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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
Flumequine is a topoisomerase II inhibitor with IC50 of 15 μM. It is a synthetic chemotherapeutic antibiotic.
Synonyms: R-802; (±)-Flumequine
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Batch number can be found on the product's label following the word 'Batch'.
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Batch number can be found on the product's label following the word 'Batch'.
Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.
Search for reports by entering the product batch number.
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CAS No. : | 42835-25-6 |
Formula : | C14H12FNO3 |
M.W : | 261.25 |
SMILES Code : | CC1CCC2=C3N1C=C(C(O)=O)C(=O)C3=CC(F)=C2 |
Synonyms : |
R-802; (±)-Flumequine
|
MDL No. : | MFCD00079298 |
InChI Key : | DPSPPJIUMHPXMA-UHFFFAOYSA-N |
Pubchem ID : | 3374 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example N. 2b Flumequine preparation 9.5g (28.5 mmole) of the product of Example 2a and 18g of polyphosphoric acid are kept under stirring for 1 hour at 110-115C. The reaction mixture is cooled to about 40C, 80 ml of water are added and stirred for 1 hour at 0C. The flumequine precipitated from the mixture is filtered and washed with water to neutrality. Yield: 6.78g m.p.: 252-4C | ||
Example N. 5b Flumequine preparation Flumequine is prepared by heating at 110-115C under stiring for 3 hours a mixture of 5g (13.1 mmole) of the product of Example 5a, 10 g of polyphosphoric acid and 25 ml of xylene. The mixture is then treated according to the procedure of Example 1b. Yield: 2,5 g m.p.: 253-4C | ||
Example N. 4b Flumequine preparation Flumequine is prepared by heating under stirring at 110-115C for a few hours a mixture of 3.8g (10.3 mmole) of the product of Example 4a, 7.5 g of polyphosphoric acid and 20 ml of xylene. The mixture is then treated according to the procedure of Example 1b. Yield: 1.7g m.p.: 253-254C |
Example N. 3b Flumequine preparation Flumequine is prepared according to the procedure of Example 1b, starting from 8g (23.16 mmole) of the product of Example 3a and 16g of polyphosphoric acid in 40ml of xylene. Yield: 5.6 g m.p.: 253-5C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Intermediate 32: 9-({2-r(2-Hvdroxyethyl)oxylethyl}amino)-5-methyl-1 -oxo-6,7- dihvdro-1f/.5H-pyridor3,2,1-//1quinoline-2-carboxylic acid formate salt A suspension of <strong>[42835-25-6]flumequine</strong> (0.261 g) and 2-[(2-aminoethyl)oxy]ethanol (1.2 mL) in N- methylpyrrolidinone (1.2 mL) was microwaved at 220C for 1 h. The reaction mixture was purified by mass directed automatic preparative HPLC to give the title compound as a yellow solid (0.152 g); ESMS m/z 347.3 [M+H]+. EPO <DP n="65"/>t>4 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Intermediate 33: 9-({2-f(2-Aminoethyl)oxy1ethyl>amino)-5-methyl-1 -oxo-6J-dihydro- 1H,5H-pyridor3,2,1-//lquinoline-2-carboxylic acid formate saltA suspension of <strong>[42835-25-6]flumequine</strong> (0.13 g) and {2-[(2-aminoethyl)oxy]ethyl}amine (0.25 mL) in N-methylpyrrolidinone (0.25 mL) was microwaved at 2000C for 1 h. The reaction mixture was purified by mass directed automatic preparative HPLC to give the title compound as a yellow oil (0.144 g) containing some N-methylpyrrolidinone; ESMS m/z 346.4 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Intermediate 42: 9-r(2-Aminoethyl)aminol-5-methyl-1-oxo-6,7-dihvdro-1H,5H- pyridor3,2,1-//lquinoline-2-carboxylic acid formate salt A suspension of <strong>[42835-25-6]flumequine</strong> (0.522 g) and 1 ,2-diaminoethane (0.668 mL) in N- methylpyrrolidinone (1 mL) was microwaved at 180C for 1.5 h. The reaction mixture was purified by mass directed automatic preparative HPLC to give the title compound as a yellow solid (0.35 g); ESMS m/z 302.3 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 4h; | a) 9-Fluoro-5-methyl-1 -oxo-6,7-dihydro-1 H,5H-pyrido[3,2,1 -//]quinoline-2-carboxylic acid ethyl ester; A suspension of <strong>[42835-25-6]flumequine</strong> (1.045 g), ethyl iodide(3.1 mL) and potassium carbonate (2.75 g) in DMF (50 mL) was heated at 700C for 4 h. The reaction mixture was concentrated in vacuo. The residue was preabsorbed on silica gel and purified by chromatography (silica gel, 0 to 1% [9:1 MeOH/20M aqueous ammonia] in DCM to give the title compound as a white solid (1.1 g); ESMS m/z 290.3 [M+Hf. | |
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 4h; | Intermediate 1 :; 9-r(2-Aminoethyl)thio1-5-(R,S)-methyl-1 -oxo-6.7-dihvdro-1 H,5H- pyridof3,2,1-//lquinoline-2-carboxylic acid trifluoroacetate salt; a) Ethyl 9-fluoro-5-(R,S)-methyl-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1- /y]quinoline-2-carboxylate; A suspension of <strong>[42835-25-6]flumequine</strong> (1.045 g, 4 mmol), iodoethane (3.1 mL, 40 mmol) and potassium carbonate (2.75 g, 20 mmol) in dimethylformamide (50 mL) was heated at 700C for 4 h. The reaction mixture was concentrated in vacuo. The residue was pre-absorbed on silica gel and purified by chromatography (silica gel, 0 to 5% [9:1 methanol/20 M ammonia] in dichloromethane) to give the title compound as a white solid (1.1 g); ESMS m/z 290.3 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; | EXAMPLE 3 9-fluoro-6,7-dihydro-5-methyl-N-[(4-pyridyl)methyl]-1-oxo-1H,5H-benzo-[i,j]quinolizine-2-carboxamide <strong>[42835-25-6]Flumequine</strong> (0.46 g) and dichloromethane (16.3 ml) were combined under nitrogen and cooled to 0 C. Triethylamine (0.27 ml) was then added dropwise, followed by isopropenylchloroformate (0.21 ml) and the whole stirred for 60 minutes. 4-(Aminomethyl)pyridine (0.2 ml) was then added and the reaction stirred for 20 h, after which time it was diluted with dichloromethane, washed with water (3 times), dried (MgSO4), concentrated in vacuo and triturated with acetone to give the title compound (0.49 g) as a yellow solid. TLC Rf =0.43 (10% MeOH/CH2 Cl2) m.p.=199-200 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; | EXAMPLE 1 9-fluoro-6,7-dihydro-5-methyl-N-[2-(4-pyridyl)ethyl]-1-oxo-1H,5H-benzo-[i,j]quinolizine-2-carboxamide <strong>[42835-25-6]Flumequine</strong> (0.46 g) and dichloromethane (16.3 ml) were combined under nitrogen and cooled to 0 C. Triethylamnine (0.27 ml) was then added dropwise, followed by isopropenyl chloroformate (0.21 ml) and the whole stirred for 60 minutes. 4-(2-Aminoethyl)pyridine (0.23 ml) was then added and the reaction stirred for 20 h, concentrated onto silica and purified by flash column chromatography to give the title compound (0.55 g) as a white solid. TLC Rf =0.27 (5% MeOH/CH2 Cl2) mp=217 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1-methyl-pyrrolidin-2-one; at 200℃; for 0.5h;Microwave irradiation; | Intermediate 12:; 9-r(2-aminoethyl)amino1-5-(RS)-methyl-1-oxo-6,7-dihvdro-1H,5H- pyridor3,2,1 -//lquinoline-2-carboxylic acid; A solution of <strong>[42835-25-6]flumequine</strong> (0.26 g, 1 mmol) and 1 ,2-diaminoethane (0.334 mL) in Lambda/-methyl- 2-pyrrolidinone (0.5 mL) was microwaved at 2000C for 0.5 h. The reaction mixture was concentrated then purified by preparative reverse phase HPLC (MeCN/H2O/0.1%HCO2H eluent) to give the title compound as a pale yellow solid (0.15 g). ESMS m/z 302.3 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1-methyl-pyrrolidin-2-one; at 200℃; for 1h;Microwave irradiation; | Intermediate 11; : 9-({2-r(2-aminoethyl)oxylethyl)amino)-5-(ft,S)-methyl-1 -oxo-6 J- dihvdro-1H,5H-pyridor3,2,1-//]quinoline-2-carboxylic acid; A solution of <strong>[42835-25-6]flumequine</strong> (0.13 g, 0.5 mmol) and {2-[(2-aminoethyl)oxy]ethyl}amine (0.25 mL) in Lambda/-methyl-2-pyrrolidinone (0.25 mL) was microwaved at 2000C for 1 h. The reaction mixture was purified by preparative reverse phase HPLC (MeCN/H2O/0.1%HCO2H eluent) to give the title compound as a yellow oil (0.14 g). ESMS m/z 346.4 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With PPA; In water; toluene; | EXAMPLE 3 A mixture of 606 kg of diethyl ethoxymethylenemalonate and 400 kg of 6-fluorotetrahydroquinaldine was stirred and heated at about 125 C. for 5 hours. The mixture was cooled to about 95 C. and evaporated. To the stirred reaction mixture was added 450 liters of toluene, then 908 kg of polyphosphoric acid at a rate to maintain a reaction temperature of 90 to 100 C. The mixture was then heated at reflux for fourteen hours. To this mixture was added 950 liters of water over five hours. The ester was saponified by heating for 13 hours at 110 to 115 C. while removing the toluene via the toluene-water azeotrope. The solid product flumequine was separated by filtration, washed thrice with hot water, then with N,N-dimethylformamide. Recrystallization form N,N-dimethylformamide gave white solid flumequine. | |
In sodium hydroxide; toluene; | EXAMPLE 2 6-Fluorotetrahydroquinaldine (12.05 kg containing 10% of toluene) and diethyl ethoxymethylene malonate (16.2 kg) were charged to a 225 liter Pfaudler reactor and heated at 125 C. under vacuum for 4 hours. Ethanol (3.1 kg) was recovered. The product was cooled, diluted with toluene (35 liters) and tetraphosphoric acid (35 kg), reheated to reflux for 2 hours, cooled to 80 C., diluted with water (128 liters) and refluxed for 6 hours to complete the hydrolysis. The crude flumequine was collected, washed acid free with water and rinsed with methanol. The damp cake was dissolved in sodium hydroxide solution (2.94 kg/59 liters) filtered hot through a cartridge filter heated to 90 C. and acidified with hydrochloric acid (6.64 liters). The product was collected, washed acid free, rinsed with methanol and dried in a vacuum oven. The yield of flumequine was 15.4 kg (90.8%). The dry solid was dissolved in N,N-dimethylformamide (70 liters) at 125 C., allowed to cool with stirring to 100 C. then cooled to 7 C. with cold water. The product was collected, washed with methanol and dried as before. The yield of recrystallized flumequine was 14.4 kg (82.3%) overall. | |
With PPA; In water; toluene; | EXAMPLE 4 A mixture of 606 kg of diethyl ethoxymethylenemalonate and 400 kg of 6-fluorotetrahydroquinaldine was stirred and heated at about 125 C. for 5 hours. The mixture was cooled to about 95 C. and evaporated. To the stirred reaction mixture was added 450 liters of toluene, then 908 kg of polyphosphoric acid at a rate to maintain a reaction temperature of 90 to 100 C. The mixture was then heated at reflux for fourteen hours. To this mixture was added 950 liters of water over five hours. The ester was saponified by heating for 13 hours at 110 to 115 C. while removing the toluene via the toluene-water ezeotrope. The solid product flumequine was separated by filtration, washed thrice with hot water, then with N,N-dimethylformamide. Recrystallization form N,N-dimethylformamide gave white solid flumequine. |
In sodium hydroxide; toluene; | EXAMPLE 3 6-Fluorotetrahydroquinaldine (12.05 kg containing 10% of toluene) and diethyl ethoxymethylene malonate (16.2 kg) were charged to a 225 liter Pfaudler reactor and heated at 125 C. under vacuum for 4 hours. Ethanol (3.1 kg) was recovered. The product was cooled, diluted with toluene (35 liters) and tetraphosphoric acid (35 kg), reheated to reflux for 2 hours, cooled to 80 C., diluted with water (128 liters) and refluxed for 6 hours to complete the hydrolysis. The crude flumequine was collected, washed acid free with water and rinsed with methanol. The damp cake was dissolved in sodium hydroxide solution (2.94 kg/59 liters) filtered hot through a cartridge filter heated to 90 C. and acidified with hydrochloric acid (6.64 liters). The product was collected, washed acid free, rinsed with methanol and dried in a vacuum oven. The yield of flumequine was 15.4 kg (90.8%). The dry solid was dissolved in N,N-dimethylformamide (70 liters) at 125 C., allowed to cool with stirring to 100 C. then cooled to 7 C. with cold water. The product was collected, washed with methanol and dried as before. The yield of recrystallized flumequine was 14.4 kg (82.3%) overall. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In methanol; diethyl ether; ethanol; water; | EXAMPLE 55 6,7-Dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]-quinolizine-2-carboxylic acid (31 g., 0.12 mole), sodium hydroxide (4.75 g., 0.12 mole) and ethanol (300 ml.) are mixed, and about 85 ml. of water are added with stirring. After 1 hour the mixture is filtered, then the filtrate is evaporated to dryness. The residue is azeotroped twice with an ethanol-benzene mixture. The solid is dissolved in methanol, the solution is filtered, and the product is precipitated by the addition of diethyl ether. The product is sodium 6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylate hydrate, m.p. >195 C. Analysis: Calculated for C14 H11 FNNaO3.3/4 H2 O: C,56.8; H,4.3; N,4.7. Found: C,56.6; H,4.4; N,4.7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; | A. Preparation of an acyl chloride derivative. 6,7-Dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]-quinolizine-2-carboxylic acid (5.0 g., 0.0192 mole) is stirred with thionyl chloride (75 ml.), and the mixture is heated to its reflux temperature and maintained at reflux for about 18 hours. The mixture is evaporated to dryness, then azeotroped thrice with 50 ml. portions of benzene to provide an off-white solid, 6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxyl chloride, m.p. 183-186 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; | Example N. 6 Preparation of 5- [1-(6-fluoro-2-methyl-1,2,3,4-tetrahydroquinolyl) ] -methylene-2,2-dimethyl 1,3-dioxan-4,6-dione 1.65 g (10 mmole) of 6-fluoro-2-methyl-1,2-3,4-tetrahydroquinoline and 2,05 g (11 mmole) of 2,2-dimethyl-5-methoxymethylene-1,3-dioxan-4,6-dione [prepared according to Monatshafte fuer Chemie, 98 , 565 (1967)] are reached under stirring and heating at 100-110C for 1 hour. The cooled reaction mass is taken up in tetrahydrofurane and the solids are filtered and dried. Yield: 2.5 g m.p.: 163-5C Flumequine is prepared from the resulting product according to the procedure of Example 1b. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; PPA; In 5,5-dimethyl-1,3-cyclohexadiene; | Example N. 1b Flumequine preparation 3.99 g (12.5 mmole) of 5-[1-(6-fluoro-2-methyl -1,2,3,4-tetrahydroquinolyl)] -methylene-2,2-dimethyl-1,3-dioxan-4,6-dione, 8g of polyphosphoric acid and 20 ml of xylene are heated to 110-115C under vigorous stirring. After 1 hour of heating under stirring, the reaction mixture is cooled to about room temperature and 10% aqueous sodium hydroxide is added up to pH 8.5-9. The mixture is allowed to return to room temperature under stirring, the organic layer is separated and the aqueous alkaline solution is washed a few times with ethyl ether. The alkaline solution is cooled in an ice-bath and acidified to pH 3 with concentrated HCl. The resulting precipitate is filtered and washed with water. Yield: 3.05 g m.p.: 253-5C The product is identical (m.p., IR, TLC) with a true flumequine sample and is pure enough so that further treatments are not necessary. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | General procedure: Oxolinic acid (0.4 mmol, 105 mg) dissolved in CH3OH (10 mL) was deprotonated by KOH (0.4 mmol, 22 mg). The resultant solution was stirred for about 20 min at ambient temperature. The solution of deprotonated oxolinic acid and a methanolic solution (5 mL) of phen (0.4 mmol, 72 mg) were added simultaneously dropwise to a methanolic solution (5 mL) of ZnCl2 (0.4 mmol, 56 mg). The reaction mixture was stirred for about 1 h and left for slow evaporation. Colorless crystals of [Zn(oxo)(phen)Cl] · MeOH, 1 · MeOH, suitable for X-ray structure determination were collected after a few days. Yield: 170 mg, 75%. Anal. Calcd. for [Zn(oxo)(phen)Cl] · MeOH (C26H22N3O6ClZn) (MW = 573.31): C 54.47, H 3.87, N 7.33; found C 54.31, H 4.05, N 6.95. IR (KBr pellet): numax/cm- 1 nu(C = O)pyridone 1641(very strong (vs)); nuasym(CO2): 1597(vs); nusym(CO2): 1392(vs); Delta = nuasym(CO2) - nusym(CO2): 205 cm- 1; UV-vis: lambda/nm (epsilon/M- 1 cm- 1) as nujol mull: 340, 325, 293; in DMSO: 338 (8200), 324 (8500), 293 (10400). 1H-NMR: delta (300 MHz; d6-DMSO): 1.38 (3H, t, H1b-oxo), 4.52 (2H, m, H1a-oxo), 6.28 (2H, s, H12-oxo), 7.58 (2H, s, H5- and H8-oxo), 7.65 (2H, d, H3- and H8-phen), 8.08 (2H, s, H5- and H6-phen), 8.25 (2H, s, H4- and H7-phen), 8.89 (2H, d, H2- and H9-phen), 8.99 (1H, s, H2-oxo). The complex is soluble in N,N-dimethylformamide (DMF) and DMSO (LambdaM = 14 mho cm2 mol- 1, in 1 mM DMSO solution). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With potassium hydroxide; | A methanolic solution (10 mL) containing <strong>[42835-25-6]flumequine</strong> (0.4 mmol, 105 mg) and KOH (0.4 mmol, 22 mg) and a methanolic solution (5 mL) of phen (0.2 mmol, 36 mg) were added simultaneously and dropwise to a methanolic solution (5 mL) of ZnCl2 (0.2 mmol, 28 mg). The reaction mixture was stirred for 1 h and left for slow evaporation. Colorless crystals of [Zn(flmq)2(phen)] · MeOH, 5 · 2MeOH, suitable for X-ray structure determination were deposited after a few days. Yield: 95 mg, 60%. Anal. Calcd. for [Zn(flmq)2(phen)] · 2MeOH (C42H38F2N4O8Zn) (MW = 830.13): C 60.77, H 4.61, N 6.74; found C 61.31, H 4.39, N 6.85. IR (KBr pellet): numax/cm- 1 nu(C = O)pyridone 1637(vs); nuasym(CO2): 1590(vs); nusym(CO2): 1373(vs); Delta = 217 cm- 1; UV-vis: lambda/nm (epsilon/M- 1 cm- 1) as nujol mull: 340, 325, 295; in DMSO: 340 (15100), 326 (18500), 296 (16100). 1H-NMR: delta (300 MHz; (5:1) d6-DMSO:CDCl3): 1.38 (6H, d, H10a-flmq), 2.10 (4H, d, H8-flmq), 3.10 (4H, m, H9-flmq), 4.68 (2H, m, H10-flmq), 7.35 (2H, d, H7-flmq), 7.53 (2H, m, H5-flmq), 7.92 (2H, q, H3- and H8-phen), 8.10 (2H, s, H5- and H6-phen), 8.67 (2H, d, H4- and H7-phen), 8.92 (2H, d, H2- and H9-phen), 9.17 (2H, s, H2-flmq). Complex 5 is soluble in DMSO (LambdaM = 11 mho cm2 mol- 1, in 1 mM DMSO solution). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With potassium hydroxide; at 150℃; for 72h;Autoclave; High pressure; | A mixture of Zn(OAc)2?H2O (87mg, 0.4mmol), Hflmq (52mg, 0.2mmol), H2bdc (33mg, 0.2mmol) and distilled water (8ml) was adjusted to pH with KOH (22mg, 0.4mmol) solution and then sealed in an 18ml Teflon-lined autoclave which was heated in an oven at 150C for 72h. After slow cooling to room temperature, brown block crystals of 1 were separated by filtration, washed with distilled water and dried at ambient temperature (Yield 48% based on Zn). Elemental analysis: Calcd. for C36H30F2N2O12Zn2: C, 50 .74; H, 3.52; N, 3.29. Found: C, 51.20; H, 4.05; N,3.52%. IR (KBr,cm-1): 1385s, 1390vs, 1587vs, 1589s, 1625s, 1630vs. |