth 500 ml flask with refrigerant, thermometer, mechanical stirring and nitrogen bubbler with the outlet connected to a washing flask with a solution of H2SO4 is placed 50 g (0.1694 moles, 1 eq) of the compound II, 150 ml of acetonitryl (3 volumes), and it is heated to T = 76-80 C (reflux). Once reflux has been reached, and maintaining T = 76-80 C, a compensated addition funnel is used to add 19.14 g (0.1186 moles, 0.7 eq) of hexamethyldisilazane. Once addition has been completed, the reaction is maintained with stirring at T = 76-80 C for 1 hour. Once that period has elapsed the reaction mixture is cooled to T = 0-15 C and 28.85 g (0.2033 moles, 1.2 eq) of boron trifluoride etherate is added, maintaining T<15 C. Once the addition has been completed, it is maintained at T = 0-15 C until the starting product has disappeared (approximately 2 hours), and it is then adjusted to pH = 8-9 with triethylamine (approximately 30 ml). To the resulting suspension is added a solution of 32.07 g (0.2541 moles, 1.5 eq) of (S,S)-2,8-diazabicyclo[4.3.0]nonane and 25.71 g of triethylamine (0.2541 moles, 1.5 eq) in 150 ml of acetonitryl and maintaining T at 15-25C. The resulting amber solution is maintained with stirring under those conditions until the starting product has disappeared (approximately 5-6 hours). Once the reaction is completed it is distilled until a stirrable paste is obtained, 250 ml of methanol is added, the resulting solution is brought to T = 63-67 C (reflux) and is maintained under those conditions until the boron complex (compound VIII) has disappeared, (approximately 5-6 hours). The reaction completed, the methanol is distilled at low pressure and to the resulting concentrate is added 340 ml of water. The resulting suspension is taken to pH = 12 with NaOH 30% and then to pH = 8.0-8.2 with HCl 35%. The dark solution obtained is heated to T = 50-60 C and is maintained under those conditions until the product has precipitated. Once the product has precipitated out, it is maintained under those conditions for 2 hours, following which it is cooled to T = 40 C and filtered. The solid obtained is washed with 10 ml of water and dried at 40C, to provide 48.52 g of base Moxifloxacin as a yellow solid. Example 3: Obtaining Moxifloxacin fluorhydrate In a four-mouth 500 ml flask with refrigerant, thermometer, mechanical stirring and nitrogen bubbler with the outlet connected to a washing flask with a solution of H2SO4 is placed 50 g (0.1694 moles, 1 eq) of the compound II, 150 ml of acetonitryl (3 volumes), and it is heated to T = 76-80 C (reflux). Once reflux has been reached, and maintaining T = 76-80 C, a compensated addition funnel is used to add 19.14 g (0.1186 moles, 0.7 eq) of hexamethyldisilazane. Once addition has been completed, the reaction is maintained with stirring at T = 76-80 C for 1 hour. Once that period has elapse...
In acetonitrile; at 76 - 80℃; for 1h;Heating / reflux;
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.
The diacyl QUINOLINYL BORATES were prepared by the procedure reported in U. S. patent 5,157, 117. A mixture of boric acid (2.4 g, 38. 7 MMOL), acetic anhydride (13.8 mL, 146 MMOL) and zinc chloride (52 mg, 0.38 MMOL) was warmed to 110C for 1.5 h, treated with acetic acid (51 mL) and was allowed to stir. an additional hour at 110C. The resulting mixture was allowed to cool to 60C, treated with 1-CYCLOPROPYL-1, 4-dihydro-6, 7-difluoro- 8-methoxy-4-oxo-quinoline-3-carboxylic acid (18) (7.3 g, 25.9 MMOL) and acetic acid (26 mL). The resulting solution was warmed to 60C for 5 h, cooled to room temperature, and was concentrated in vacuo. The residue was treated with water (50 mL) and the solid was collected by filtration. The resulting solid was washed with water (3 x 50 mL), and dried to afford the title compound as a white solid, which was used as such in the next reaction.
To a suspension of 1-cyclopropyl-6, 7-difluoro-8-methoxy-4-oxo-1, 4-dihydro-quinoline-3- carboxylic acid (10 G) in DMSO (80 mL), ethanolamine (20.68 mL) was added. The reaction mixture was stirred at 90 C for 1.5 hours. The pH of mixture was then adjusted to 4.5 and the product was precipitated. The precipitate was filtered off yielding 10.45 G of the title compound (according to LC-MS 100% pure compound). MS (ES+) M/Z: [MH] += 337.32.
1-cyclopropyl-7-([S,S]-2,8-diazabicyclo-[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Reference Example. Preparation of Moxifloxacin 1-CYCLOPROPYL-6, 7-difluoro-1, 4-DIHYDRO-4-OXO-8-METHOXY QUINOLONE-3-CARBOXYLIC acid (100 GRAMS), (S, S) DIAZABICYCLO NONANE (60 GRAMS) AND 1, 8-DIAZABICYCLO [5. 4. 0. ] UNDEC-7- ene (DBU) (LU. gms) were added to N-METHYLPYROLIDINONE (250 ml) and the reaction mixture was slowly heated to the 60-70C temperature and stirred till the reaction was substantially completed. 5% aqueous isopropyl alcohol was added to the reaction mass, and pH was adjusted towards basic with caustic lye. Then the reaction mass was filtered, through clarifying filter, washed with 5% aqueous isopropyl alcohol. Combined total filtrate and adjusted pH to 7.0 to 7.2 with aqueous Hcl. and isolated at a temperature of 10-15C to afford moxifloxacin. Moxifloxacin then treated with Hydrochloric acid in 10% aqueous methanol to yield corresponding hydrochloride salt. (Wet weight: 115 grams)
1-cyclopropyl-7-([S,S]-2,8-diazabicyclo-[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 4. Preparation of novel crystalline form III of anhydrous moxifloxacin hydrochloride 1-CYCLOPROPYL-6, 7-DIFLUORO-L, 4-dihydro-4-oxo-8-methoxy quinolone-3- carboxylic acid (50 KGS), (S, S) diazabicyclo nonane (1.49 equivalents) and 1,8- diazabicyclo [5.4. 0. ] undec-7-ene (DBU) (5KGS) were added to N-METHYLPYROLIDINONE (125L) in SS Reactor and the reaction mixture was slowly heated to the 60-65 C temperature and stirred till the reaction was substantially completed. 500L of 5% aqueous isopropyl alcohol was added to the reaction mass, and pH was adjusted to 5.0-6. 0 and the product is isolated at 20-25 C. Wet cake is recrystallised in aqueous methanol at pHl. 5- 2. 0, and is made slurry in 5% aqueous methanol. Then wet cake was dissolved in aqueous methanol and the reaction mass was filtered through clarifying filter, washed with aqueous methanol. Combined total filtrate pH was adjusted to 1.5-2. 0 with Aqueous Hcl. Finally, wet cake is taken with methyl isobutylketone (800ML) and heated to reflux while collecting the low boilers and refluxed azeotropically between 115-120 C and then reaction mass is cooled to 25-35 C and product is filtered and dried at 80-90C under vacuum to afford the novel crystalline form III of anhydrous moxifloxacin hydrochloride. (Weight: 31. 3Kgs, M. C. by KF is 0.60% ; Purity by HPLC : 99.94%).
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 75℃;
Step 6: 7- (3-1- [ (1-tert-Butoxycarbonyl-piperidin-4-yl)-methyl-amino]- cyclopropyl}-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1, 4-dihydro- quinoline-3-carboxylic acid: A solution of 4- [methyl- (l-pyrrolidin-3-yl-cyclopropyl)-amino]- piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.31 mmol) in acetonitrile (30.0 mL) was added l-cyclopropyl-6, 7-difluoro-8-methoxy-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid (98 mg, 0.33 mmol) and DBU (0.23 mL, 1.53 mmol). The suspension was heated to 75C overnight. The reaction mixture was partitioned between ethyl acetate and 5% citric acid. The separated organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (10% methanol in dichloromethane) to give the title compound as a yellow solid (102 mg, 62%). ESI MS m/z 599.3 (M + H+)-
With triethylamine; In acetonitrile;Heating / reflux;
Step 3. 7- {3- [1- ( N', N'-Di-tert-butoxycarbonyl-hydrazino)-ethyl]- pyrrolidin-1-yl}-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid: To a solution of N [l- (pyrrolidin-3-yl)-ethyl]-N'-tert-butoxycarbonyl- hydrazinecarboxylic acid tert-butyl ester (750 mg) in CH3CN (10 mL) were added and 1- cyclopropyl-6, 7-difluoro-8-methoxy-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid (300 mg) and triethylamine and refluxed overnight. The mixture was cooled to 0 C and quenched with 0.5 N HC1 and extracted with CH2Cl2. The combined organic layer was dried over MgS04, filtered and evaporated. The resulting residue was purified with flash silica gel column chromatography to give the desired product (320 mg, 58%).
A mixture of 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (1 g, 3,38 mmol) and 1,1-carbonyldiimidazole (2.19 g, 13,54 mmol) in 15 ml CCl3 was heated to reflux and refluxed overnight. The mixture was cooled and the solvent was removed under reduced pressure. To the residue a small amount of diethyl ether was added and the resulting solid was collected by filtration and washed with diethyl ether to give an imidazolide intermediate in a quantitative yield. To the mixture of NaH (0.28 g, 0,0116 mmol, 60% disperse oil) and nitromethane (0.62 ml, 0.01158 mol) in 20 ml of anhydrous THF, a solution of imidazolide intermediate (1 g, 2.89 mmol) in 20 ml of anhydrous THF was added dropwise and heated to reflux for 18 h. The mixture was cooled and 20 ml of H2O was slowly added and neutralized by HCl, and then extracted with CH2Cl2. The organic layer was washed with H2O and brine, dried by anhydrous Na2SO4 and evaporated. The product was precipitated and filtrated off yielding 0.56 g of title product. (93.46% pure compound according to LC-MS). MS (ES+) m/z: [MH]+=339.1
100%
In chloroform;Heating / reflux;
A mixture of 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3- carboxylic acid (1 g, 3,38 mmol) and 1,1-carbonyldiimidazole (2,19 g, 13,54 mmol) in 15 ml CCl3 was heated to reflux over the night. The mixture was cooled and the solvent was removed under reduced pressure. To the resudue a small amount of diethyl ether was added and the resulting solid was collected by filtration and washed with diethyl ether to give a imidazolide intermediate in a quantitative yield. To the mixture of NaH (0,28 g, 0,0116 mmol, 60 % disperse oil) and nitromethane (0,62 ml, 0,01158 mol) in 20 ml of anhydrous THF a solution of imidazolide intermediate (1 g, 2,89 mmol) in 20 ml of anhydrous THF was added dropwise and heated to reflux for 18 h. The mixture was cooled and 20 ml of H20 was slowly added and neutralized by HCI, and then extracted with CH2Cl2. The organic layer was washed with H20 and brine, dried by anhydrous Na2S04 and evaporated. The product was precipitated and filtrated off yielding 0,56g of title product. (93,46 % pure compound according to LC-MS). MS (ES+) m/z : [MH]+ = 339.1
100%
In tetrahydrofuran;Heating / reflux;
A mixture of l-cyclopropyl-^-difluoro-S-memoxy^-oxo-l^-dihydro-quinoline-S- carboxylic acid (1 g, 3,38 mmol) and 1,1-carbonyldiimidazole (2,19 g, 13,54 mmol) in 15 ml CCl3 was heated to reflux over the night. The mixture was cooled and the solvent, was removed under reduced pressure. To the residue a small amount of diethyl ether was added and the resulting solid was collected by filtration and washed with diethyl ether to give an imidazolide intermediate in a quantitative yield.
100%
In tetrahydrofuran;Heating / reflux;
Intermediate 3 1-CvaoDtoDYl-6,7-difluoro-8-methoxv-4-oxo-1,4-dihYdro-auinoline-3-(2-nitroacetvli A mixture of I -cyclopropyl-6,7-difluoro-8-methoxy-4-oxo- 1 ,4-dillydro-quinoline-3- carboxylic acid (1 g, 3,38 mmol) and 1,1-carbonyldiimidazole (2,19 g, 13,54 mmol) in 15 ml CC13 was heated to reflux over the night. The mixture was cooled and the solvent was removed under reduced pressure. To the resudue a small amount of diethyl ether was added and the resulting solid was collected by filtration and washed with diethyl ether to give a imidazolide intermediate in a quantitative yield. To the mixture of NaH (0,28 g, 0,0116 mmol, 60 % disperse oil) and nitromethane (0,62 ml, 0,01158 mol) in 20 ml of anhydrous THF a solution of imidazolide intermediate (1 g, 2,89 mmol) in 20 ml of anhydrous THF was added dropwise and heated to reflux for 18 h. The mixture was cooled and 20 ml of H20 was slowly added and neutralized by HCI, and then extracted with CH2Cl2. The organic layer was washed with H20 and brine, dried by anhydrous Na2S04 and evaporated. The product was precipitated and filtrated off yielding 0,56g of title product. (93,46 % pure compound according to LC-MS). MS (ES+) m/z: [MH] (at) = 339.1
e. 1-Cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid A mixture of ethyl-1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinoline carboxylic acid (500 mg, 1.55 mmol), glacial acetic acid (5 mL), and 1N hydrochloric acid (1 mL) was allowed to reflux for 2 hours and was poured into ice water. The resulting precipitate was collected by suction filtration and washed with distilled water and diethyl ether to give 420 mg, 91% yield of a white solid, m.p. 187-189 C.
1-Cyclopropyl-1,4-dihydro-6,7-difluoro-8-methoxy-4-oxo-quinoline-3-carboxylic acid (Precursor A) (0.059 g), Trans,3-tert-butoxycarbonylamino-4-ethyl-piperidine (Precursor F) (0.048 mg) and triethylamine (0.075 mL) are dissolved in N-methyl-pyrrolidone (2 mL). The reaction mixture is stirred at 80 C. for 5 hours, then is poured on an ice/water mixture. The pH is lowered to 2 with diluted HCl and the resulting precipitate is filtered. The solid is then suspended in ethanol and 6N HCl is added. After 18 hours at room temperature, the desired final productproduct is collected by filtration.
24
Trans 4-(2-hydroxy-ethyl)-3-tertbutoxycarbonylamino-piperidine[ No CAS ]
[ 112811-72-0 ]
7-[Trans-3-amino-4-(2-hydroxy-ethyl)-piperidine-1-yl]-1-Cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-4-oxo-quinoline-3-carboxylic acid hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 2 7-[Trans-3-amino-4-(2-hydroxy-ethyl)-piperidine-1-yl]-1-Cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-4-oxo-quinoline-3-carboxylic acid hydrochloride A procedure similar to Example 1 above is used, using 1-Cyclopropyl-1,4-dihydro-6,7-difluoro-8-methoxy-4-oxo-quinoline-3-carboxylic acid (Precursor A) and Trans 4-(2-hydroxy-ethyl)-3-tertbutoxycarbonylamino-piperidine (Precursor G) as the starting materials. The procedure utilizes the same reaction conditions and molar ratio of reactants as Example 1.
3-(S)-tert-butoxycarbonylamino-4-(S)-fluoromethylpyrrolidine[ No CAS ]
[ 112811-72-0 ]
7-[3-(S)-amino-4-(S)-fluoromethyl-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
185 mg (47%)
With hydrogenchloride; dimethyl sulfoxide; triethylamine; citric acid; In water-containing ethanol;
INVENTIVE EXAMPLE 2 7-[3-(S)-Amino-4-(S)-fluoromethyl-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid To a dimethyl sulfoxide (2 ml) solution of <strong>[112811-72-0]1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid</strong> EF2 complex (345 mg, 1.00 mmol) were added 3-(S)-tert-butoxycarbonylamino-4-(S)-fluoromethylpyrrolidine (327 mg, 1.00 mmol) and triethylamine (400 mul), subsequently carrying out 1 day of stirring at room temperature. Triethylamine was evaporated, the resulting residue was mixed with 10% citric acid aqueous solution and then the thus precipitated material was collected by filtration and washed with water. This was dissolved in 80% water-containing ethanol (50 ml), mixed with triethylamine (5 ml) and then heated overnight under reflux. The solvent was evaporated, and the thus obtained residue was mixed with concentrated hydrochloric acid and stirred at room temperature for 15 minutes. The reaction solution was washed with chloroform and then, while cooling in an ice bath, alkalified with 50% sodium hydroxide aqueous solution. This was adjusted to pH 7.4 with concentrated hydrochloric acid, and the aqueous layer was extracted with chloroform (300 ml*3). The organic layer was dried over sodium sulfate, the solvent was evaporated, and the resulting residue was isolated and purified by a preparative TLC through its development with a lower layer of chloroform:methanol:water=7:3:1 and then recrystallized from 28% aqueous ammonia-ethanol to give 185 mg (47%) of the title compound in the form of light yellow crystals. 1H-NMR (0.1N NaOD) delta: 0.90-1.20 (4H, m), 2.73-2.78 (1H, m), 3.41-3.44 (1H, m), 3.58 (3H, s), 3.64-3.73 (3H, m), 3.90-3.96 (1H, m), 4.03-4.09 (1H, m), 4.66-4.82 (1H, m), 7.65 (1H, d, J=14.65 Hz), 8.49 (1H, s). Elemental analysis data for C19H21F2N3O4·0.25H2O: Calcd.: C, 57.35; H, 5.45; N, 10.56 Found: C, 57.36; H, 5.46; N, 10.41
1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-(morpholino)-3-quinolinecarboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In water; acetonitrile;
Example 3 Synthesis of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-(morpholino)-3-quinolinecarboxylic acid A mixture of 1.48 g of <strong>[112811-72-0]1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid</strong> (5 mmol), 0.85 g of morpholine (10 mmol), 1.04 g of trimethoxyborane (10 mmol) and 7.5 ml of acetonitrile was refluxed with heating for 4 hours. The reaction solution was cooled to room temperature, 20 ml of water was added therein, a pH was adjusted to 8 with 6N--HCl, and separated crystals were filtered and dried to obtain 1.30 g of the objective compound. Melting point: 210.0 C. (decomposition) NMR spectrum (CDCl3): 14.885(s,1H), 8.706(s,1H), 7.753(d,J=12.54 Hz,1H), 4.0-4.2(m,1H), 3.806(s,3H), 3.3-3.4(m,4H), 2.5-2.6(m,4H), 1.0-1.2(m,4H)
1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-7-(pyrrolidin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88.2%
In ethanol; acetonitrile;
Example 8 Synthesis of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-pyrrolidino-3-quinolinecarboxylic acid 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), 1.42 g of pyrrolidine (20 mmol), 1.04 g of trimethoxyborane (10 mmol) and 20 ml of acetonitrile was refluxed with heating for 3.5 hours. The reaction solution was cooled to room temperature, acetonitrile was distilled under vacuum and 15 ml of ethanol was added into the resultant product. Separated crystals were filtered and dried to obtain 3.05 g of the objective compound (88.2%). Melting point: 257.0-258.0 C. NMR spectrum (CDCl3): 15.095(s,1H), 8.768(s,1H), 7.790(d,J=13.86 Hz,1H), 4.0-4.1(m,1H), 3.538(s,3H), 3.5-3.7(m,4H), 1.8-2.0(m,4H), 1.0-1.2 (m, 4H)
1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-[3-(N-acetyl-N-methylamino)pyrrolidino]pyrrolidino-3-quinolinecarboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83.9%
In ethanol; acetonitrile;
Example 9 Synthesis of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-[3-(N-acetyl-N-methylamino)pyrrolidino]pyrrolidino-3-quinolinecarboxylic acid 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), 2.84 g of 3-(N-acetyl-N-methylamino)pyrrolidine (20 mmol), 1.04 g of trimethoxyborane (10 mmol) and 20 ml of acetonitrile was refluxed with heating for 3.5 hours. The reaction solution was cooled to room temperature, acetonitrile was distilled under vacuum and 15 ml of ethanol was added into the resultant product. Separated crystals were filtered and dried to obtain 3.50 g of the objective compound (83.9%). Melting point: 206.0-207.0 C. NMR spectrum (CDCl3): 14.394(s,1H), 8.786(s,1H), 7.801(d,J=13.53 Hz,1H), 5.3-5.4(m,1H), 3.5-4.0(m,5H), 3.032(s,1H), 2.160(s,3H), 2.0-2.3(m,3H), 0.9-1.3(m,4H)
1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-(1-pyrazinyl)-3-quinolinecarboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In water; acetonitrile;
Example 1 Synthesis of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-(1-pyrazinyl)-3-quinolinecarboxylic acid A mixture of 1.48 g of <strong>[112811-72-0]1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid</strong> (5 mmol), 0.86 g of anhydrous piperazine (10 mmol), 1.04 g of trimethoxyborane (10 mmol) and 7.5 ml of acetonitrile was refluxed with heating for 4 hours. The reaction solution was cooled to room temperature, 20 ml of water was added therein, a pH was adjusted to 8 with 6N--HCl, and separated crystals were filtered and dried to obtain 1.46 g of the objective compound. Melting point: 174.0-177.0 C. NMR spectrum (DMSO): 8.795(s,1H), 7.731(d,J=12.5 Hz,1H), 4.05-4.15(m,1H), 3.771(s,3H), 2.8-3.0(m,4H), 1.0-1.2(m,4H)
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.
3-(5-methyl-1,2,3-triazol-1-yl)-pyrrolidine hydrochloride[ No CAS ]
[ 112811-72-0 ]
1-Cyclopropyl-6-fluoro-8-methoxy-7-[3-(5-methyl-1,2,3-triazol-1-yl)pyrrolidin-1-yl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile;
EXAMPLE 66 1-Cyclopropyl-6 -fluoro-8-methoxy-7-[3-(5-methyl-1,2,3-triazol-1-yl)pyrrolidin-1-yl]-1,4-dihydro-4-oxoquinoline -3-carboxylic acid 3-(5-methyl-1,2,3-triazol-1-yl)pyrrolidine hydrochloride (64 mg, 0.34 mmol) and DBU (77 mg, 0.51 mmol) was added to a suspension of 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (50 mg, 0.17 mmol) in acetonitrile (5 ml). The reaction mixture was refluxed for 18 hrs and then concentrated to dryness. The residue was triturated with water and thus separated solid was filtered, washed with water, acetonitrile and dried to give 5 mg of title product. m.p. 226-228 C.; 1 H NMR (TFA) delta: 9.35 (s, 1H), 8.32 (s, 1H), 8.08 (d, 1H), 5.72 (m, 1H), 4.30-4.80 (m, 4H), 4.10 (m, 1H), 3.80 (s, 3H), 2.90 (m, 2H), 2.72 (s, 3H), 1.12-1.64 (m, 4H).
2-Methyl-2,5-diazabicyclo[2.2.1]heptane dihydrochloride[ No CAS ]
[ 6674-22-2 ]
[ 112811-72-0 ]
[ 135235-87-9 ]
Yield
Reaction Conditions
Operation in experiment
In dimethyl sulfoxide;
f. 1-Cyclopropyl-6-fluoro-8-methoxy-7- [(1S:4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid A mixture of <strong>[112811-72-0]1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid</strong> (400 mg, 1.4 mmol), (1S:4S)-2-methyl-2,5-diazabicyclo-[2.2.1]heptane dihydrochloride (300 mg, 1.63 mmol, 1.2 equiv) and 1,8-diazabicyclo[5.4.0]undec-7-ene (710 mL, 4.75 mmol, 3.4 equiv) in anhydrous dimethyl sulfoxide (25 mL) was heated to 75 C. for 18 hours. The reaction mixture was cooled to room temperature and poured into distilled water adjusted to pH=7.4 with saturated aqueous sodium bicarbonate. The aqueous phase was extracted several times with chloroform. The chloroform layer was then extracted with 1N HCl and the acidic aqueous phase was back extracted with chloroform. The aqueous layer was adjusted to pH=7.4 with saturated aqueous sodium bicarbonate and extracted with chloroform. The chloroform extracts were dried over sodium sulfate, filtered and concentrated in vacuo to a dark oil which was purified by flash chromatography (chloroform/methanol 10:1 v/v) to give 65 mg, 12% yield of a white solid, m.p. 190-212 C with decomposition. Anal.: Calcd. for C20 H22 FN3 O4. 0.5H2 O: C, 60.60; H, 5.80; N, 10.60. Found: C, 60.57; H, 5.70; N, 10.59.
[1α,5α,6β]-6-amino-1-methyl-3-azabicyclo[3.2.0]heptane[ No CAS ]
[ 112811-72-0 ]
7-([1α,5α,6β]-6-amino-1-methyl-3-azabicyclo[3.2.0]heptane-3-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
15%
In ethanol; water; dimethyl sulfoxide;
EXAMPLE 44 7-([1alpha,5alpha,6beta]-6-Amino-1-methyl-3-azabicyclo[3.2.0]heptane-3-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1,4,dihydro-4-oxoquinoline-3-carboxylic acid 100 mg of 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 120 mg of [1alpha,5alpha,6beta-6-amino-1-methyl-3-azabicyclo-[3.2.0]heptane were added to 2 ml of DMSO. The resulting mixture was heated at 80 to 90 C. for 2 hours. To the reaction solution was added 5 ml of water. The resulting solution was adjusted to pH 7 with an aqueous 5% hydrochloric acid solution and extracted twice with 30 ml of chloroform. The chloroform layer was removed and concentrated under reduced pressure. A small amount of water and ethanol was added to the residue. The resulting mixture was stirred at room temperature for an hour. The solids formed were collected by filtration, and then dried to give 20 mg of the titled compound as white solids (yield: 15%). m.p.: 195-200 C. 1 H-NMR(DMSO-d6 +TFA-d) delta: 8.73(1H, s), 7.77(1H, d, J=14.2 Hz), 4.3-1.9 (9H, m), 3.65(3H, s), 1.35(3H, s), 1.4-0.7 (4H, m).
[1α,6α,8β]-8-amino-3-azabicyclo[4.2.0]octane[ No CAS ]
[ 112811-72-0 ]
7-([1α,6α,8β]-8-amino-3-azabicyclo[4.2.0]octane-3-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44%
With pyridine; In water;
EXAMPLE 66 7-([1alpha,6alpha,8beta]-8-Amino-3-azabicyclo[4.2.0]octane-3-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid To 3 ml of pyridine, 100 mg of 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 50 mg of [1alpha,6alpha,8beta]-8-amino-3-azabicyclo-[4.2.0]octane were added. The resulting mixture was heated under reflux with stirring for 2 hours, and then cooled to room temperature. To the solution, 3-4 drops of water were added. After cooling in an ice bath with stirring, the solids precipitated were collected by filtration, washed with cold ethanol, and then dried to give 60 mg of the titled compound as white solids (yield: 44%). m.p.: 186-190 C. 1 H-NMR(DMSO-d6 +TFA) delta: 8.15(1H, s),7.70(1H, d, J=12 Hz),4.50-3.76 (6H, m),3.70(3H, s),3.57-1.28(6H, m),1.09 (4H, m).
EXAMPLE Z19 STR107 1-Cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid is reacted in an analogous manner to Example Z1A and the reaction product is purified by chromatography (silica gel, eluent: methylene chloride/methanol/17% strength aqueous ammonia=30:8:1). 1-Cyclopropyl-7-([S,S]-2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid with a melting point of 203-208 C. (with decomposition) is obtained. [alpha]D23: -193 (c=0.4, CHCl3)
EXAMPLE 20 STR33 208 mg (2 mmol) of trimethyl borate, 123 mg (1.1 mmol) of 1,4-diazabicyclo[2.2.2]octane and 185 mg (1.1 mmol) of 4-aza-tricyclo[5.2.2.02,6 ]undec-1-ylamine are added to 295 mg (1 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy4-oxo-3-quinolinecarboxylic acid in 3 ml of acetonitrile at room temperature and the mixture is then heated under reflux for 4 hours. The reaction mixture is concentrated at 80 C./20 mbar, the residue is stirred with water and the precipitate which has separated out is filtered off with suction, washed with water and dried at 100 C. under a high vacuum. Yield: 218 mg (51% of theory) of 7-(1-amino-4-azatricyclo[5.2.2.02,6 ]undec-4-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid, Melting point: 234-237 C. (with decomposition).
7-(4-aminomethyl-3-benzyloxyimino-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 45 Synthesis of 7-(4-aminomethyl-3-benzyloxyimino-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid STR96 590 mg of 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 584 mg of the compound prepared in Preparation 8 were suspended in 15 ml of acetonitrile and then 913 mg of 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU) was slowly added thereto.
EXAMPLE 45 Synthesis of 7-(4-aminomethyl-3-benzyloxyimino-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid STR97 590 mg of 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 584 mg of the compound prepared in Preparation 8 were suspended in 15 ml of acetonitrile and then 913 mg of 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU) was slowly added thereto.
Example 45 Synthesis of 7-(4-aminomethyl-3-benzyloxyimino-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 590mg of 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 584mg of the compound prepared in Preparation 8 were suspended in 15ml of acetonitrile and then 913mg of 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU) was slowly added thereto.
(+)-2,8-diazabicyclo[4.3.0]non-5-ene dihydrogen chloride[ No CAS ]
[ 112811-72-0 ]
[ 157644-12-7 ]
Yield
Reaction Conditions
Operation in experiment
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile;
EXAMPLE 3 Preparation of 1-cyclopropyl-6-fluoro-7-(((+)-2,8-diazabicyclo[4.3.0]non-5-en)-8-yl)-8-methoxy-1,4-dihydro-4-oxo-3-quinoline carboxylic acid 195 mg of (+)-2,8-diazabicyclo[4.3.0]non-5-ene dihydrogen chloride, 457 mg of DBU and 295 mg of 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinoline carboxylic acid were added to 2.5 ml of acetonitrile and stirred for 10 hours under reflux. The reaction mixture was cooled to room temperature to result in solid products. The resulting solid product was filtered, washed with 3 ml of acetonitrile and dried to give 312 mg of desired white solid product. 1 H-NMR(CDCl3, delta); 1.16(4H, m), 2.11(1H, m), 2.70~4.20(7H, m), 4.02(3H, s), 4.65(1H, d), 5.70(1H, s), 7.84(1H, d), 8.80(1H, s)
7-(3-aminomethyl-4-t-butyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
EXAMPLE 94 Synthesis of 7-(3-aminomethyl-4-t-butyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid STR150 143 mg (0.5 mmole) of 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid was refluxed for 10 hours under heating according to the same manner as Example 89. Then, the resulting residue was purified with preparative HPLC to obtain 92 mg (Yield: 40%) of the title compound. 1 H NMR (DMSO-d6, ppm): delta 8.9(1H, s), 7.8(1H, d), 4.5(2H, s), 4.3(1H, m), 4.1(1H, m), 3.9 (1H, m), 3.0(1H, m), 2.8-2.7(2H, m), 2.7(3H, s), 1.3(9H, s), 1.25(2H, m), 0.9(2H, s); FAB MS(POS): [M+H]+ =461
40%
Example 94 Synthesis of 7-(3-aminomethyl-4-t-butyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 148mg (0.5 mmole) of 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was refluxed for 10 hours under heating according to the same manner as Example 89. Then, the resulting residue was purified with preparative HPLC to obtain 92mg (Yield: 40%) of the title compound.
1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-(morpholino)-3-quinolinecarboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In dimethyl sulfoxide;
[Step (A1)] 1.2 g (0.012 mole) of morpholine was added to a solution of 0.9 g (0.003 mole) of 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (IIc) (prepared as described in Preparation 6) in 5 ml of dimethyl sulfoxide, and the mixture was stirred at 70 C. for 6 hours. At the end of this time, the solvent and the excess morpholine were removed at the same temperature by evaporation under reduced pressure. The residue was washed with ethyl acetate and then subjected to silica gel column chromatography eluted with methanol, to afford 0.65 g of 1-cyclopropyl-6-fluoro-8-methoxy-7-morpholino-1,4-dihydro-4-oxoquinoline-3-carboxylic acid as a pale brown powder melting at 235-237 C. Mass Spectrum: m/e 362 (M+), 318 (M+ -CO2).
1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In dimethyl sulfoxide;
EXAMPLE 2 Synthesis of 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid A mixture of <strong>[112811-72-0]1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid</strong> (200 mg), N-methylpiperazine (140 mg) and anhydrous DMSO (3 ml) was stirred for 5 hours at 70 to 95 C. on an oil bath. The reacting 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 colorless needles, mp 221-222 C. (decompd.). Analysis (%) for C19 H22 FN3 O4; Calcd. (Found): C, 60.79 (60.82); H, 5.91 (5.90); N, 11.19 (11.24).
1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In dimethyl sulfoxide;
[Step (A1)] 0.12 g (0.0012 mole) of N-methylpiperazine was added to a solution of 0.09 g (0.0003 mole) of 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (IIc) (prepared as described in Preparation 6) in 0.5 ml of dimethyl sulfoxide, and the mixture was stirred at 70 C. for 6 hours. At the end of this time, the solvent and the excess N-methylpiperazine were removed by evaporation under reduced pressure at the same temperature, and the residue was washed with ethyl acetate and subjected to silica gel column chromatography, eluted with methanol, to afford 0.03 g of 1-cyclopropyl-6-fluoro-8-methoxy-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid as colorless powdery crystals, melting at 211-214 C.
1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid boron difluoride chelate[ No CAS ]
trans-4-methoxypyrrolidin-3-amine dihydrochloride[ No CAS ]
[ 13842-55-2 ]
[ 112811-72-0 ]
7-(trans-3-amino-4-methoxy-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium methylate; triethylamine; In water; dimethyl sulfoxide;
EXAMPLE 64 7-(trans-3-Amino-4-methoxy-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride [Steps (A3)+(A4)] 0.19 g (0.0036 mole) of sodium methoxide was added to a suspension of 0.34 g (0.0018 mole) of trans-3-amino-4-methoxypyrrolidine dihydrochloride (prepared as described in Preparation 18) in 1.5 ml of dimethyl sulfoxide, and the mixture was stirred at room temperature for 30 minutes. 0.31 g (0.0009 mole) of a chelate (IV) of 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and boron difluoride (prepared as described in Preparation 7) were added to the resulting solution, followed by 0.27 g (0.0027 mole) of triethylamine. The mixture was then allowed to stand at room temperature overnight. At the end of this time, 50 ml of water were added to the mixture, and a chelate (V) separated out. This was collected by filtration to give yellow crystals.
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; for 6h;
EXAMPLE 9 Synthesis of 1-cyclopropyl-7-(3-ethylaminomethyl-1-pyrrolidinyl)-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid A mixture of <strong>[112811-72-0]1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid</strong> (200 mg), 3-ethylaminomethylpyrrolidine (100 mg), DBU (110 mg) and anhydrous acetonitrile (3 ml) was refluxed for 6 hours. After cooling, the resulting precipitate was collected by filtration and recrystallized from methanol to give the title compound (120 mg) as colorless prisms, mp 217-219 C. Analysis (%) for C21 H26 FN3 O4.2/3 H2 O; Calcd. (Found): C, 60.71 (60.59); H, 6.63 (6.43); N, 10.11 (10.03).
7-(3-aminomethylpiperidin-1-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In N,N-dimethyl-formamide; acetonitrile;
EXAMPLE 11 A suspension of <strong>[112811-72-0]1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid</strong> (1.48 g), 3-aminomethylpiperidine (1.14 g) and triethylamine (1.5 g) in acetonitrile (20 ml) and N,N-dimethylformamide (10 ml) was refluxed overnight. Concentration of the reaction mixture followed by purification by silica gel column chromatography (chloroform:methanol:ammonium hydroxide=15:5:1) gave 7-(3-aminomethylpiperidin-1-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid, which was recrystallized from isopropanol-water to afford yellow prisms. m.p. 192-193 C. MS m/e: 389 (M+)
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.
1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-7-[4-(2-benzothiazolyl)piperazin-1-yl]quinoline-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
(Preparation example 145) Synthesis of 1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-7-[4-(2-benzothiazolyl)piperazin-1-yl]quinoline-3-carboxylic acid Reaction of 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid with 1-(2-benzothiazolyl)piperazine and purification of the reaction mixture were carried out in a similar manner to that described in Preparation example 63 to afford the title compound.
Example 35 Synthesis of 7-[3(R)-amino-4(R)-methyl-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid hydrochloride The reaction was performed similarly to Example 34 using 1.03 g of <strong>[112811-72-0]1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid</strong> and 0.89 g of 3(R)-[(t-butoxycarbonyl)amino]-4(R)-methylpyrrolidine to obtain 0.63 g of aimed product. Melting point: 175-184C (decomposed gradually) Specific rotation: [alpha] [20/D ] = +85.1 (c=1.07, DMSO)
trans-3-tert-butoxycarbonylamino-4-methylpyrrolidine[ No CAS ]
[ 112811-72-0 ]
[ 137172-74-8 ]
Yield
Reaction Conditions
Operation in experiment
Example 36 Synthesis of 7-[3(R)-amino-4(S)-methyl-l-pyrrolidinyl]-l-cyclopropyl-6-fluoro-1-4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid hydrochloride The reaction was performed similarly to Example 33 using 639 mg of <strong>[112811-72-0]1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid</strong> and 650 mg of 3(R)-[(t-butoxycarbonyl)amino]-4(S)-methylpyrrolidine to obtain 350 mg of aimed product. Melting point: 195-197C Specific rotation: [alpha] [20/D ] = - 126.9 (c=1.10, DMSO)
1-amino-5-azaspiro[2.4] heptane hydrobromide[ No CAS ]
[ 6674-22-2 ]
[ 112811-72-0 ]
7-(1-amino-5-azaspiro[2.4]heptane-5-yl)-1-cyclopropyl-6-fluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
In chloroform; acetonitrile;
Example 19 Preparation of 7-(1-amino-5-azaspiro[2,4]heptane-5-yl)-1-cyclopropyl-8-methoxy-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid 530mg of 1-cyclopropyl-8-methoxy-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 520mg of 1-amino-5-azaspiro[2,4] heptane hydrobromide and 878mul of 1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 10ml of acetonitrile; and the resulting solution was refluxed for 4 hours and concentrated under a reduced pressure. The resultant was dissolved in 30ml of chloroform and washed with water several time. The organic layer was dried over magnesium sulfate and concentrated under a reduced pressure. The resulting material thus obtained was fractionated on silica gel column chromatography(chloroform methanol: water=15:3:1) to obtain 300mg of the desired compound(yield 50%). m.p. 183~185C
7-[3(S)-[(t-butoxycarbonyl)amino]-4(R)-methyl-l-pyrrolidinyl]-l-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With citric acid; In dichloromethane; acetonitrile;
Example 33 Synthesis of 7-[3(S)-amino- 4(R)-methyl-l-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid hydrochloride To 30 ml of anhydrous acetonitrile were added 3.69 g of <strong>[112811-72-0]1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid</strong>, 3.02 g of 3(S)-[(t-butoxycarbonyl) amino]-4(R)-methylpyrrolidine and 1.90 g of 1,8-diazabicyclo-[5,4,0]-7-undecene (DBU), and the mixture was refluxed for 8 hours at 100C. The reaction liquor was concentrated and the residue was dissolved into 150 ml of methylene chloride, which was washed with 10 % aqueous solution of citric acid and then with saturated saline solution, dried over magnesium sulfate, and then concentrated. The residue was purified through silica gel column (elution solvent, chloroform:methanol: concentrated aqueous ammonia=50:10:1) to obtain 5.05 g of 7-[3(S)-[(t-butoxycarbonyl)amino]-4(R)-methyl-l-pyrrolidinyl]-l-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid.
Example 1 Preparation of 1-cyclopropyl-7-[(S,S)-2,8-diazabicyclo[4.3.0]non-8-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. (III) Dimethylsulfoxide (600 ml), 50 g of 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid (IV) and 25.70 ml of [S,S]-2,8-diazabicyclo [4.3.0] nonane (V) were stirred at 65 - 70 C for 6 - 8 hours. Completion of the reaction was monitored by HPLC. The reaction mass was cooled to 25-30 C, 100 ml of water was added and stirred for 2 hours. The solid was filtered off with suction, washed with 100 ml water and dried under vacuum at 75C, affording 61.0 g of the title compound. Yield: 89.7 % Purity: 98 % (HPLC) Chiral impurity (R,R isomer content): 3 - 5 %
66%
With triethylamine; In N,N-dimethyl-formamide; acetonitrile; at 0 - 78℃; for 11h;Reflux;
1 -cyclopropyl-^-difiuoro-delta-methoxy^-oxo- 1 ,4-dihydro-3-quinolinecarboxylic acid (100g, 0.338 mole) and triethylamine were taken in mixture of acetonitrile (300 ml) and dimethylformamide (80 ml) . To it was added (S,S)-2,8-diazabicyclo [4.3.0] nonane (47g, 0.373 mole) and refluxed at 72- 78C for 10 hours at reflux. The reaction mixture was cooled to room temperature, and further to 0-5C maintained for 1 hr, filtered and washed with acetonitrile (50 ml) to get the desired product.Dry wt: 89.7g, Yield: 66%.
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 85℃; for 12h;
A mixture of l-Cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-l,4-dihydro-3- quinoline carboxylic acid (100 grams), [S,S]-2,8-diazabicyclo [4,3,0] nonane (52 grams), l,8-Diazabicyclo(5,4,0)undec-7-ene (10 grams) and acetonitrile (300 ml) was heated to 850C. The reaction mixture was stirred for 12 hours at 85C. The solvent was distilled off completely under reduced pressure at below 7O0C. The reaction mixture cooled to 6O0C and water was added. The pH of the reaction mixture was adjusted to 5.8 with hydrochloric acid. The reaction mixture was extracted with methylene chloride. The solvent was distilled off completely under reduced pressure. Acetone (300 ml) was added to the obtained residue. The reaction mixture was stirred for 30 minutes at 25-300C. The obtained solid was filtered, washed with acetone and dried at 600C. The obtained solid was recrystallized by using acetone as a solvent. Yield: 100 grams. Water content: 2.2% Chloride content: 130 ppm.
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 65 - 75℃;Product distribution / selectivity;
Reference Example: Preparation of Moxifloxacin; A solution of lOOg of 1-Cyclopropyl -6,7difluoro-l,4-dihydro-4-oxo-methoxyquinolone- 3-carboxilic acid), 52gr of (S,S)2,8 diazabicyclo[4,3,0]nonane, lOgr of 1,8- diazabycyclo[5,4,0]undec-7-ene and 300ml of acetonitrile is heated to 65 -70C temperature and stirred till the reaction get completed and evaporated the solvent. Added 5 %aqueous isopropylalcohol to the reaction mass and adjusted the pH to basic with caustic solution and then filtered the reaction mass. Combined the total filtrate and adjusted the pH to 5.0 to 6.0 with aqueous HCl.and isolated the separated solid at a temperature of 10-150C to afford Moxifloxacin.; Example 5: Preparation of novel crystalline form X of anhydrous Moxifloxacin hydrochloride5Og of 1-cyclopropyl -6,7-difluoro -1,4-difluoro-l, 4 - dihydro - 4 - oxo-8-methoxy quinolone-3-carboxilic acid , (S, S) diazabicyclo nonane and 5gr of 1,8-diazabicyclo [5,4,0] undec-7-ene (5g) in 300 ml acetonitrile heated to 65-75C and stirred. Evaporated the solvent completely and added 5 % aqueous isopropyl alcohol. Adjusted the pH to 8.5 with caustic solution, then the reaction mass filtered. Adjusted the pH filtrate to 5 with aqueous hydrochloric acid. Cooled the reaction mixture to 10- 150C. Isolated the separated solid to afford moxifloxacin. This wet Moxifloxacin, suspended in 400 ml Toluene and heated 110-1120C to reflux azeotropically and then reaction mass is cooled to 25-35C. Quenched the reaction mass with 200 ml of isopropyl alcohol and adjusted pH to .98 with hydrochloric acid in Isopropyl alcohol. Isolated the solid by filtration and washed the material with isopropyl alcohol. Dried at 80-90C under vacuum to afford the novel crystalline form -X of anhydrous Moxifloxacin hydrochloride. (Weight: 33.0 grams, M.C by KF method is 0.09%w/w, Purity by HPLC: 99.94%)
50.0 g of 1-Cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinic acid of formula (V) (1.0 mol. equiv.), 15.80 g of Mg(OH)2 (1.6 mol. equiv.) and 300 mL of Acetonitrile were introduced into a 4-neck flask provided with a mechanical stirrer, thermometer, cooler and thermostat. Heating is carried out at 78C for one hour under slow stirring with the aim of forming the Moxifloxacin complex with Magnesium. A solution formed by 34.20 g of (4aS, 7aS)-Octahydro-1H-pyrrole[3,4-b]pyridine of formula (VI) and 150 mL of Acetonitrile is dosed in 1 hour. The reaction mixture is left at reflux for another 4 hours. Upon completing the reaction (conversion exceeding 90%) the mixture is cooled at 50C and the ACN is distilled under vacuum up to obtaining a soft pasty residue. Such residue is cooled at 0C and a cold solution at 0C made up of 150 mL of Acetone and 300 mL of Dichloromethane is then added slowly. Stirring is carried out for 10 minutes at room temperature then 2.5 g of dicalite and 2.5 g of acticarbone are added. Stirring is carried out for 10 minutes then filtration is carried out on a dicalite panel. The filtrate is concentrated to dryness in the rotavapor then recovered using 300 mL of dichloromethane. This organic solution is washed using a solution made up of 100 mL of a saturated NaHCO3 solution and 50 mL of purified water. The underlying organic phase containing the product is separated and the aqueous phase is re-extracted using 100 mL of dichloromethane. The organic phases are mixed again and then dried obtaining 71.0 g of Moxifloxacin base, with HPLC purity equivalent to 90.27% and with formula (VII) impurity equivalent to 1.09%.
50.0 g of 1-Cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinic acid of formula (V) (1.0 mol. equiv.), 15.80 g of Mg(OH)2 (1.6 mol. equiv.) and 300 mL of Acetonitrile were introduced into a 4-neck flask provided with a mechanical stirrer, thermometer, cooler and thermostat. Heating was carried out at 78C for one hour under slow stirring with the aim of forming the Moxifloxacin complex with Magnesium. A solution formed by 34.20 g of (4aS,7aS)-Octahydro-1H-pyrrole[3,4-b]pyridine of formula (VI) and 150 mL of Acetonitrile was dosed in 1 hour. The reaction mixture was left at reflux for another 4 hours. Upon completing the reaction (conversion exceeding 90%) the mixture was cooled at 50C and the ACN was distilled under vacuum up to obtaining a soft pasty residue. Such residue was cooled at 0C and a cold solution at 0C made up of 150 mL of Acetone and 300 mL of Dichloromethane was then added slowly. Stirring was carried out for 10 minutes at room temperature then 2.5 g of dicalite and 2.5 g of acticarbone were added. Stirring was carried out for 10 minutes then filtration was carried out on a dicalite panel. The filtrate was concentrated to dryness in the rotavapor then recovered using 300 mL of dichloromethane. This organic solution was washed using a solution made up of 100 mL of a saturated NaHCO3 solution and 50 mL of purified water. The underlying organic phase containing the product was separated and the aqueous phase was re-extracted using 100 mL of dichloromethane. The organic phases were mixed again and then dried obtaining 71.0 g of Moxifloxacin base, with HPLC purity equivalent to 90.27% and with formula (VII) impurity equivalent to 1.09%. The solid residue was recovered using 100 mL of purified water and 800 mL of Isopropanol. Heating was carried out at reflux up to complete dissolution. A solution of 26.06 g of paratoluenesulfonic acid (1.1 mol. equiv.) in 100 mL of Isopropanol was dripped at 70C in one hour. It was slowly brought to 35C, then it was left under stirring at 35C for one night. The suspension was paper-filtered at 35C and the solid was washed using 100 mL of Isopropanol. The solid was dried in an oven at 50C for at least 8 hours. 72.5 g equivalent to a 74.6% molar yield of Moxifloxacin Tosylate were obtained as a hazelnut-coloured solid with HPLC purity equivalent to 98.46% and with a formula (VII) impurity content equivalent to 0.54%.1H-NMR (400 MHz, DMSO-d6): delta/ppm=0.84-1.24 (m, 4H), 1.70-1.85 (m, 4H), 2.30 (s, 3H), 2.65-2.2.72 (m, 1H), 2.98-3.03 (m, 1H), 3.24-3.28 (m, 1H), 3.52-3.55 (m, 1H), 3.59 (s, 3H), 3.75-3.92 (m, 3H), 4.09-4.20 (m, 2H), 7.12 (d, 1H, j=7.88 Hz), 7.49 (d, 1H, j=8.04 Hz), 7.71 (d, 1H, j=14.13 Hz), 8.69 (s, 1H). Melting point=273C (determined using DSC).
With potassium chloride; In acetone;Heating / reflux;Product distribution / selectivity;
A volume of approximately 500 mL of DMSO filtrate after the step of nucleophilic substitution was put into a 1000 mL reactor and, under stirring, CaCl2 (approximately 33 g) was added. The mixture was cooled under stirring to 0-5C (-5C-25C) in 30 minutes. The pH was adjusted to the value of 4 with a 15% HC1 aqueous solution and it was stirred for 3 hours under maintaining the temperature between 0 nad 5C. The precipitated product was filtered, thoroughly washed with acetone and dried. Dry 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-hydroxy-4-oxo-3-quinoline carboxylic acid (approximately 35 g) with a purity over 90% was isolated.Dry 1 -cyclopropyl-6,7-difluoro-1,4-dihydro-8-hydroxy-4-oxo-3-quinoline carboxylic acid was added to acetone (approximately 160 mL) and potassium chloride (approximately 26 g) and dimethyl sulfate (18 mL) were added. Alternatively, 1,4-dioxan or tetrahydrofuran (THF) could be used as the solvent instead of acetone. The reaction mixture was heated to reflux temperature and was left to reflux until the completion of the reaction. After the completed reaction the suspension was cooled to room temperature and filtered. A mixture (58.4 g) of unreacted salts was isolated, which were added to an aqueous potassium carbonate solution, heated to reflux and the ester bond was hydrolyzed for from 30 minutes to some hours. The solution at reflux was cooled to room temperature and l-cyclopropyl-6,7-difluoro-l,4-dihydro-4-oxo-3-quinoline carboxylic acid formed was isolated. The yield of methylation and hydrolysis was approximately 17%.
With hydrogenchloride; calcium chloride; In water; dimethyl sulfoxide; at -5 - 25℃; for 3.5h;pH 4;
A volume of approximately 500 mL of DMSO filtrate after the step of nucleophilic substitution was put into a 1000 mL reactor and, under stirring, CaCl2 (approximately 33 g) was added. The mixture was cooled under stirring to 0-5C (-5C-25C) in 30 minutes. The pH was adjusted to the value of 4 with a 15% HC1 aqueous solution and it was stirred for 3 hours under maintaining the temperature between 0 nad 5C. The precipitated product was filtered, thoroughly washed with acetone and dried. Dry 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-hydroxy-4-oxo-3-quinoline carboxylic acid (approximately 35 g) with a purity over 90% was isolated.
With hydrogen bromide; acetic acid; at 100℃; for 24h;
Example 1: (/iS^tfSH-cyclopropyl^-fluoro-l-beta-fluoro- 4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxym ethyl] - 16-hydroxy-4-oxo- 1,4,13, 15,16,17-hexahydro-12H-ll-oxa-l,14-diaza-cyclopenta[a]phenanthrene- 3-carboxylic acid:l; .i. l-cyclopropyl-6, 7-difluoro-8-hydroxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid:; A solution of l-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline- 3-carboxylic acid (13.02 g) in HBr in AcOH (33%; 100 ml) was stirred at 1000C for 1 day. The reaction mixture was cooled to 00C and diluted with water (400 ml). The resulting crystals were collected by filtration, affording, after drying, 12.4 g of a colourless material. 1H NMR (DMSOd6; delta ppm): 1.09-1.23 (4H, m); 4.32 (IH, m); 7.70 (dd, IH, J = 8 and J = 10); 8.75 (IH, s); 11.66 (IH, broad); 14.78 (IH, s).
A solution of 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (13.02 g) in HBr in AcOH (33%; 100 ml) was stirred at 100 C. for 1 day. The reaction mixture was cooled to 0 C. and diluted with water (400 ml). The resulting crystals were collected by filtration affording after drying 12.4 g of colourless material.1H NMR (DMSOd6; delta ppm): 1.09-1.23 (4H, m); 4.32 (1H, m); 7.70 (dd, 1H, J=8 and J=10); 8.75 (1H, s); 11.66 (1H, broad); 14.78 (1H, s).
With hydrogen bromide; acetic acid; at 100℃; for 24h;
A solution of l-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline- 3-carboxylic acid (13.02 g) in HBr in AcOH (33%; 100 ml) was stirred at 100C for 1 day. The reaction mixture was cooled to 0C and diluted with water (400 ml). The resulting crystals were collected by filtration affording after drying 12.4 g of colourless material.1H NuMR (DMSOd6; delta ppm): 1.09-1.23 (4H, m); 4.32 (lH,m); 7.70 (dd, IH, J = 8 and J = 10); 8.75 (IH, s); 11.66 (IH, broad); 14.78 (IH, s).
With water; potassium carbonate; for 0.5h;Heating / reflux;Product distribution / selectivity;
A volume of approximately 500 mL of DMSO filtrate after the step of nucleophilic substitution was put into a 1000 mL reactor and, under stirring, CaCl2 (approximately 33 g) was added. The mixture was cooled under stirring to 0-5C (-5C-25C) in 30 minutes. The pH was adjusted to the value of 4 with a 15% HC1 aqueous solution and it was stirred for 3 hours under maintaining the temperature between 0 nad 5C. The precipitated product was filtered, thoroughly washed with acetone and dried. Dry 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-hydroxy-4-oxo-3-quinoline carboxylic acid (approximately 35 g) with a purity over 90% was isolated.Dry 1 -cyclopropyl-6,7-difluoro-1,4-dihydro-8-hydroxy-4-oxo-3-quinoline carboxylic acid was added to acetone (approximately 160 mL) and potassium chloride (approximately 26 g) and dimethyl sulfate (18 mL) were added. Alternatively, 1,4-dioxan or tetrahydrofuran (THF) could be used as the solvent instead of acetone. The reaction mixture was heated to reflux temperature and was left to reflux until the completion of the reaction. After the completed reaction the suspension was cooled to room temperature and filtered. A mixture (58.4 g) of unreacted salts was isolated, which were added to an aqueous potassium carbonate solution, heated to reflux and the ester bond was hydrolyzed for from 30 minutes to some hours. The solution at reflux was cooled to room temperature and l-cyclopropyl-6,7-difluoro-l,4-dihydro-4-oxo-3-quinoline carboxylic acid formed was isolated. The yield of methylation and hydrolysis was approximately 17%.
Example 8 Preparation of 1-cyclopropyl-7-[(S,S)-2,8-diazabicyclo[4.3.0]non-8-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid -L-(+)-tartarate (IIa) (Insitu preparation without isolation of Moxifloxacin base) 750 ml of N, N-dimethylformamide, 50 g of 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinoline carboxylic acid (IV) and 25.70 ml of [S,S]-2,8-diazabicyclo [4.3.0] nonane (V) were stirred at 65 - 70 C for 6-8 hours. Completion of the reaction was monitored by HPLC. The reaction mass was cooled to 25-30 C, 50 g of L-(+)-tartaric acid was added, and the reaction mass was stirred at 75 - 80 C for 3-4 hours. The reaction mass was cooled to 25-30C and stirred for 10 12 hours. The solid was filtered off with suction, washed with 150 ml of N, N-dimethylformamide and dried under vacuum at 75C, affording 84.5 g of the title compound. Yield: 90.32 % Purity: 99.80 % (HPLC) Chiral impurity (R,R isomer content): 0.06 %
3-Pyrroline (1 g; 14.5 mmol) and acid 52 (2.1 g; 7.2 mmol) in DMF (10 mL) were heated at 100 C. overnight. After cooling, the reaction mixture was filtered and washed with water. Acid 119 was isolated.MS 345 (M+H).
In N,N-dimethyl-formamide; at 100℃;
3-Pyrroline (1g; 14.5 mmol) and acid 52 (2.1 g; 7.2 mmol) in DMF (10 ml_) were heated at 1000C overnight. After cooling, the reaction mixture was filtered and washed with water. Acid 119 was isolated.MS 345 (M + H).
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 60 - 65℃; for 48h;
To a stirred solution of 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (295 mg, 1.0 mmol) in acetonitrile (5 mL) was added 4-(piperidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (339 mg, 1.2 mmol) followed by the addition of 8-diazabicyclo[5.4.0]undec-7-ene (DBU, 182 mg, 1.2 mmol). The resulting stirred solution was then heated in a 60-65 C. oil bath for two days. The cooled reaction mixture was filtered through a fritted funnel. The filtrate was condensed to dryness. Dichloromethane was added into this residue and washed with water twice. The resulting organic layer was washed one more time with saturated brine and dried over sodium sulfate. The solvent was removed under reduced pressure to give crude material as light brown syrup. This crude product was further purified with 10% methanol in dichloromethane by preparative TLC plate to afford pure title product as yellow solid (100 mg). ESI MS m/z 559 (M+H+); 1H NMR (400 MHz, CDCl3) delta 8.73 (s, 1H), 7.76 (d, J=12.4 Hz, 1H), 3.98 (m, 3H), 3.71 (s, 3H), 3.51 (d, J=12.1 Hz, 2H), 3.17 (t, J=12.3 Hz, 2H), 2.76 (br s, 1H), 1.92 (d, J=11.8 Hz, 2H), 1.83 (d, J=11.6 Hz, 2H), 1.49 (q, J=8.6 Hz, 2H), 1.38 (s, 9H), 1.20 (q, J=7.9 Hz, 2H), 1.15 (d, J=7.1 Hz, 2H), 0.94 (d, J=5.6 Hz, 2H).
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%
In tetrahydrofuran; for 36h;Reflux; Inert atmosphere;
Commercially available 1 -cyclopropyl-1 ,4-dihydro-6,7-difluoro-8-methoxy-4- oxo-quinoline-3-carboxylic acid (52) (10.08 g; 34.14 mmol) and boron thfluoride etherate (30 ml 236 mmol) in anhydrous THF (150 ml_) were heated at reflux temperature under a nitrogen atmosphere for 36 hours. After cooling, ether (250 ml_) was added. The resulting white solid was collected by filtration, washed with ether and dried to give i-cyclopropyl-i ^-dihydro-ej-difluoro-delta-methoxy^-oxo- quinoline-3-carboxylic acid difluoroborate ester (61) as a white solid.MS 344 (M + H).
Example 6: One-pot Preparation of Moxifloxacin hydrochloride monohydrate.Added 70gr of l-Cyclopropyl-6,7-difluro-8-methoxy-4-oxo-l,4-dihyro-3-quinoline carboxylic acid to a solution of 14.7 gr of boric acid andl75ml of acetic anhydride ,0.07g of zinc chloride at 25-45C. Heated the reaction mixture to 100-1200C. Stirred for 90 min. Cooled the reaction mixture to 0-50C. Isolated the material by filtration and washed with hexanes. A solution of 7Og of the obtained wet material [(l-cylcopropyl)-6,7- difluoro-8-methoxy,-4-oxo-l ,4-dihydro,quinoline -3-carboxylate-O3, O4)-bis-(acetate-O) boran], 30 g of [S, S]-2,8-diaza bicyclo (4,3,0)nonane, 30 ml of triethylamine and 300ml of acetonitrile is heated to reflux. Stirred at reflux for 90 mins. Distilled the solvent completely under reduced pressure at 85C. Added 316ml of aqueous sodium hydroxide solution at 50-70C. Heated the reaction mixture to 85-95C and stirred for 2 hrs. Adjusted the pH of the reaction mixture to 9 with acetic acid at 25-350C. Extracted the reaction mixture with methylene chloride and separated the organic phase. Distilled the EPO <DP n="16"/>solvent completely under reduced pressure at 60C. Dissolved the residue in 240ml of acetone at 40-50C, stirred for 15 min. Adjusted the pH to 1.0 with hydrochloric acid at 40-500C. Cooled to 10-150C and stirred for 90min. Filtered the precipitated solid and washed with acetone to get l-Cyclopropyl-6-fluoro-l,4-dihydro-8-methoxy-7[(4aS,7aS)- octahydro-6H-pyrrolo [3 ,4-b]pyridine-6-yl]-4-oxo-3 -quinoline carboxylic acid hydrochloride which is further purified using 405ml of methanol and 45 ml of water. Dissolved the compound by adjusting the pH to 7.8 with aqueous sodium hydroxide solution at 50-60C and treated with carbon. Filtered through hiflow and washed with methanol and water. Cooled the filtrate to 10-150C. Adjusted the pH with hydrochloric acid and stirred for 90 min. Filtered the precipitated solid and washed with methanol. Dried the compound at 50-600C until the water content reaches to 3-6%w/w to get Moxifloxacin hydrochloride monohydrate. Yield : 50 gr
7-((R)-3-((S)-2-cyano-1-(methylamino)ethyl)pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride[ No CAS ]
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