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CAS No. : | 86393-33-1 | MDL No. : | MFCD00792458 |
Formula : | C13H9ClFNO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ISPVACVJFUIDPD-UHFFFAOYSA-N |
M.W : | 281.67 | Pubchem ID : | 483180 |
Synonyms : |
Ciprofloxacin Impurity A;Q-Acid
|
Num. heavy atoms : | 19 |
Num. arom. heavy atoms : | 10 |
Fraction Csp3 : | 0.23 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 68.9 |
TPSA : | 59.3 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.34 cm/s |
Log Po/w (iLOGP) : | 1.8 |
Log Po/w (XLOGP3) : | 2.36 |
Log Po/w (WLOGP) : | 3.18 |
Log Po/w (MLOGP) : | 2.18 |
Log Po/w (SILICOS-IT) : | 2.92 |
Consensus Log Po/w : | 2.49 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -3.33 |
Solubility : | 0.132 mg/ml ; 0.000467 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.25 |
Solubility : | 0.16 mg/ml ; 0.000568 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.65 |
Solubility : | 0.0633 mg/ml ; 0.000225 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 1.91 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P273 | UN#: | N/A |
Hazard Statements: | H302-H412 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
97% | With nano iron oxide on ZrO2 coated sulfonic acid In water for 0.316667 h; Reflux | A mixture of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1a (1 mmol) and Nethylpiperazine2y (1.5 mmol) and n-FZSA (0.06 g) as catalystin H2O (5 ml) were heated under reflux for the appropriatetime. The reaction was monitored by TLC. After appropriatetime, the catalyst was separated using an externalmagnet and washed with hot ethanol (5 mL). The reactionmixture was then cooled to room temperature. The precipitatedsolid was collected by filtration, and recrystallized fromethanol 96percent to give desired compound in high yields. |
93% | at 150℃; for 0.416667 h; Microwave irradiation | General procedure: A mixture of 6-chloro-4-cyclopropyl-7-fluoro-1-oxo-1,4-dihydronaphthalene-2-carboxylic acid 1a (1 g, 3.5 mmol) with N-ethylpiperazine 2c (0.6 g, 5.25mmol) was loaded in a small flask fitted with a micro condenser, placed in the microwave reactor and irradiated for 25 min at 150°C under solvent free conditions. The reaction progress was monitored by TLC. Upon completion of the process, addition of hot absolute ethanol (10 mL) to the reaction mixture was followed by filtration. The filtrate was concentrated and stored at room temperature for precipitation. The solid was filtered off and recrystallized from absolute ethanol to give compound 3c. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | In dimethyl sulfoxide for 0.583333h; Irradiation; microwave; | |
75% | In dimethyl sulfoxide at 140℃; for 2h; | |
61% | at 115℃; for 1.5h; Microwave irradiation; | 2 4.2 General procedure for MW-assisted amination of quinolone carboxylic acid 1a General procedure: A mixture of quinolone carboxylic acid 1a (0.30 mmol), cyclic amine (1.50 mmol) and DMPU (0.5 M solution) was heated at fixed temperature, at 115 °C (power value ranging from 7 to 10 W) in the CEM Discover microwave reactor for 1.5 h. The reaction mixture was cooled to room temperature and EtOAc (1 mL) was added. The precipitate was filtered and dried at reduced pressure affording the aminated quinolone as an off-white solid. |
58% | In dimethyl sulfoxide at 140℃; for 0.75h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | In dimethyl sulfoxide at 140℃; for 2h; | |
62% | at 115℃; for 1.5h; Microwave irradiation; | 2 4.2 General procedure for MW-assisted amination of quinolone carboxylic acid 1a General procedure: A mixture of quinolone carboxylic acid 1a (0.30 mmol), cyclic amine (1.50 mmol) and DMPU (0.5 M solution) was heated at fixed temperature, at 115 °C (power value ranging from 7 to 10 W) in the CEM Discover microwave reactor for 1.5 h. The reaction mixture was cooled to room temperature and EtOAc (1 mL) was added. The precipitate was filtered and dried at reduced pressure affording the aminated quinolone as an off-white solid. |
61% | In dimethyl sulfoxide at 140℃; for 0.75h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | at 115℃; for 1.5h; Microwave irradiation; | 4.2 General procedure for MW-assisted amination of quinolone carboxylic acid 1a General procedure: A mixture of quinolone carboxylic acid 1a (0.30 mmol), cyclic amine (1.50 mmol) and DMPU (0.5 M solution) was heated at fixed temperature, at 115 °C (power value ranging from 7 to 10 W) in the CEM Discover microwave reactor for 1.5 h. The reaction mixture was cooled to room temperature and EtOAc (1 mL) was added. The precipitate was filtered and dried at reduced pressure affording the aminated quinolone as an off-white solid. |
85% | In dimethyl sulfoxide at 140℃; for 0.75h; | |
74% | In dimethyl sulfoxide at 140℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With nano iron oxide on ZrO2 coated sulfonic acid In water for 0.366667h; Reflux; | 3.2. General Experimental Procedure General procedure: A mixture of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1a (1 mmol) and Nethylpiperazine2y (1.5 mmol) and n-FZSA (0.06 g) as catalystin H2O (5 ml) were heated under reflux for the appropriatetime. The reaction was monitored by TLC. After appropriatetime, the catalyst was separated using an externalmagnet and washed with hot ethanol (5 mL). The reactionmixture was then cooled to room temperature. The precipitatedsolid was collected by filtration, and recrystallized fromethanol 96% to give desired compound in high yields. |
90% | at 150℃; Microwave irradiation; | Typical experimental procedure General procedure: A mixture of 6-chloro-4-cyclopropyl-7-fluoro-1-oxo-1,4-dihydronaphthalene-2-carboxylic acid 1a (1 g, 3.5 mmol) with N-ethylpiperazine 2c (0.6 g, 5.25mmol) was loaded in a small flask fitted with a micro condenser, placed in the microwave reactor and irradiated for 25 min at 150°C under solvent free conditions. The reaction progress was monitored by TLC. Upon completion of the process, addition of hot absolute ethanol (10 mL) to the reaction mixture was followed by filtration. The filtrate was concentrated and stored at room temperature for precipitation. The solid was filtered off and recrystallized from absolute ethanol to give compound 3c. |
89.7% | With aluminum tri-bromide In ethanol at 75℃; for 4h; | 7-9; 2 Example 8 100 g of 1-cyclopropyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 160 g of piperazine, and 50 g of ethanol were placed in a four-necked flask. 5g of aluminum tribromide, heated to 75 ° C, The reaction was kept for 4 hours, 30 g of sodium hydroxide was added, and the pressure was reduced to dryness to recover piperazine. Then, 400 g of water was added to the residue to dissolve, and then 0.2 g of activated carbon was added. Decolorize at 70 degrees for 30 minutes, filtration, the filtrate was added with hydrochloric acid to adjust the pH to neutrality, and cooled to room temperature to obtain a crude ciprofloxacin, which was then recrystallized by ethanol to obtain 106 g of ciprofloxacin. The molar yield liquid phase monitoring purity is 99.51%, and the 6-position fluorine substitution impurity is 0.15%. The molar yield was 89.7%. |
84% | In dimethyl sulfoxide for 0.333333h; Irradiation; microwave; | |
79% | In pyridine for 8h; Heating; | |
75% | In dimethyl sulfoxide for 2h; Microwave irradiation; | |
74% | at 115℃; for 1.5h; Microwave irradiation; | 5 4.2 General procedure for MW-assisted amination of quinolone carboxylic acid 1a General procedure: A mixture of quinolone carboxylic acid 1a (0.30 mmol), cyclic amine (1.50 mmol) and DMPU (0.5 M solution) was heated at fixed temperature, at 115 °C (power value ranging from 7 to 10 W) in the CEM Discover microwave reactor for 1.5 h. The reaction mixture was cooled to room temperature and EtOAc (1 mL) was added. The precipitate was filtered and dried at reduced pressure affording the aminated quinolone as an off-white solid. |
In butan-1-ol at 135℃; for 5h; | ||
In 2-methoxy-ethanol at 127 - 129℃; for 7.5 - 8h; | 6 Example 6: Synthesis of crude ciprofloxacin (4); 240 ml of 2-methoxyethanol, 48.9 kg of piperazine anhydrous and 40 kg of 1-cyclopropyl-7-chloro-6-fluoro-1, 4-dihydro-4- oxo-3-quinolinecarboxylic acid are charged into a flask. The reaction mixture is refluxed at 127 to 129 °C for 7.5 to 8 hours. The solvent is evaporated under reduced pressure (200 to 250 mbar and at a temperature of 100 to 110 °C) resulting in 170 to 180 ml of 2-methoxyethanol. To the residue 200 ml water are added and the suspension is refluxed at a temperature of 98 to 100 °C for 30 minutes. The reaction mixture is cooled to a temperature of 15 to 18 °C within 30 minutes and it is agitated at this temperature for another 30 minutes. The obtained precipitate is filtered off and washed with 200 ml water which is cooled to 10 to 15 °C. | |
In butan-1-ol at 118 - 122℃; | 1 The mixture of 7-chloro-l-cyclopropyl-6-fluoro-l, 4-dihydro-4-oxo- quinoline-3-carboxylic acid (100 gm), piperazine (81 gm), anhydrous aluminium chloride (5 gm) and n-butanol (175 ml) was heated to reflux temperature i.e. 1 18-122 C and maintained for 10-14 hours. After the completion of the reaction, reaction mass was cooled to 70-80 C, n-butanol was distilled out completely under vacuum, added water and adjusted the reaction mass pH 6.5-6.6 with hydrochloric acid, heated the contents to 50-55 C and adjusted the reaction mass pH 4.0-4.5 with acetic acid, stirred the mass for 1.0 hour at the same conditions, activated carbon (6.8 gm) and EDTA (0.046gm) were charged and stirred for 1.0 hour at 55-60 C, filtered the carbon the filtrate pH adjusted 6.8 to 7.2 with 20% aqueous sodium hydroxide solution and stirred for 1.0 hour and filtered the isolated compound, washed with water (Wet weight of Ciprofloxacin base is 200-250 gm). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With nano iron oxide on ZrO2 coated sulfonic acid In water for 0.416667h; Reflux; | 3.2. General Experimental Procedure General procedure: A mixture of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1a (1 mmol) and Nethylpiperazine2y (1.5 mmol) and n-FZSA (0.06 g) as catalystin H2O (5 ml) were heated under reflux for the appropriatetime. The reaction was monitored by TLC. After appropriatetime, the catalyst was separated using an externalmagnet and washed with hot ethanol (5 mL). The reactionmixture was then cooled to room temperature. The precipitatedsolid was collected by filtration, and recrystallized fromethanol 96% to give desired compound in high yields. |
89% | at 150℃; Microwave irradiation; | Typical experimental procedure General procedure: A mixture of 6-chloro-4-cyclopropyl-7-fluoro-1-oxo-1,4-dihydronaphthalene-2-carboxylic acid 1a (1 g, 3.5 mmol) with N-ethylpiperazine 2c (0.6 g, 5.25mmol) was loaded in a small flask fitted with a micro condenser, placed in the microwave reactor and irradiated for 25 min at 150°C under solvent free conditions. The reaction progress was monitored by TLC. Upon completion of the process, addition of hot absolute ethanol (10 mL) to the reaction mixture was followed by filtration. The filtrate was concentrated and stored at room temperature for precipitation. The solid was filtered off and recrystallized from absolute ethanol to give compound 3c. |
67% | In dimethyl sulfoxide at 140℃; for 2.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With nano iron oxide on ZrO2 coated sulfonic acid; In water; for 0.316667h;Reflux; | A mixture of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1a (1 mmol) and Nethylpiperazine2y (1.5 mmol) and n-FZSA (0.06 g) as catalystin H2O (5 ml) were heated under reflux for the appropriatetime. The reaction was monitored by TLC. After appropriatetime, the catalyst was separated using an externalmagnet and washed with hot ethanol (5 mL). The reactionmixture was then cooled to room temperature. The precipitatedsolid was collected by filtration, and recrystallized fromethanol 96% to give desired compound in high yields. |
93% | at 150℃; for 0.416667h;Microwave irradiation; | General procedure: A mixture of 6-chloro-4-cyclopropyl-7-fluoro-1-oxo-1,4-dihydronaphthalene-2-carboxylic acid 1a (1 g, 3.5 mmol) with <strong>[5308-25-8]N-ethylpiperazin</strong>e 2c (0.6 g, 5.25mmol) was loaded in a small flask fitted with a micro condenser, placed in the microwave reactor and irradiated for 25 min at 150C under solvent free conditions. The reaction progress was monitored by TLC. Upon completion of the process, addition of hot absolute ethanol (10 mL) to the reaction mixture was followed by filtration. The filtrate was concentrated and stored at room temperature for precipitation. The solid was filtered off and recrystallized from absolute ethanol to give compound 3c. |
92% | With aluminum tri-bromide; In ethanol; at 75℃; for 4h; | 100 g of 1-cyclopropyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, <strong>[5308-25-8]N-ethylpiperazin</strong>e 200 g, ethanol 40 g were placed in a four-necked flask. ,5g of aluminum tribromide, heated to 75 C,The reaction was kept for 4 hours, and 30 g of sodium hydroxide was added. Reduce the N-ethyl piperazine to dryness under reduced pressure. Then, 400 g of water was added to the residue to dissolve, and then 0.2 g of activated carbon was added. Decolorize at 70 degrees for 30 minutes, filter, and adjust the pH to neutral with hydrochloric acid. Cool to room temperature and filter to obtain crude enrofloxacin. The ethanol was recrystallized and filtered to obtain 118 g of enrofloxacin finished product. The molar yield liquid phase monitoring purity is 99.5%, The 6-position fluorine-substituted impurity was 0.16%, and the molar yield was 92.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | In dimethyl sulfoxide at 140℃; for 2.5h; | |
In water; dimethyl sulfoxide | 19 EXAMPLE 19 STR50 EXAMPLE 19 STR50 A suspension of 2.81 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 5.2 g of N-(2-hydroxyethyl)-piperazine in 25 ml of dimethylsulphoxide is heated at 135°-140° C. for 2 hours. The solvent is distilled off under a fine vacuum, the residue is boiled up with 20 ml of water, the mixture is left to stand overnight at room temperature and the precipitate is filtered off with suction, while cooling with ice, washed with water and dried over calcium chloride in vacuo at 80° C. 2.1 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[4-(2-hydroxyethyl)-1-piperazinyl]-3-quinolinecarboxylic acid of decomposition point 237°-239° C. are obtained. Mass spectrum m/e: 375 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With sulfuric acid In water for 1.5h; Heating; | |
88% | With sodium carbonate In water for 0.166667h; microwave irradiation; | |
With hydrogenchloride In ethanol at 120 - 130℃; for 3h; Yield given; |
With hydrogenchloride In water | ||
With sodium hydroxide; water at 20℃; Heating / reflux; | Condensation of 2,4-dichloro-5-fluoroacetophenone 2 with diethyl carbonate in the presence of NaH yielded ethyl 2,4-dichloro-5-fluorobenzoylacetate 3. Treatment of the latter with triethyl orthoformate in acetic anhydride gave the carbon homologue enol ether intermediate 4 which was allowed to react with a slight excess of cyclopropylamine in methylene chloride at room temperature to give the enaminoketoester 5. Cyclization of the latter with 1 molar equivalent of NaH in refluxing dioxane yielded ethyl 1,4-dihydro-4-oxo-quinoline-3-carboxylate 6 which was then hydrolysed with aqueous NaOH to give 1-cyclopropyl-6-chloro-7-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (IM) 7. See also Scheme 1 below (Maurer, F. and Grohe, K., DE 3 435 392 through Chem. Abst., Vol. 105, No.5, 1984, pp. 97158e). Compound data:Molecular Weight: 281.667; Composition: C(55.43%), H(3.22%), Cl(12.59%), F(6.74%), N(4.97%), O(17.04%); NMR (δ ppm; relative intensity): 14.41;0.13, 8.65;6.37, 8.22;1.62, 4.11;2.3, 1.22;0.06, 1.12;0.14, 1.03;0.14, 1.17;0.91, 1.00;0.90, 0.92;0.06. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With sodium hydroxide for 2h; Reflux; | 17 Example 17 Add 148.00g of intermediate 4 solid and 500ml of 8% sodium hydroxide solution to a 1000ml reaction device (four-necked flask), reflux under stirring at 400rmp for 2h, adjust pH to 1 with hydrochloric acid, cool to 25°C, filter, The filter cake was washed with water and dried at 60°C to obtain 138.15 g of cyclopropanecarboxylic acid with a purity of 98.99% and a yield of 97%. The obtained cyclopropanecarboxylic acid was identified by mass spectrometry, and its mass spectrum was shown in Figure 2. |
92% | With sulfuric acid In water monomer; acetic acid for 1.5h; Heating; | |
92% | With sodium hydroxide In water monomer at 80 - 90℃; for 3h; |
Alkaline hydrolysis; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | In dimethyl sulfoxide at 130 - 140℃; for 3h; | |
41% | In dimethyl sulfoxide at 140℃; for 0.75h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile for 0.5h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With boron trifluoride diethyl etherate In diethyl ether; dichloromethane for 5h; Heating; | |
With boron trifluoride diethyl etherate; diethylamine In dichloromethane at 20℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | Stage #1: 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid With boric acid; acetic anhydride at 80℃; for 2h; Stage #2: 6-aza-2-thiothymine With triethylamine In dimethyl sulfoxide at 60℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid With boric acid; acetic anhydride at 80℃; for 2h; Stage #2: 3-thio-4,6-dimethyl-1,2,4-triazine-3,5-dione With triethylamine In dimethyl sulfoxide at 60℃; for 5h; Stage #3: With sodium hydroxide Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With 1,4-diazabicyclo[5.4.0]-7-undecene In 1-methyl-pyrrolidin-2-one at 120℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With pyridine In N,N-dimethyl-formamide Heating / reflux; | 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (4 g, 14.2 mmol; hereinafter denoted “IM”) and 4-picolylamine (8 g) as nucleophilic reagent were refluxed overnight in DMF (50 ml) and pyridine (3 ml). After completion of the reaction, the solvents were evaporated and cold water was added, whereby a precipitate was obtained. The precipitate was washed with water followed by methanol, after which it was filtered and dried. JA 68 was obtained as a pale yellowish powder (73% yield) which was recrystallized from chloroform/acetone 70:30. A TLC spot of JA 68 displays fluorescence when exposed to UV light. Compound data:Molecular Weight: 353.347;Composition: C(64.58%), H(4.56%), F(S.38%), N(11.89%), O(13.58%); NMR: 11.77, 8.70, 8.65, 8.08, 7.48, 6.41, 4.33, 4.11, 1.17, 1.00. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With thionyl chloride In 1,2-dichloro-ethane; N,N-dimethyl-formamide at 20℃; for 5h; Reflux; | 4.1 First step reaction: 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-yl chloride At room temperature,7-Chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid(16.9g, 0.06mol),Dichloroethane (90ml)And N,N-dimethylformamide (0.2g) was added to the three-neck bottle.To the above mixture was added dropwise chlorosulfoxide (14.6 g, 0.12 mol).Heat to reflux for 5 hours. Stop heating,The solvent and residual thionyl chloride are removed under reduced pressure.Product16.2 g, yield 90%. |
With thionyl chloride In N,N-dimethyl-formamide at 80℃; | ||
With thionyl chloride In benzene at 80℃; |
With thionyl chloride In N,N-dimethyl-formamide; benzene at 80℃; | ||
1.5 g | With thionyl chloride In toluene for 8h; Reflux; | 3.3 7-Chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbonylchloride (4) A mixture of 1 (1.5 g, 5.3 mmol) and thionyl chloride (SOCl2)(4 mL, 54 mmol) in 20 mL of dry toluene was stirred underreflux for 8 h. After cooling to room temperature, tolueneand excess SOCl2 were evaporated under reduced pressure.The solid residue was suspended in dry hexane and thesuspension was evaporated to dryness to afford the solidresidue which was used without further purification. Yield1.5 g (95 %). - IR (KBr): v = 3071, 2982, 1726, 1705, 1460, 1361cm-1. - 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ = 1.17 (m,2H) and 1.37 (m, 2H), (2′-H/3′-H), 3.51 (m, 1H, 1′-H), 8.00 (s,1H, 8-H), 8.17 (d, 3JH-F = 10 Hz, 1H, H-5), 8.53 (s, 1H, 2-H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 90 percent / Na2CO3 / dimethylsulfoxide / 0.07 h / microwave irradiation 2: 88 percent / Na2CO3 / H2O / 0.17 h / microwave irradiation | ||
With potassium hydroxide In 1,4-dioxane; water | 1 EXAMPLE 1 STR42 EXAMPLE 1 STR42 3.44 g of 80 percent strength sodium hydride are added in portions to a solution of 31.9 g of ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-cyclopropylaminoacrylate in 300 ml of anhydrous dioxane, while cooling with ice and stirring. The mixture is then stirred at room temperature for 30 minutes and under reflux for 2 hours and the dioxane is stripped off in vacuo. The residue (40.3 g) is suspended in 150 ml of water, 6.65 g of potassium hydroxide are added and the mixture is refluxed for 1.5 hours. The warm solution is filtered and the residue is rinsed with water. The filtrate is then acidified to pH 1-2 with half-concentrated hydrochloric acid, while cooling with ice, and the precipitate is filtered off with suction, washed with water and dried in vacuo at 100° C. 27.7 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 234°-237° C. are obtained in this manner. | |
In 1,4-dioxane; water | A EXAMPLE A STR18 3.44 g of 80 percent strength sodium hydride are added in portions to a stirred ice-cooled solution of 31.9 g of ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-cyclopropylamino-acrylate (6) in 100 ml of anhydrous dioxane. Thereafter, the mixture is stirred for 30 minutes at room temperature and for 2 hours under reflux, and the dioxane is stripped off in vacuo. The residue (40.3 g) is suspended in 150 ml of water, 6.65 g of caustic alkali are added and the mixture is refluxed for 1.5 hours. The warm solution is filtered, and the residue is rinsed with H2 O. The ice-cooled filtrate is then acidified to pH=1-2 with semi-concentrated hydrochloric acid, and the precipitate is filtered off under suction, washed with water and dried in vacuo at 100° C. In this manner, 27.7 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid Via of melting point 234°-237° C. are obtained. |
Multi-step reaction with 2 steps 1: sodium hydride / 1,3-dioxane / 20 °C / Heating / reflux 2: sodium hydroxide; water / 20 °C / Heating / reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dimethyl sulfoxide | 1 Example 1, Preparation of 1-cyclopropyl-6-fluoro-7-(3-methylthiomethylpyrrolidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid Example 1 Preparation of 1-cyclopropyl-6-fluoro-7-(3-methylthiomethylpyrrolidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid A mixture of 0.2g(0.71 mmole) of 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.9g(3.5 mmole) of 3-methylthiomethylpyrrolidine hydroiodide, and 0.4g(3.96 mmole) of triethylamine in 6mlof dimethylsulfoxide was stirred for 6 hours at 110°C and cooled to room temperature. The reaction mixture was diluted with 15mlof water, adjusted at PH 7.4 with 1N HCl, and then allowed to stand for 1 day. The precipitated product was filtered, washed with water and methanol, and recrystallized from methanol: dichloromethane(1:1) to afford 0.19g of the title compound as pale yellow solid. m.p.: 196 ~ 198°C 1 NMR(ppm, CDCl3: 1.19 ~ 1.31(m, 4H), 1.50 ~ 2.50(m, 3H), 2.17(s, 3H), 2.67(d, 2H), 3.20 ~ 4.01(m, 5H), 6.84(d, 1H), 7.80(d, 1H), 8.59(s, 1H), 15.29(br, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl acetamide at 100 - 115℃; for 8.5h; | 13 Intermediate 13; 6-[(2-Aminoethyl)amino]-7-chloro-1-cyclopropyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid 7-Chloro-l-cyclopropyl-1, 4-DIHYDRO-6-FLUORO-4-OXO-QUINOLINE-3-CARBOXYLIC acid (56.3 g) and ethylenediamine (36 g) were dissolved in N, N-dimethylacetamide (650 mL) at 100°C and stirred for 8.5 h at 115°C. Water (700 ML) was added to the reaction mixture cooled at room temperature. The reaction mixture was stirred at room temperature for 2 h, cooled at 0-5°C and stirred for 1 h. The precipitate obtained was filtered, washed with cold water, cold EtOH, and dried at 110°C under reduced pressure for 1 h. The crude product was treated with HCI (6% aqueous solution) heating for 1 h in the presence of charcoal. After filtration, the solution was cooled to 35-40°C and a first precipitation happened. The precipitate was filtered, washed with water and dried at 110°C FOR 1 h. The title compound (6.4 g) was obtained as the hydrochloride salt. The hydrochloride salt was then converted to the free base using standard conditions. | |
In N,N-dimethyl acetamide at 0 - 115℃; for 14.5h; | 1 Intermediate 1; 6-[(2-Aminoethyl)amino]-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid 7-CHLORO-1-CYCLOPROPYL-1, 4-DIHYDRO-6-FLUORO-4-OXO-QUINOLINE-3-CARBOXYLIC acid (56.3 g) and ethylenediamine (36 g) were dissolved in N, N-dimethylacetamide (650 mL) at 100oC and stirred for 8.5 h at 115oC. Water (700 mL) was added to the reaction mixture cooled at room temperature. The reaction mixture was stirred at room temperature for 2 h, cooled at 0-5oC and stirred for 1 h. The precipitate obtained was filtered, washed with cold water, COLD ETOH, and dried at 110oC under reduced pressure for 1 h. The crude product was treated with HCI (6% aqueous solution) heating for 1 h in the presence of charcoal. After filtration, the solution was cooled to 35-40oC and a first precipitation happened. The precipitate was filtered, washed with water and dried at 110oC for 1 h. The title compound (6.4 g) was obtained as the hydrochloride salt. The hydrochloride salt was then converted to the free base using standard conditions; ESMS m/z 320 [M-H]-. | |
In N,N-dimethyl acetamide; water at 0 - 115℃; for 12.5h; | 1 Intermediate 1; 6-[(2-Aminoethyl)amino]-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid 7-CHLORO-1-CYCLOPROPYL-6-FLUORO-4-OXO-1, 4-DIHYDRO-QUINOLINE-3-CARBOXYLIC acid (56.3 g) and ethylenediamine (36 g) were dissolved in N, N-dimethylacetamide (650 mL) at 100oC and stirred for 8.5 h at 115oC. Water (700 mL) was added to the reaction mixture cooled at room temperature. The reaction mixture was stirred at room temperature for 2 h, cooled at 0-5oC and stirred for 1 h. The precipitate obtained was filtered, washed with cold water, COLD ETOH, and dried at 110oC under reduced pressure for 1 h. The crude product was treated with HCI (6% aqueous solution) heating for 1 h in the presence of charcoal. After filtration, the solution was cooled to 35-40oC and a first precipitation happened. The precipitate was filtered, washed with water and dried at 110oC for 1 h. The title compound (6.4 g) was obtained as the hydrochloride salt. The hydrochloride salt was then converted to the free base using standard conditions; ESMS m/z 320 [M-H]-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | at 110℃; for 20h; | 4.8.1. General procedure for aminolysis General procedure: To a solution of compounds 2-5 (1 eq) in 1-methyl-2-pyrolidone, 2-amino-ethanol or 2-(2-aminoethoxy)-ethanol (2 eq) were added. The reaction mixture was warmed up to 110 °C, and stirred at this temperature over 20 h. Then it was cooled to 20-25 °C, water was added and pH was adjusted to 12. The resulting solution was extracted with DCM, then pH value of water solution was corrected to 6, and after 10 min crystalline product was collected on filter affording pure products 6a, 8a-11a. |
In 1-methyl-pyrrolidin-2-one at 95 - 105℃; for 22h; | 29 Intermediate 29; 7-Chloro-1-cyclopropyl-6-(2-hydroxy-ethylamino)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (A) and 1-cyclopropyl-6-fluoro-7-(2-hydroxy-ethylamino)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (B) To a solution of ethanolamine (55.5 ml) in N-methyl pyrrolidinone (500 ml) at 95 °C, 7- CHLORO-L-CYCLOPROPYL-6-FLUORO-4-OXO-1, 4-DIHYDRO-QUINOLINE-3-CARBOXYLIC acid (50.0 g) was slowly added under vigorous stirring. The temperature was increased to 105 °C and the reaction mixture was stirred at this temperature for 22 hours. The reaction mixture was cooled to about 60 °C and poured into MEOH (800 ml). This mixture was stirred in an ice bath and the precipitate was filtered off and dried affording a mixture of Intermediate 29A and Intermediate 29B (49 g) in a 1: 1 ratio. Intermediate 29A: MS; m/z (ES): 322.99 [MH] + Intermediate 29B: MS; m/z (ES): 307.02 [MH] + | |
In N-methyl pyrrolidinone at 95 - 105℃; for 22h; | 14 Intermediate 14; 7-Chloro-1-cyclopropyl-6-(2-hydroxy-ethylamino)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (A) and 1-Cyclopropyl-6-fluoro-7-(2-hydroxy-ethylamino)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (B) To a solution of ETHANOLAMINE (55.5 mL) in N-methyl pyrrolidinone (500 mL) at 95 oC, 7- CHLORO-1-CYCLOPROPYL-6-FLUORO-4-OXO-1, 4-DIHYDRO-QUINOLINE-3-CARBOXYLIC acid (50.0 g) was slowly added under vigorous stirring. The temperature was increased to 105 oC and the reaction mixture was stirred at this temperature for 22 hours. The reaction mixture was cooled to about 60 oC and poured into MEOH (800 mL). This mixture was stirred in an ice bath and the precipitate was filtered off and dried affording a mixture of Intermediate 14A and Intermediate 14B (49 g) in a 1: 1 ratio. Intermediate 14A: MS ; m/z (ES): 322.99 [MH] Intermediate 14B: MS; m/z (ES): 307.02 [MH] + |
With 1-methyl-pyrrolidin-2-one at 95 - 105℃; for 22h; | 15 Intermediate 15; 7-Chloro-1-cyclopropyl-6-(2-hydroxy-ethylamino)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (A) and 1-Cyclopropyl-6-fluoro-7-(2-hydroxy-ethylamino)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (B) To a solution of ethanolamine (55.5 mL) in N-methyl pyrrolidinone (500 mL) at 95 oC, 7- chloro-1-cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid (50.0 g) was slowly added under vigorous stirring. The temperature was increased to 105 oC and the reaction mixture was stirred at this temperature for 22 hours. The reaction mixture was cooled to about 60 oC and poured into MeOH (800 mL). This mixture was stirred in an ice bath and the precipitate was filtered off and dried affording a mixture of Intermediate 15A and Intermediate 15B (49 G) in a 1: 1 ratio. Intermediate 15A: MS; m/z (ES): 322.99 [MH] + Intermediate 15B: MS; m/z (ES): 307.02 [MH] + | |
In N-methyl pyrrolidinone at 95 - 105℃; for 22h; | 1 Intermediate 1; 7-Chloro-1-cyclopropyl-6-(2-hydroxy-ethylamino)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (A) and 1-Cyclopropyl-6-fluoro-7-(2-hydroxy-ethylamino)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (B) To a solution of ETHANOLAMINE (55.5 mL) in N-methyl PYRROLIDINONE (500 mL) at 95 oC, 7- CHLORO-1-CYCLOPROPYL-6-FLUORO-4-OXO-1, 4-DIHYDRO-QUINOLINE-3-CARBOXYLIC acid (50.0 g) was slowly added under vigorous stirring. The temperature was increased to 105 oC and the reaction mixture was stirred at this temperature for 22 hours. The reaction mixture was cooled to about 60 oC and poured into MEOH (800 mL). This mixture was stirred in an ice bath and the precipitate was filtered off and dried affording a mixture of Intermediate 1A and Intermediate 1B (49 g) in a 1: 1 ratio. Intermediate 1A : MS; m/z (ES): 322.99 [MH] + Intermediate 1B: MS; m/z (ES): 307.02 [MH] + |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: ethylene glycol With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 90℃; for 0.166667h; Stage #2: 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid In dimethyl sulfoxide at 105℃; for 6.33h; | 1 Intermediate 1; 7-Chloro-1-cyclopropyl-6-(2-hydroxy-ethoxy)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (A) and 1-Cyclopropyl-6-fluoro-7-(2-hydroxy-ethoxy)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (B) To a mixture of DMSO (5 mL) and ethyleneglycol (6 mL), KOtBu (1.6 g, 14.23 MMOL) was added portionwise over 10 min, and then heated to 90 oC. To the mixture, 7-CHLORO-1- cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid (1.0 G) was added portionwise over 20 min, the temperature was increased to 105 oC and the mixture was stirred for 6 h. Water (30 mL) was added to the reaction solution and the pH of the solution was adjusted to pH=5. The resulting solution was left in the refrigerator overnight. The precipitate obtained was filtered, washed with cold water, and dried affording a 2: 1 mixture of Intermediate 1A and Intermediate 1B (1.0 g). Part of the crude product (700 mg) was dissolved in ETOH (15 mL) by heating to the reflux. The resulting solution was cooled to 30oC and a first precipitation occurred. The precipitate was filtered, washed with cold EtOH and dried under reduced pressure. Intermediate 1A (204 mg) was obtained as a white solid ; H-NMR (500 MHz, DMSO-d6) 8 : 15.06 (s, 1H), 8.71 (s, 1 H), 8.40 (s, 1H), 7. 86 (s, 1H), 4.97 (t, 1H), 4.25 (t, 2H), 3.87 (m, 1H), 3.82 (q, 2H), 1.32 (m, 2H), 1.20 (m, 2H). 3C-NMR (75 MHz, DMSO-d6) 8 : 176.61, 165.67, 152.47, 147.54, 135.34, 129.48, 124.95, 120.02, 106. 90, 106.66, 71.22, 59.15, 35.99, 7.46. MS; m/z (ES): [MH] +. | |
Stage #1: ethylene glycol With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 90℃; for 0.166667h; Stage #2: 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid In dimethyl sulfoxide at 105℃; for 6.5h; | To a mixture of DMSO (5 mL) and ethyleneglycol (6 mL), KOtBu (1.6 g, 14.23 mmol) was added portionwise over 10 min, and then heated to 90 °C. To the mixture, 7-chloro-l- cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (1.0 g) was added portionwise over 20 min, the temperature was increased to 105 °C and the mixture was stirred for 6 h. Water (30 mL) was added to the reaction solution and the pH of the solution was adjusted to pH=5. The resulting solution was left in the refrigerator overnight. The precipitate obtained was filtered, washed with cold water, and dried affording a 2: 1 mixture of Intermediate 24A and Intermediate 24B (1.0 g). Part of the crude product (700 mg) was dissolved in EtOH (15 mL) by heating to the reflux. The resulting solution was cooled to 30°C and a first precipitation occurred. The precipitate was filtered, washed with cold EtOH and dried under reduced pressure. Intermediate 24A (204 mg) was obtained as a white solid; ¹H-NMR (500 MHz, DMSO-d6) No.: 15.06 (s, 1H), 8.71 (s, 1H), 8.40 (s, 1H), 7.86 (s, 1H), 4.97 (t, 1H), 4.25 (t, 2H), 3.87 (m, 1H), 3.82 (q, 2H), 1.32 (m, 2H), 1.20 (m, 2H); ¹3C-NMR (75 MHz, DMSO-d6) No.: 176.61,165.67, 152.47,147.54, 135.34,129.48, 124.95,120.02, 106.90, 106.66, 71.22, 59.15,35.99, 7.46; | |
Stage #1: ethylene glycol With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 90℃; for 0.166667h; Stage #2: 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid In dimethyl sulfoxide at 90 - 105℃; for 6.33333h; | 21 7-Chloro-l-cyclopropyl-6-(2-hydroxy-ethoxy)-4-oxo-l,4-dihydro-quinoMne-3-carboxylic acid (A) and l-Cyclopropyl-6-fluoro-7-(2-hvdroxy-ethoxy)-4-oxo-1.4-dmydro-quinoline-3-carboxyIic acid (B) EPO To a mixture of DMSO (5 mL) and ethyleneglycol (6 mL), KO^u (1.6 g, 14.23 mmol) was added portionwise over 10 min, and then heated to 90 0C. To the mixture, 7-chloro-l- cyclopropyl-6-fluoro-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid (1.0 g) was added portionwise over 20 min, the temperature was increased to 105 0C and the mixture was stirred for 6 h. Water (30 mL) was added to the reaction solution and the pH of the solution was adjusted to pH=5. The resulting solution was left in the refrigerator overnight. The precipitate obtained was filtered, washed with cold water, and dried affording a 2:1 mixture of Intermediate 21 A and Intermediate 2 IB (1.0 g).Part of the crude product (700 mg) was dissolved in EtOH (15 mL) by heating to the reflux. Part of the crude product (700 mg) was dissolved in EtOH (15 mL) by heating to the reflux.The resulting solution was cooled to 300C and a first precipitation occurred. The precipitate was filtered, washed with cold EtOH and dried under reduced pressure. Intermediate 21A(204 mg) was obtained as a white solid;1H-NMR (500 MHz, DMSO-d6) δ: 15.06 (s, IH), 8.71 (s, IH), 8.40 (s, IH), 7.86 (s, IH), 4.97 (t, IH), 4.25 (t, 2H), 3.87 (m, IH), 3.82 (q, 2H), 1.32 (m, 2H), 1.20 (m, 2H); 13C-NMR(75 MHz, DMSO-d6) δ: 176.61, 165.67, 152.47, 147.54, 135.34, 129.48, 124.95, 120.02,106.90, 106.66, 71.22, 59.15, 35.99, 7.46; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl acetamide; water at 0 - 115℃; for 11.5h; | 12; 13 Intermediate 12 and Intermediate 13; 6-[(2-Amino-ethyl)amino]-7-chloro-1-cyclopropyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid hydrochloride (12) and 7-[(2-amino-ethyl)amino]-1-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-quinoline-3-carboxylic acid hydrochloride (13) 7-CHLORO-1-CYCLOPROPYL-1, 4-DIHYDRO-6-FLUORO-4-OXO-QUINOLINE-3-CARBOXYLIC acid (56.3 g) and ethylenediamine (36 G) were dissolved in N, N-DIMETHYLACETAMIDE (650 mL) at 100oC and stirred for 8.5 h at 115oC. Water (700 mL) was added to the reaction mixture cooled at room temperature. The reaction mixture was stirred at room temperature for 2 h, cooled at 0-5oC and stirred for 1 h. The precipitate obtained was filtered, washed with cold water, cold ETOH, and dried at 110oC under reduced pressure for 1 h. The crude product was treated with HCI (6% aqueous solution) heating for 1 h in the presence of charcoal. After filtration, the solution was cooled to 35-40oC and a first precipitation occurred. The precipitate was filtered, washed with water and dried at 110oC FOR 1 h. Intermediate 12 (6.4 g) was obtained as a hydrochloride salt. The mother liquors, after first precipitation, were cooled at room temperature and stirred overnight. The precipitate was filtered, washed with water and dried at 110oC for 1 h to give a mixture containing Intermediates 12 AND 13 (14. 18 G). INTERMEDIATE 12 : 1H-NMR (300 MHz, CF3COOD) d: 8.94 (s, 1H), 8.40 (s, 1 H), 7.40 (s, 1 H), 3.85 (m, 1H), 3.76 (m, 2H), 5.45 (m, 2H), 1.42 (m, 2H), 1.77 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | Stage #1: ethylene glycol With potassium <i>tert</i>-butylate In dimethyl sulfoxide for 0.5h; Stage #2: 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid In dimethyl sulfoxide at 90 - 110℃; | 4.8.1.6. 7-Chloro-1-cyclopropyl-1,4-dihydro-6-[(2-hydroxyethyl)oxy]-4-oxo-3-quinolincarboxylic acid (7a) and 1-cyclopropyl-1,4-dihydro-6-fluoro-7-[(2-hydroxyethyl)oxy]-4-oxo-3-quinolincarboxylic acid (7b) To a solution of ethylene glycol (6 mL, 107.59 mmol) in DMSO (5 mL) KOtBu (1.60 g, 14.23 mmol) was added portionwise over 30 minutes. Then, to the reaction mixture at 90 °C under vigorous stirring 7-chloro-1-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-3-quinolincarboxylic acid 5 (1 g, 3.55 mmol) was added. The reaction mixture was warmed up to 110 °C, and stirred at this temperature over 6 h. Then it was cooled down, water was added and the pH value was corrected to 5. While stirring overnight at 4 °C 1.0 g of mixture of products 7a and 7b (1:1) was collected on filter. Crystallisation of such mixture (0.7 g) from boiling EtOH (15 mL) and cooling down to 30 °C pure product 7a (0.2 g, Y=12%) was obtained; 1H NMR (500 MHz, DMSO-d6) d 8.68 (s, 1H), 8.37 (s, 1H), 7.84 (s, 1H), 5.09 (t, 1H), 4.36 (t, 2H), 3.86 (m, 1H+2H), 1.33 (m, 2H), 1.20 (m, 2H); 13C NMR (125 MHz, DMSO-d6) d 176.65, 165.64, 152.53, 147.54, 135.40, 129.56, 125.03, 120.00, 106.99, 106.84, 71.29, 59.14, 35.96, 7.46; MS (ESI) m/z calcd for C15H14ClNO5 [M+H]+ 324.0639; found 324.0642. |
With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 90 - 105℃; for 6.33333h; | To a mixture of DMSO (5 mL) and ethyleneglycol (6 mL), KOtBu (1.6 g, 14.23 mmol) was added portion-wise over 10 min, and then heated to 90° C. To the mixture, 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (1.0 g) was added portionwise over 20 min, the temperature was increased to 105° C. and the mixture was stirred for 6 h. Water (30 mL) was added to the reaction solution and the pH of the solution was adjusted to pH=5. The resulting solution was left in the refrigerator overnight. The precipitate obtained was filtered, washed with cold water, and dried affording a 2:1 mixture of Intermediate 25A and Intermediate 25B (1.0 g). Part of the crude product (700 mg) was dissolved in EtOH (15 mL) by heating to the reflux. The resulting solution was cooled to 30° C. and a first precipitation occurred. The precipitate was filtered, washed with cold EtOH and dried under reduced pressure. Intermediate 24A (204 mg) was obtained as a white solid. 1H-NMR (500 MHz, DMSO-d6) δ: 15.06 (s, 1H), 8.71 (s, 1H), 8.40 (s, 1H), 7.86 (s, 1H), 4.97 (t, 1H), 4.25 (t, 2H), 3.87 (m, 1H), 3.82 (q, 2H), 1.32 (m, 2H), 1.20 (m, 2H); 13C-NMR (75 MHz, DMSO-d6) δ: 176.61, 165.67, 152.47, 147.54, 135.34, 129.48, 124.95, 120.02, 106.90, 106.66, 71.22, 59.15, 35.99, 7.46. | |
Stage #1: ethylene glycol With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 90℃; for 0.166667h; Stage #2: 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid In dimethyl sulfoxide at 105℃; for 6.33333h; | 26 Intermediate 26; 7-Chloro-1-cyclopropyl-6-(2-hydroxy-ethoxy)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (A) and 1-cyclopropyl-6-fluoro-7-(2-hydroxy-ethoxy)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (B) To a mixture of DMSO (5 ml) and ethyleneglycol (6 ml), KOtBu (1.6 g, 14.23 mmol) was added portionwise over 10 min, and then heated to 90 °C. To the mixture, 7-CHLORO-1- cyclopropyl-6-fluoro-4-oxo-1, 4-DIHYDRO-QUINOLINE-3-CARBOXYLIC acid (1.0 g) was added portionwise over 20 min, the temperature was increased to 105 °C and the mixture was stirred for 6 h. Water (30 ml) was added to the reaction solution and the pH of the solution was adjusted to pH=5. The resulting solution was left in the refrigerator overnight. The precipitate obtained was filtered, washed with cold water, and dried affording a 2: 1 mixture of Intermediate 26A and Intermediate 26B (1.0 g). Part of the crude product (700 mg) was dissolved in ETOH (15 ml) by heating to the reflux. The resulting solution was cooled to 30°C and a first precipitation occurred. The precipitate was filtered, washed with cold ETOH and dried under reduced pressure. Intermediate 26A (204 mg) was obtained as a white solid. 'H-NMR (500 MHz, DMSO-d6) 8 : 15.06 (s, 1H), 8.71 (s, 1H), 8.40 (s, 1H), 7.86 (s, 1H), 4.97 (t, 1H), 4.25 (t, 2H), 3.87 (M, IH), 3.82 (q, 2H), 1.32 (M, 2H), 1.20 (M, 2H).'3C-NMR (75 MHz, DMSO-d6) 8 : 176.61, 165.67, 152.47, 147.54, 135.34, 129.48, 124.95, 120.02, 106. 90,106. 66,71. 22,59. 15,35. 99,7. 46. MS; M/Z (ES): [MH] + |
With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 90 - 105℃; for 6.5h; | 18 Intermediate 18; 7-Chloro-1-cyclopropyl-6-(2-hydroxy-ethoxy)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (A) and 1-Cyclopropyl-6-fluoro-7-(2-hydroxy-ethoxy)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (B) To a mixture of DMSO (5 mL) and ethyleneglycol (6 mL), KOtBu (1.6 g, 14.23 MMOL) was added portionwise over 10 min, and then heated to 90 oC. To the mixture, 7-CHLORO-1- cyclopropyl-6-fluoro-4-oxo-1, 4-DIHYDRO-QUINOLINE-3-CARBOXYLIC acid (1.0 g) was added portionwise over 20 min, the temperature was increased to 105 oC and the mixture was stirred for 6 h. Water (30 mL) was added to the reaction solution and the pH of the solution was adjusted to pH=5. The resulting solution was left in the refrigerator overnight. The precipitate obtained was filtered, washed with cold water, and dried affording a 2: 1 mixture of Intermediate 18A and Intermediate 18B (1.0 g). Part of the crude product (700 mg) was dissolved in ETOH (15 mL) by heating to the reflux. The resulting solution was cooled to 30oC and a first precipitation occurred. The precipitate was filtered, washed with cold EtOH and dried under reduced pressure. Intermediate 18A (204 mg) was obtained as a white solid ;'H-NMR (500 MHz, DMSO- d6) 8 : 15.06 (s, 1H), 8.71 (s, 1H), 8.40 (s, 1H), 7.86 (s, 1 H), 4.97 (t, 1H), 4.25 (t, 2H), 3.87 (m, 1H), 3.82 (q, 2H), 1.32 (m, 2H), 1.20 (m, 2H) ;'3C-NMR (75 MHz, DMSO-d6) 8 : 176. 61, 165.67, 152.47, 147. 54, 135.34, 129.48, 124. 95, 120.02, 106.90, 106.66, 71.22, 59.15, 35.99, 7.46 ; MS; m/z (ES): [MH] +. | |
Stage #1: ethylene glycol With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 90℃; for 0.166667h; Stage #2: 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid In dimethyl sulfoxide at 105℃; for 6.33h; | 4 Intermediate 4; 7-Chloro-1-cyclopropyl-6-(2-hydroxy-ethoxy)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (A) and 1-Cyclopropyl-6-fluoro-7-(2-hydroxy-ethoxy)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (B) To a mixture of DMSO (5 mL) and ethyleneglycol (6 ML), KOtBu (1.6 G, 14.23 MMOL) was added portionwise over 10 min, and then heated to 90 oC. To the mixture, 7-CHLORO-1- cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid (1.0 G) was added portionwise over 20 min, the temperature was increased to 105 oC and the mixture was stirred for 6 h. Water (30 mL) was added to the reaction solution and the pH of the solution was adjusted to pH=5. The resulting solution was left in the refrigerator overnight. The precipitate obtained was filtered, washed with cold water, and dried affording a 2: 1 mixture of Intermediate 4A and Intermediate 4B (1.0 g). Part of the crude product (700 mg) was dissolved in ETOH (15 mL) by heating to the reflux. The resulting solution was cooled to 30oC and a first precipitation occurred. The precipitate was filtered, washed with cold EtOH and dried under reduced pressure. Intermediate 4A (204 mg) was obtained as a white solid. 'H-NMR (500 MHz, DMSO-d6) 8 : 15.06 (s, 1H), 8.71 (s, 1H), 8.40 (s, 1H), 7.86 (s, 1H), 4.97 (t, 1H), 4.25 (t, 2H), 3.87 (m, 1H), 3.82 (q, 2H), 1.32 (m, 2H), 1. 20 (m, 2H). 13C-NMR (75 MHz, DMSO-d6) 5 : 176. 61, 165.67, 152. 47, 147. 54, 135.34, 129.48, 124.95, 120.02, 106. 90, 106.66, 71.22, 59.15, 35.99, 7.46. MS; m/z (ES): [MH] + | |
Stage #1: ethylene glycol With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 20 - 90℃; for 0.166667h; Stage #2: 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid In dimethyl sulfoxide at 90 - 105℃; for 6.33h; | 16 Intermediate 16: 7-Chloro-l-cyclopropyl-6-(2-hydroxy-ethoxv)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (A) and I-Cyclopropyl-6-fluoro-7-(2-hydroxy-ethoxy)-4-oxo-1,4-dihydro-ciuinoline-3-carboxylic acid (B) To a mixture of DMSO (5 mL) and ethyleneglycol (6 mL), KOtBu (1.6 g, 14.23 mmol) was added portionwise over 10 min, and then heated to 90 °C. To the mixture, 7-chloro-l- cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (1.0 g) was added portionwise over 20 min, the temperature was increased to 105 °C and the mixture was stirred for 6 h. Water (30 mL) was added to the reaction solution and the pH of the solution was adjusted to pH=5. The resulting solution was left in the refrigerator overnight. The precipitate obtained was filtered, washed with cold water, and dried affording a 2: 1 mixture of Intermediate 16A and Intermediate 16B (1.0 g). Part of the crude product (700 mg) was dissolved in EtOH (15 mL) by heating to the reflux. The resulting solution was cooled to 30°C and a first precipitation occurred. The precipitate was filtered, washed with cold EtOH and dried under reduced pressure. Intermediate 16A (204 mg) was obtained as a white solid; (at)H-NMR (500 MHz, DMSO-d6) 8: 15.06 (s, 1H), 8.71 (s, 1H), 8.40 (s, 1H), 7.86 (s, 1H), 4.97 (t, 1H), 4.25 (t, 2H), 3.87 (m, 1H), 3.82 (q, 2H), 1.32 (m, 2H), 1.20 (m, 2H); ¹3C-NMR (75 MHz, DMSO-d6) 8: 176.61,165.67, 152.47,147.54, 135.34,129.48, 124.95,120.02, 106.90,106.66, 71.22, 59.15, 35.99, 7.46; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With pyridine for 48h; Heating / reflux; | 8.1 Step 1. (R)-7-(3-tert-Butoxyvarbonylarnino-pyrrolidin-l-yl)-l-cyclopropyl- 6-fluoro-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid: To a stirred solution of 7-chloro-1- cyclopropyl-6-fluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid (756 mg, 2.68 mmol) in pyridine (30 ml) was added (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (1.0 g, 5.36 mmol). This was heated at reflux for 48 hours. The reaction mixture was cooled to room temperature, MeOH (30 ml) was added to precipitate the title product as a white solid in 48% yield. ESI MS m/z 432 (M + H+) ; 1H NMR (400 MHz, DMSO-d6) No. 8.58 (s, 1H), 7.84 (d, J= 14. 8 Hz, 1H), 7.08 (d, J=7.8 Hz, 1H), 3.94-3. 44 (m, 5H), 2.31 (m, 1H), 2.15 (m, 2H), 1.37 (s, 9H) 1.28 (n, 2H), 1.14 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | at 110℃; for 20h; | 4.8.1. General procedure for aminolysis General procedure: To a solution of compounds 2-5 (1 eq) in 1-methyl-2-pyrolidone, 2-amino-ethanol or 2-(2-aminoethoxy)-ethanol (2 eq) were added. The reaction mixture was warmed up to 110 °C, and stirred at this temperature over 20 h. Then it was cooled to 20-25 °C, water was added and pH was adjusted to 12. The resulting solution was extracted with DCM, then pH value of water solution was corrected to 6, and after 10 min crystalline product was collected on filter affording pure products 6a, 8a-11a. |
In 1-methyl-pyrrolidin-2-one at 110℃; for 24h; | 37.a a) 7-ChIoro-1 -cyclopropyl-6-[2-(2-hydroxy-ethoxy)-ethyl amino]-4-oxo-1 ,4-dihydro- quinoline-3-carboxylic acidA mixture of 7-chloro-1-cycIopropyl-6-fluoro-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid(10 g) in 1-methyl-2-pyrroIidinone (70 ml_) was treated with 2-(2-amino-ethoxy)-ethanol (18 mL), and the mixture stirred at 1100C. After 24 hours the mixture was diluted with water (200 mL) and DCM (60 mL) and the pH adjusted to 10. The aqueous layer was extracted with DCM (5x50 mL) and then adjusted to pH 6.7. After 10 minutes a precipitate formed, which was filtered off to give the title compound (2.7 g). After standing overnight a second precipitate formed, which was filtered off to give a 1 :1 mixture (by LCMS) of the title compound and 1-cyclopropyl-6-fluoro-7-[2-(2-hydroxy-ethoxy)-ethylamino]-4-oxo-1 ,4-dihydro-quinoline-3-carboxylic acid as yellow solid (7.7 g); ESMS m/z 367.2 [M+H]+. | |
In 1-methyl-pyrrolidin-2-one at 110℃; for 24h; | 1-Cyclopropyl-6-fluoro-7-[2-(2-hydroxy-ethoxy)-ethylamino]-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (A) and 7-Chloro-1-cyclopropyl-6-[2-(2-hydroxy-ethoxy)-ethyl amino]-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (B) To a mixture of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (10 g, 0.035 mol) in 1-methyl-2-pirolidone (70 mL) 2-(2-amino-ethoxy)-ethanol (18 mL, 0.18 mol, 5 eq.) was added, the reaction mixture was stirred at 110° C. for 24 hours. Then was diluted with water (200 mL) and CH2Cl2 (60 mL) and the pH was adjusted to 10. The aqueous layer was extracted with CH2Cl2 (5*50 mL) and then the pH was adjusted to 6.7. After 10 minutes first product precipitated. Filtrated off yielding 2.7 g of crude 7-chloro-1-cyclopropyl-6-[2-(2-hydroxy-ethoxy)-ethylamino]-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid. (according to LC-MS 100% pure Intermediate 6B) Over night second product precipitated. Filtrated off yielding 7.7 g of yellow product (according to LC-MS a mixture of Intermediate 6A and Intermediate 6B in a 1:1 ratio). |
With 1-methyl-pyrrolidin-2-one at 110℃; for 24h; | To a mixture of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (lOg, 0,035 mol) in I-methyl-2-pirolidone (70 mL) 2- (2-amino-ethoxy)-ethanol mL, 0,18 mol, 5 eq. ) was added, the reaction mixture was stirred at 110 °C for 24 hours. Then was diluted with water (200 mL) and CH2C12 (60 mL) and pH was adjusted to 10. The aqueous layer was extracted with CH2C12 (5x50 mL) and then pH was adjusted to 6,7. After 10 minutes first product precipitated. Filtrated off yielding 2,7g of crude 7-chloro-1- cyclopropyl-6-[2-(2-hydroxy-ethoxy)-ethylamino]-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid. (according to LC-MS 100 % pure Intermediate 6B) Over night second product precipitated. Filtrated off yielding 7,7g of yellow product (according to LC-MS a mixture of Intermediate 6A and Intermediate 6B in a 1:1 ratio). | |
In 1-methyl-pyrrolidin-2-one at 110℃; for 24h; | 6 To a mixture of 7-chloro-l-cyclopropyl-6-fluoro-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid (1Og, 0,035 mol) in l-methyl-2-pirolidone (70 mL) 2-(2-amino-ethoxy)-ethanol (18 mL, 0,18 mol, 5 eq.) was added, the reaction mixture was stirred at 110 °C for 24 hours. Then was diluted with water (200 mL) and CH2Cl2 (60 mL) and the pH was adjusted to 10. The aqueous layer was extracted with CH2Cl2 (5x50 mL) and then the pH was adjusted to 6,7. After 10 minutes first product precipitated. Filtrated off yielding 2,7g of crude 7-chloro-l- cyclopropyl-6-[2-(2-hydroxy-ethoxy)-ethylamino]-4-oxo-l,4-dihydro-quinolirie-3-carboxylic acid, (according to LC-MS 100 % pure Intermediate 6B) Over night second product precipitated. Filtrated off yielding 7,7 g of yellow product (according to LC-MS a mixture of Intermediate 6 A and Intermediate 6B in a 1:1 ratio). | |
In 1-methyl-pyrrolidin-2-one at 110℃; for 24h; | 6 Intermediate 6 1-CvdoproDvl-6-fluoro-7-12-(2-hvdroxY-ethoxvi-ethvlaminol-4-oxo-1,4-dihvdro- quinoline-3-carboxylic acid (A) and 7-Chloro-l-cvclopropvl-6-r2-(2-hvdroxv-ethoxv)-ethvl amino] -4-oxo-1,4-di.aydro" quinoline-3-carboxylic acid (B) To a mixture of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (lOg, 0,035 mol) in 1-methyl-2-pirolidone (70 mL) 2- (2-amino-ethoxy)-ethanol mL, 0,18 mol, 5 eq. ) was added, the reaction mixture was stirred at 110 °C for 24 hours. Then was diluted with water (200 mL) and CH2Cl2 (60 mL) and pH was adjusted to 10. The aqueous layer was extracted with CH2Cl2 (5x50 mL) and then pH was adjusted to 6,7. After 10 minutes first product precipitated. Filtrated off yielding 2,7g of crude 7-chloro-l- cyclopropyl-6-[2-(2-hydroxy-ethoxy)-ethylamino]-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid. (according to LC-MS 100 % pure Intermediate 6B) Over night second product precipitated. Filtrated off yielding 7,7g of yellow product (according to LC-MS a mixture of Intermediate 6A and Intermediate 6B in a 1:1 ratio). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In tetrahydrofuran Heating / reflux; | A mixture of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (1 g, 3,55 mmol) and 1,1-carbonyldiimidazole (2.88 g, 17.75 mmol) in 15 ml CCl3 was heated to reflux and refluxed over night. The mixture was cooled and the solvent was removed under reduced pressure. A small amount of diethyl ether was added to the residue 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 (0.26 g, 0.0108 mol, 60% disperse oil) and nitromethane (0.58 m,l 0.0108 mol) in 20 ml of anhydrous THF a solution of imidazolide intermediate (0.9 g, 0.289 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 0.4 g of title compound. (90.6% pure compound according to LC-MS). MS (ES+) m/z: [MH]+=325.1 |
100% | In chloroform for 17h; Heating / reflux; | A mixture of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (1 g, 3,55 mmol) and of 1,1-carbonyldiimidazole (2,88 g, 17,75 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 (0,26 g, 0,0108 mol, 60 % disperse oil) and of nitromethane (0,58 m,l 0,0108 mol) in 20 ml of anhydrous THF a solution of imidazolide intermediate (0,9 g, 0,289 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 0,4g of title compound. (90,6 % pure compound according to LC-MS). MS (ES+) m/z : [MH] (at) = 325.1 Intermediate 8 1-Cyclopropyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-3-f (2-methanesulfonyl)acetyll- Quinoline. A mixture of 1-cyclopropyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (2 g, 0.0071 mol) and 1,1'-carbonyldiimidazole (5.76 g, 0.035 mol) in 15 mL CHC13 was heated to reflux for 17 hours. The solvent was removed by reduced pressure. To the residue ether was added and then stirred at room temperature for 30 min. The solid was filtered and dried affording 1.64 g of 3-imidazolide derivative. Imidazolide derivative (1 g, 0.003mol) was dissolved in 40 mL acetonitrile, then methanesulphonylacetone (2 g, 0.015 mol) and K2CO3 were added and the mixture was heated to reflux for 21 hours. The solvent was removed under reduced pressure and 120 mL of H20 was added. The solution was acidified by 2N HCI (pH (at) 3) and extracted with EtOAc. The organic layer was dried and concentratedto give a crude solid product. The crude product was purified by column chromatography (DCM-EtOH-NH40H = 90: 9:1.5) to give pure product 1-cyclopropyl-6- fluoro-7-chloro-4-oxo-1,4-dihydro-3-[(2-methanesulfonyl)acetyl]-quinoline. MS (ES+) m/z : [MH]+ = 358.1 ¹H NMR (500 MHz, DMSO) 08.58, 8.37,8.13, 5.22,3.78, 3.13, 1.31 and 1.16 |
100% | In tetrahydrofuran Heating / reflux; | 2 A mixture of 7-chloro-l-cyclopropyl-6-fluoro-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid (1 g, 3,55 mmol) and of 1,1-carbonyldiimidazole (2,88 g, 17,75 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; | 2 2 I-Cyclopropyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-ciuinoline-3-(2-nitroacetyl) A mixture of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (I g, 3,55 mmol) and of 1,1-carbonyldiimidazole (2,88 g, 17,75 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 (0,26 g, 0,0108 mol, 60 % disperse oil) and of nitromethane (0,58 m,l 0,0108 mol) in 20 ml of anhydrous THF a solution of imidazolide intermediate (0,9 g, 0,289 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 CH2C12. The organic layer was washed with H20 and brine, dried by anhydrous Na2S04 and evaporated. The product was precipitated and filtrated off yielding 0,4g of title compound. (90,6 % pure compound according to LC-MS). MS (ES+) m/z: [MH] (at) = 325.1 |
In chloroform for 17h; Heating / reflux; | A mixture of 1-cyclopropyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (2 g, 0.0071 mol) and 1,1'-carbonyldiimidazole (5.76 g, 0.035 mol) in 15 mL CHCl3 was heated to reflux for 17 hours. The solvent was removed by reduced pressure. To the residue ether was added and then stirred at room temperature for 30 min. The solid was filtered and dried affording 1.64 g of 3-imidazolide derivative. Imidazolide derivative (1 g, 0.003 mol) was dissolved in 40 mL acetonitrile, then methanesulphonylacetone (2 g, 0.015 mol) and K2CO3 were added and the mixture was heated to reflux for 21 hours. The solvent was removed under reduced pressure and 120 mL of H2O was added. The solution was acidified by 2N HCl (pH 3) and extracted with EtOAc. The organic layer was dried and concentrated to give a crude solid product. The crude product was purified by column chromatography (DCM-EtOH-NH4OH=90:9:1.5) to give pure product 1-cyclopropyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-3-[(2-methanesulfonyl)acetyl]-quinoline. MS (ES+) m/z: [MH]+=358.1. | |
In chloroform for 17h; Heating / reflux; | 8 A mixture of l-cyclopropyl-6-fluoro-7-chloro-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid (2 g, 0.0071 mol) and l,l'-carbonyldiimidazole (5.76 g, 0.035 mol) in 15 niL CHCl3 was heated to reflux for 17 hours. The solvent was removed by reduced pressure. To the residue, ether was added and then stirred at room temperature for 30 min. The solid was filtered and dried affording 1.64 g of 3-imidazolide derivative. Imidazolide derivative (1 g, 0.003mol) was dissolved in acetonitrile (40 ml), then methanesulphonylacetone (2 g, 0.015 mol) and K2CO3 were added and the mixture was heated to reflux for 21 hours. The solvent was removed under reduced pressure and 120 mL Of H2O was added. The solution was acidified by 2N HCl (pH ~ 3) and extracted with EtOAc. The organic layer was dried and concentrated to give a crude solid product. The crude product was purified by column chromatography (DCM-EtOH-NH4OH = 90:9:1.5) to give pure product l-cyclopropyl-6-fluoro-7-cliloro-4- oxo- 1 ,4-dihydro-3 - [(2-methanesulfonyl)acetyl] -quinoline. MS (ES+) m/z : [MH]+ = 358.1 1H NMR (500 MHz, DMSO) δ 8.58, 8.37, 8.13, 5.22, 3.78, 3.13, 1.31 and 1.16. | |
In chloroform for 17h; Heating / reflux; | 8 Intermediate 8 I-C-vclopropyl-6-fluoro-7-chloro-4-oxo-1,4-dihvdro-3-1(2-methanesulfonvl)acet-yll quinoline. A mixture of 1-cyclopropyl-6-fluoro-7-chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (2 g, 0.0071 mol) and 1,1'-carbonyldiimidazole (5.76 g, 0.035 mol) in 15 mL CHC13 was heated to reflux for 17 hours. The solvent was removed by reduced pressure. To the residue ether was added and then stirred at room temperature for 30 min. The solid was filtered and dried affording 1.64 g of 3-imidazolide derivative. Imidazolide derivative (I g, 0.003mol) was dissolved in 40 mL acetonitrile, then methanesulphonylacetone (2 g, 0.015 mol) and K2C03 were added and the mixture was heated to reflux for 21 hours. The solvent was removed under reduced pressure and 120 mL of H20 was added. The solution was acidified by 2N HCl (pH (at) 3) and extracted with EtOAc. The organic layer was dried and concentrated to give a crude solid product. The crude product was purified by column chromatography (DCM-EtOH-NH40H = 90: 9:1.5) to give pure product 1-cyclopropyl-6-fluoro-7-chloro-4- oxo-1,4-dihydro-3-[(2-methanesulfonyl)acetyl]-quinoline. MS (ES+) m/z : [MH] (at) = 358.1 ¹H NMR (500 MHz, DMSO) (at)8.58, 8.37, 8.13, 5.22, 3.78, 3.13, 1.31 and 1.16 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1-methyl-pyrrolidin-2-one at 110℃; for 24h; | 7-{2-[2-(2-amino-ethoxy)-ethoxy]-ethylamino}-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (B) A mixture of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (5 g, 0.018 mol), 2,2'-(ethylenedioxy)bis-(ethylamine) (26 mL, 0.18 mol, 10 eq.) in 1-methyl-2-pyrrolidone was heated at 110° C. for 24 hours. Reaction mixture was diluted with water (70 mL) pH was adjusted to 11 and extracted with CH2Cl2 (9*40 mL). Water layer was then acified to pH 6.8 with H2SO4, extracted with CH2Cl2 (50 mL) and evaporated. 2-Propanol was added (200 mL) and stirred at 82° C. for 30 minutes. The reaction mixture was then filtered and 2-propanol was evaporated in vacuum yielding 8 g of oily product, according to LC-MS 50% of chloro derivative (A) and 30% of fluoro derivative. Product was purified by column chromatography (eluent CH2Cl2-2-propanol=1:1) yielding pure chloro derivative (A). MS (ES+) m/z: [MH]+=409.9 (A) MS (ES+) m/z: [MH]+=393.4 (B). | |
With potassium carbonate In 1-methyl-pyrrolidin-2-one at 100℃; for 8h; Inert atmosphere; regioselective reaction; | ||
With 1-methyl-pyrrolidin-2-one at 110℃; for 24h; | A mixture of 7-chloro-l-cyclopropyl-6-fluoro-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid (5g, 0.018 mol), 2,2'-(ethylenedioxy)bis-(ethylamine) (26 mL, 0.18 mol, lOeq.) in 1-methyl- 2-pyrrolidone was heated at 110 °C for 24 hours. Reaction mixture was diluted with water (70 mL) pH was adjusted to 11 and extracted with CH2Cl2 (9x40 mL). Water layer was then acified to pH 6.8 with H2S04, extracted with CH2C12 (50 mL) and evaporated. 2-Propanol was added (200 mL) and stirred at 82 °C for 30 minutes. The reaction mixture was then filtered and 2-propanol was evaporated in vacuum yielding 8 g of oily product, according to LC-MS 50% of chloro derivative (A) and 30% of fluoro derivative. Product was purified by column chromatography (eluent CH2Cl2-2-propanol = 1:1) yielding pure chloro derivative (A). MS (ES+) m/z: [MH]+ = 409.9 (A) MS (ES+) m/z : [MH] (at) = 393.4 (B) |
In 1-methyl-pyrrolidin-2-one at 110℃; for 24h; | 23 A mixture of 7-chloro- 1 -cyclopropyl-6-fluoro-4-oxo- 1 ,4-dihydro-quinoline-3 -carboxylic acid (5g, 0.018 mol), 2,2'-(ethylenedioxy)bis-(ethylamine) (26 mL, 0.18 mol, lOeq.) in 1-methyl- 2-pyrrolidone was heated at 110 0C for 24 hours. Reaction mixture was diluted with water (70 mL) pH was adjusted to 11 and extracted with CH2Cl2 (9x40 mL). Water layer was then acified to pH 6.8 with H2SO4, extracted with CH2Cl2 (50 mL) and evaporated. 2-Propanol was added (200 mL) and stirred at 82 0C for 30 minutes. The reaction mixture was then filtered and 2-propanol was evaporated in vacuum yielding 8 g of oily product, according to LC-MS 50% of chloro derivative (A) and 30% of fluoro derivative. Product was purified by column chromatography (eluent CH2Cl2-2-propanol = 1:1) yielding pure chloro derivative (A). MS (ES+) m/z : [MH]+ = 409.9 (A) MS (ES+) m/z : [MH]+ = 393.4 (B) | |
In 1-methyl-pyrrolidin-2-one at 110℃; for 24h; | 18 Intermediate 18 6-f 2-(2-(2-amino-ethoxyl-ethoxyl-ethylamino(at)-1-cyclopropyl-7-chloro-4-oxo-1,4- dihydro-quinoline-3-carboxylic acid (A) and 7-(2- 12-(2-amino-ethoxyi-ethoxvl -ethvlamino)-I-cvdoDropyl-6-fluoro-4-oxo-1 ,4- dihydro-quinoline-3-carboxylic acid (B) A mixture of 7-chloro-I-cyclopropyl-6-fluoro-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid (5g, 0.018 mol), 2,2'-(ethylenedioxy)bis-(ethylamine) (26 mL, 0.18 mol, 10eq.) in 1-methyl- 2-pyrrolidone was heated at 110 °C for 24 hours. Reaction mixture was diluted with water (70 mL) pH was adjusted to 11 and extracted with CH2C12 (9x40 mL). Water layer was then acified to pH 6.8 with H2S04, extracted with CH2C12 (50 mL) and evaporated. 2-Propanol was added (200 mL) and stirred at 82 °C for 30 minutes. The reaction mixture was then filtered and 2-propanol was evaporated in vacuum yielding 8 g of oily product, according to LC-MS 50% of chloro derivative (A) and 30% of fluoro derivative. Product was purified by column chromatography (eluent CH2Cl2-2-propanol = 1: 1) yielding pure chloro derivative (A). MS (ES+) m/z : [MH] (at) = 409.9 (A) MS (ES+) m/z : [MH]+ = 393.4 (B) |
Yield | Reaction Conditions | Operation in experiment |
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With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 70 - 105℃; for 5h; | Mixture of 50 mL diethylene glycole and 50 mL DMSO was prepared and heated on 70° C. Into mixture 8 g of KO-t-Bu portionwise was added. Then, 5 g of fluoro-chloro quinolonic acid (17.8 mmol) was added portionwise. The temperature was increased to 105° C. After 5 hours, the 25 mL of H2O was added and the mixture was extracted with 2×20 mL of DCM. Water layer was adjusted to pH 4. The obtained precipitate was filtered off and dried under reduced pressure affording 500 mg of 7-chloro-1-cyclopropyl-6-[2-(2-hydroxy-ethoxy)-ethoxy]-4-oxo-1,4-dihydro-quinolone-3-carboxylic acid. 7-Chloro-1-cyclopropyl-6-[2-(2-hydroxy-ethoxy)-ethoxy]-4-oxo-1,4-dihydro-quinolone-3-carboxylic acid (500 mg) was dissolved in 12.5 mL of acrylonitrile, then 1 mL of DBU was added and the mixture was stirred for 24 hours at 80° C. Acrylonitrile was evaporated under reduced pressure, residue was dissolved in 300 mL of 2-propanol and the pH of the mixture was adjusted to pH 3.5. The precipitate was obtained after 12 hours, filtered off and washed with water (pH 3.5). The precipitate was dissolved in 20 mL H2O:H2SO4 (1:1) and stirred for 24 hours at room temperature. The obtained precipitate was filtered off and dried under reduced pressure affording 300 mg of the title | |
With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 70 - 105℃; for 5h; | Mixture of 50 mL diethylene glycole and 50 mL DMSO was prepared and heated on 70°C. Into mixture 8 g of KO-t-Bu portionwise was added. Then, 5 g of fluoro-chloro quinolonic acid (17.8 mmol) was added portionwise. The temperature was increased to 105°C. After 5 hours, the 25 mL of H20 was added and the mixture was extracted with 2x20 mL of DCM. Water layer was adjusted to pH 4. The obtained precipitate was filtered off and dried under reduced pressure affording 500 mg of 7-chloro-l-cyclopropyl-6-[2-(2-hydroxy-ethoxy)- ethoxy]-4-oxo-1,4-dihydro-quinolone-3-carboxylic acid. 7-Chloro-1-cyclopropyl-6-[2-(2-hydroxy-ethoxy)-ethoxy]-4-oxo-1,4-dihydro-quinolone-3- carboxylic acid (500 mg) was dissolved in 12,5 mL of acrylonitrile, then 1 mL of DBU was added and the mixture stirred for 24 hours at 80°C. Acrylonitrile was evaporated under reduced pressure, residue was dissolved in 300 mL of 2-propanol and the pH of the mixture was adjusted to pH 3.5. The precipitate was obtained after 12 hours, filtered off and washed with water (pH 3.5). The precipitate was dissolved in 20 mL H20:H2S04 (1:1) and stirred for 24 hours at room temperature. The obtained precipitate was filtered off and dried under reduced pressure affording 300 mg of the title compound. | |
With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 70 - 105℃; for 5h; | 13 Mixture of 50 mL diethylene glycole and 50 mL DMSO was prepared and heated on 70°C.Into mixture 8 g of KO-t-Bu portionwise was added. Then, 5 g of fluoro-chloro quinolonic acid (17.8 mmol) was added portionwise. The temperature was increased to 105°C. After 5 hours, the 25 mL of H2O was added and the mixture was extracted with 2x20 mL of DCM.Water layer was adjusted to pH 4. The obtained precipitate was filtered off and dried under reduced pressure affording 500 mg of 7-chloro-l-cycloρropyl-6~[2-(2-hydroxy-ethoxy)- ethoxy]-4-oxo-l ,4-dihydro-quinolone-3 -carboxylic acid. |
With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 70 - 105℃; for 5h; | 10 Intermediate 10 6-J2-[2-(2-cvano-ethoxvi-ethoxvl-ethoxvl-7-chloro-I-cvcloproDvl-4-oxo-1,4-dihvdro- quinolone-3-carboxylic acid Mixture of 50 mL diethylene glycol and 50 mL DMSO was prepared and heated on 70°C. Into mixture 8 g of KO-t-Bu portionwise was added. Then, 5 g of fluoro-chloro quinolonic acid (17.8 mmol) was added portionwise. The temperature was increased to 105°C. After 5 hours, the 25 mL of H20 was added and the mixture was extracted with 2x20 mL of DCM. Water layer was adjusted to pH 4. The obtained precipitate was filtered off and dried under reduced pressure affording 500 mg of 7-chloro-l-cyclopropyl-6-[2-(2-hydroxy-ethoxy)- ethoxy]-4-oxo-1,4-dihydro-quinolone-3-carboxylic acid. 7-Chloro-1-cyclopropyl-6-[2-(2-hydroxy-ethoxy)-ethoxy]-4-oxo-1,4-dihydro-quinolone-3- carboxylic acid (500 mg) was dissolved in 12,5 mL of acrylonitrile, then 1 mL of DBU was added and the mixture stirred for 24 hours at 80°C. Acrylonitrile was evaporated under reduced pressure, residue was dissolved in 300 mL of 2-propanol and the pH of the mixture was adjusted to pH 3.5. The precipitate was obtained after 12 hours, filtered off and washed with water (pH 3.5). |
Yield | Reaction Conditions | Operation in experiment |
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75%; 25% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In 1-methyl-pyrrolidin-2-one; at 110℃; for 18h; | To a solution of 7-chloro-l-cyclopropyl-6-fluoro-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid (0.55g, 1.95 mmol) in l-methyl-2-pyrrolidone (40 mL) bis-(2-aminoethyl)-ether dihydrochlorid (2.1g, 11.9 mmol, 6eq.) and DBU (3.49 mL, 23.4 mmol, 12 eq.) added and the reaction mixture was stirred at 110 0C for 18 hours. The reaction mixture was then diluted with water (70 mL), pH was adjusted to 11 and extracted with CH2Cl2 (9x40 mL). Water layer was then acified with H2SO4 to pH 6.8, extracted with 50 mL of CH2Cl2 and then evaporated in vacuum. Crude product was diluted in 2-propanol (60 mL), stirred at 82 0C for 20 minutes and filtrated. Precipitate was pure salt (Na2SO4). 2-Propanol was evaporated in vacuum and product was purified by column chromatography (fraction, eluent: CH2Cl2- MeOH-NH3-CH3CN=4;4:2:l) yielding 0.5g of title compounds as a mixture of chloro and fluoro derivatives in ratio 3:1 MS (ES+) m/z : [MH]+ = 365.8 (A) (75 %) MS (ES+) m/z : [MH]+ = 349.4 (B) (25 %) |
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In 1-methyl-pyrrolidin-2-one; at 110℃; for 18h; | To a solution of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (0.55 g, 1.95 mmol) in 1-methyl-2-pyrrolidone (40 mL) bis-(2-aminoethyl)-ether dihydrochloride (2.1 g, 11.9 mmol, 6eq.) and DBU (3.49 mL, 23.4 mmol, 12 eq.) added and the reaction mixture was stirred at 110 C. for 18 hours. The reaction mixture was then diluted with water (70 mL) and the pH was adjusted to 11 and extracted with CH2Cl2 (9*40 mL). Water layer was then acified with H2SO4 to pH 6.8, extracted with 50 mL of CH2Cl2 and then evaporated in vacuum. Crude product was diluted in 2-propanol (60 mL), stirred at 82 C. for 20 minutes and filtrated. Precipitate was pure salt (Na2SO4). 2-Propanol was evaporated in vacuum and product was purified by column chromatography (fraction, eluent: CH2Cl2-MeOH-NH3-CH3CN=4:4:2:1) yielding 0.5 g of title compounds as a mixture of chloro and fluoro derivatives in ratio 3:1 MS (ES+) m/z: [MH]+=365.8 (A) (75%) MS (ES+) m/z: [MH]+=349.4 (B) (25%). | |
With 1-methyl-pyrrolidin-2-one; 1,8-diazabicyclo[5.4.0]undec-7-ene; at 110℃; for 18h; | To a solution of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (O.SSg, 1.95 mmol) in 1-methyl-2-pyrrolidone (40 mL) bis-(2-aminoethyl)-ether dihydrochlorid (2.1g, 11.9 mmol, 6eq. ) and DBU (3.49 mL, 23.4 mmol, 12 eq. ) added and the reaction mixture was stirred at 110 C for 18 hours. The reaction mixture was then diluted with water (70 mL), pH was adjusted to 11 and extracted with CH2Cl2 (9x40 mL). Water layer was then acified with H2S04 to pH 6.8, extracted with 50 mL of CH2Cl2 and then evaporated in vacuum. Crude product was diluted in 2-propanol (60 mL), stirred at 82 C for 20 minutes and filtrated. Precipitate was pure salt (Na2SO4). 2-Propanol was evaporated in vacuum and product was purified by column chromatography (fraction, eluent: CH2Cl2- MeOH-NH3-CH3CN=4:4:2:1) yielding 0.5g of title compounds as a mixture of chloro and fluoro derivatives in ratio 3:1 MS (ES+) m/z : [MH]+ = 365.8 (A) (75 %) MS (ES+) m/z : [MH]+ = 349.4 (B) (25 %) |
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In 1-methyl-pyrrolidin-2-one; at 110℃; for 18h; | Intermediate 20 6-(2-(2-Amino-ethoxyl-ethylamino(at)7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro- quinoline-3-carboxylic acid (A) and 7-f 2-(2-Amino-ethoxy)-ethylaminol-1-cyclouropyl-6-flnoro-4-oxo-1,4-dihydro (at)uinoIine- 3-carboxylic acid (B) To a solution of 7-chloro-l-eyelopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (0.55g, 1.95 mmol) in 1-methyl-2-pyrrolidone (40 mL) bis-(2-aminoethyl)-ether dihydrochloride (2.1g, 11.9 mmol, 6eq. ) and DBU (3.49 mL, 23.4 mmol, 12 eq. ) added and the reaction mixture was stirred at 110 C for 18 hours. The reaction mixture was then diluted with water (70 mL), pH was adjusted to 11 and extracted with CH2Cl2 (9x40 mL). Water layer was then acified with H2S04 to pH 6.8, extracted with 50 mL of CH2C12 and then evaporated in vacuum. Crude product was diluted in 2-propanol (60 mL), stirred at 82 C for 20 minutes and filtrated. Precipitate was pure salt (Na2S04). 2-Propanol was evaporated in vacuum and product was purified by column chromatography (fraction, eluent: CH2C12- MeOH-NH3-CH3CN=4:4:2:1) yielding 0.5g of title compounds as a mixture of chloro and fluoro derivatives in ratio 3:1 MS (ES+) m/z : [MH] + = 365.8 (A) (75 %) MS (ES+) m/z : [MH] (at) = 349.4 (B) (25 %) |
Yield | Reaction Conditions | Operation in experiment |
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With 4-methyl-morpholine In 1-methyl-pyrrolidin-2-one | 4 7-[2-Acetamidomethyl-2-hydroisoxazole-5-one-4-yl]-3-carboxy-1-cyclopropyl-1,4-dihydroquinoline-4-one(Compound 13) 7-[2-Acetamidomethyl-2-hydroisoxazole-5-one-4-yl]-3-carboxy-1-cyclopropyl-1,4-dihydroquinoline-4-one(Compound 13) A mixture of Compound 12 (1.1 mmol) and 3-carboxy-1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydroquinoline-4-one (1 mmol) in N-methylpyrrolidine-2-one (20 ml) and N-methylmorpholine (0.4 mL) is stirred at 110-130° C. for 48 h. The mixture is cooled to r.t., and a majority of the solvent is removed under vacuum. The residue is triturated with water, and the resulting precipitate is filtered, sequentially washed with excess water, THF, and ether, and dried under vacuum. |
Yield | Reaction Conditions | Operation in experiment |
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With acetic anhydride In 1,4-dioxane; ethanol; hexane | 60 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[3-(3-thienyl-1-piperazinyl]-3-quinolinecarboxylic acid A mixture of 27.8 g of the above ester, 22.23 g of triethyl orthoformate and 25.52 g of acetic anhydride was heated at 150° C. for 2 hours and then evaporated under reduced pressure. A 30 g portion of the residue was dissolved in 100 ml of ethanol and 5.63 g of cyclopropylamine was added producing an exotherm. The mixture was stirred for one hour, then evaporated under reduced pressure, hexane added and the solid collected and dried. A solution of 17.25 g of this solid in a mixture of 2.64 g of 50% sodium hydride and 80 ml of dioxane was stirred at room temperature for 30 minutes, then heated at reflux for 2 hours and cooled. The mixture was neutralized with 1.5N potassium hydroxide and the product, 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, collected. |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine In <i>N</i>-methyl-acetamide; dimethyl sulfoxide | 18 Preparation of 1-cyclopropyl-6-fluoro-7-(3-hydroxy-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid EXAMPLE 18 Preparation of 1-cyclopropyl-6-fluoro-7-(3-hydroxy-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid A mixture of 1 g (3.5 mmoles) of 1-cyclopropyl-7-chloro-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 0.77 g (7.9 mmoles) of 3-hydroxyazetidine hydrochloride, 2.15 g (21.3 mmoles) of triethylamine is heated to 160° C. in 10 ml of dimethyl sulphoxide for 6 hours. The mixture is cooled, diluted with water and acidified with acetic acid. After filtering and recrystallising from dimethylformamide 0.3 g (27%) of 1-cyclopropyl-6-fluoro-7-(3-hydroxy-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are obtained, melting at 296°-8° C. |
Yield | Reaction Conditions | Operation in experiment |
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With pyridine; triethylamine In methanol; chloroform; water | 119 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[3-(1H-pyrrol-3-yl)-1-piperazinyl]-3-quinolinecarboxylic acid EXAMPLE 119 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[3-(1H-pyrrol-3-yl)-1-piperazinyl]-3-quinolinecarboxylic acid A mixture of 337 mg of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.2 g of 1-(phenylsulfonyl)-3-(2-piperazinyl)-1H-pyrrole and 5 ml of pyridine was heated in a pressure bottle at 135° C. for 16 hours, then allowed to cool and the pyridine removed under reduced pressure. The crude substance was purified by column chromatography using chloroform:methanol:water:triethylamine (9:0.5:0.01:0.01), giving 270 mg of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[3-[1-(phenylsulfonyl)-1H-pyrrol-3-yl]-1-piperazinyl]-3-quinolinecarboxylic acid. |
Yield | Reaction Conditions | Operation in experiment |
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With pyridine; triethylamine In methanol; chloroform; water | 118 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[3-(3-pyridinyl)-1-piperazinyl]-3-quinolinecarboxylic acid A mixture of 733.5 mg of 2-(3-pyridinyl)piperazine, 421.5 mg of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 10 ml of pyridine was heated at 135° C. for 24 hours. The solvent was removed and the residue purified by chromatography on silica gel using chloroform:methanol:triethylamine:water (9.5:0.5:0.01:0.01), giving 120 mg of the desired product. |
Yield | Reaction Conditions | Operation in experiment |
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With pyridine; | EXAMPLE 66 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[4-methyl-3-(3-thienyl)-1-piperazinyl]-3-quinolinecarboxylic acid A mixture of 1.124 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 2.688 g of 3-thienylpiperazine and 12 ml of pyridine was reacted as described in Example 60, giving 900 mg of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[3-(3-thienyl)-1-piperazinyl]-3-quinolinecarboxylic acid. A 207 mg portion of the above compound was then reacted as described in Example 55, giving 150 mg of the desired product, mp 230 C. |
Yield | Reaction Conditions | Operation in experiment |
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In 1,4-dioxane; water monomer | 24.b EXAMPLE 24 STR31 3.44 g of 80 percent sodium hydride were added in portions to a solution of 31.9 g of ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-cyclopropylamino-acrylate (R1 =C2 H5) in 100 ml of anhydrous dioxane while cooling with ice and stirring. The mixture was then stirred at room temperature for 30 minutes and under reflux for 2 hours, and the dioxane was stripped off in vacuo. The residue (40.3 g) was suspended in 150 ml of water, 6.65 g of caustic potash were added, and the mixture was refluxed for 1.5 hours. The warm solution was filtered and the residue was rinsed with H2 O. The filtrate was then acidified to pH=1 to 2 with semiconcentrated hydrochloric acid, while cooling with ice, and the precipitate was filtered off under suction, washed with water and dried in vacuo at 100° C. 27.7 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (R1 =H) of melting point 234° to 237° C. were obtained in this manner. | |
In 1,4-dioxane; water monomer | 24.b EXAMPLE 24 STR31 3.44 g of 80 percent sodium hydride were added in portions to a solution of 31.9 g of ethyl 2-(2,4-dichloro-5-fluoro-benzoyl)-3-cyclopropylamino-acrylate (R1 =C2 H5) in 100 ml of anhydrous dioxane while cooling with ice and stirring. The mixture was then stirred at room temperature for 30 minutes and under reflux for 2 hours, and the dioxane was stripped off in vacuo. The residue (40.3 g) was suspended in 150 ml of water, 6.65 g of caustic potash were added, and the mixture was refluxed for 1.5 hours. The warm solution was filtered and the residue was rinsed with H2 O. The filtrate was then acidified to pH=1 to 2 with semiconcentrated hydrochloric acid, while cooling with ice, and the precipitate was filtered off under suction, washed with water and dried in vacuo at 100° C. 27.7 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (R1 =H) of melting point 234° to 237° C. were obtained in this manner. |
Yield | Reaction Conditions | Operation in experiment |
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In water monomer | A Example A STR17 A mixture of 19.7 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 30.1 g of anhydrous piperazine and 100 ml of dimethylsulphoxide is heated at 135° to 140° C. for 2 hours. The solvent is distilled off under a fine vacuum and the residue is suspended in H2 O, filtered off with suction and washed with water. For further purification, the moist crude product is boiled up with 100 ml of water, filtered off with suction at room temperature, washed with H2 O and dried to constant weight at 100° C. over CaCl2 in a vacuum drying cabinet. 19.6 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid of decomposition point 255° to 257° C. are obtained; | |
In water monomer | 20 EXAMPLE 20 STR51 EXAMPLE 20 STR51 A mixture of 19.7 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 30.1 g of anhydrous piperazine and 100 ml of dimethylsulphoxide is heated at 135°-140° C. for 2 hours. The solvent is distilled off under a fine vacuum, the residue is suspended in water and the solid is filtered off with suction and washed with water. For further purification, the moist crude product is boiled up with 100 ml of water and the solid is filtered off with suction at room temperature, washed with water and dried to constant weight over calcium chloride in a vacuum drying cabinet at 100° C. 19.6 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid of decomposition point 255°-257° C. are obtained. | |
In CaCl2; water monomer | 1 Ciprofloxacin STR3 EXAMPLE 1 Ciprofloxacin STR3 A mixture of 19.7 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 30.1 g of anhydrous piperazine and 100 ml of dimethyl sulphoxide is heated at 135°-140° C. for 2 h. The solvent is removed by distillation under high vacuum, and the residue is suspended in H2 O, filtered off with suction and washed with water. For further purification, the moist crude product is boiled with 100 ml of water, filtered with suction at room temperature, washed with H2 O and dried to constant weight in a vacuum drying oven over CaCl2 at 100° C. 19.6 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid of decomposition point 255°-257° C. are obtained. The compound prepared in Example 1 is dissolved in 50 ml of hot 10% hydrochloric acid. The solution is filtered, 150 ml of ethanol are added, then it is cooled in ice, and the product is filtered off with suction, washed with alcohol and dried in vacuo at 100° C. 18.5 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid hydrochloride are obtained as colorless crystals of decomposition point 308°-310° C. |
In water monomer | 23 EXAMPLE 23 STR30 EXAMPLE 23 STR30 A mixture of 19.7 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, 30.1 g of anhydrous piperazine and 100 ml of dimethylsulphoxide was heated at 135° to 140° C. for 2 hours. The solvent was distilled off under a fine vacuum, and the residue was suspended in H2 O, filtered off under suction and washed with water. For further purification, the moist crude product was boiled with 100 ml of water, filtered off under suction at room temperature, washed with H2 O and dried over CaCl2 in a vacuum drying cabinet at 100° C. until its weight remained constant. 19.6 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid which decomposed at 255° to 257° C. were obtained. The compound prepared according to Example 3 was dissolved in 50 of hot 10 percent hydrochloric acid. 150 ml of ethanol were added to the filtered solution, the mixture was cooled with ice, and the product was filtered off under suction, washed with alcohol, and dried in vacuo at 100° C. 18.5 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid hydrochloric were obtained as colourless crystals which decomposed at 326°-328° C. The monohydrate of this hydrochloride has a m.p. 318°-320° C. | |
In CaCl2; water monomer | A EXAMPLE A STR18 EXAMPLE A STR18 A mixture of 19.7 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, 30.1 g of anhydrous piperazine and 100 ml of dimethylsulphoxide is heated for 2 hours at 135°-140° C. The solvent is distilled off in a fine vacuum, and the residue is suspended in H2 O, filtered off and washed with water. For further purification, the moist crude product is boiled up with 100 ml of water, filtered off at room temperature, washed with H2 O and dried in a vacuum drying oven over CaCl2 at 100° C. until the weight remains constant. 19.6 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(piperazin-1-yl)-quinoline-3-carboxylic acid which decomposes at 255°-257° C. are obtained. | |
In water monomer | A EXAMPLE A STR19 EXAMPLE A STR19 A mixture of 19.7 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 30.1 g of anhydrous piperazine and 100 ml of dimethylsulphoxide is heated at 135° to 140° C. for 2 hours. The solvent is distilled off under a fine vacuum and the residue is suspended in H2 O, filtered off with suction and washed with water. For further purification, the moist crude product is boiled up with 100 ml of water, filtered off with suction at room temperature, washed with H2 O and dried to constant weight over CaCl2 at 100° C. in a vacuum drying cabinet. 19.6 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid of decomposition point 255° to 257° C. are obtained. | |
In water monomer | 23 EXAMPLE 23 STR30 EXAMPLE 23 STR30 A mixture of 19.7 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, 30.1 g of anhydrous piperazine and 100 ml of dimethylsulphoxide was heated at 135° to 140° C. for 2 hours. The solvent was distilled off under a fine vacuum, and the residue was suspended in H2 O, filtered off under suction and washed with water. For further purification, the moist crude product was boiled with 100 ml of water, filtered off under suction at room temperature, washed with H2 O and dried over CaCl2 in a vacuum drying cabinet at 100° C. until its weight remained constant. 19.6 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid which decomposed at 255° to 257° C. were obtained. The compound prepared according to Example 3 was dissolved in 50 of hot 10 percent hydrochloric acid. 150 ml of ethanol were added to the filtered solution, the mixture was cooled with ice, and the product was filtered off under suction, washed with alcohol, and dried in vacuo at 100° C. 18.5 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-piperazino-quinoline-3-carboxylic acid hydrochloric were obtained as colourless crystals which decomposed at 326°-328° C. The monohydrate of this hydrochloride has a m.p. 318°-320° C. |
Yield | Reaction Conditions | Operation in experiment |
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88% | 4 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic Acid (R1: Cyclopropyl; R2: Hydrogen) EXAMPLE 4 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic Acid (R1: Cyclopropyl; R2: Hydrogen) In a manner similar to that of Example 1, 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (II, R1: cyclopropyl; X: chloro) is reacted with 1-(t-butylmethylsilyl)piperazine (III, R2: hydrogen; R3 and R4: methyl; R5: t-butyl) to afford a solid compound. Yield: 88%. |
Yield | Reaction Conditions | Operation in experiment |
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12% | In sodium hydroxide | 1 EXAMPLE 1 STR9 After dissolution of the acid in an equivalent amount of 5% strength sodium hydroxide solution and evaporation of the resulting solution, the corresponding sodium salt is obtained. It decomposes above 300° C. When the corresponding reaction with 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is carried out at 120° C. for 16 hours, then a 12% yield of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-oxo-1-piperazinyl)-3-quinolinecarboxylic acid is obtained. |
Yield | Reaction Conditions | Operation in experiment |
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With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile | 33 7-(cis-3-Amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid EXAMPLE 33 7-(cis-3-Amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid A mixture of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.7 g), cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.62 g), DBU (0.43 g) and anhydrous acetonitrile (30 ml) was refluxed for 52 hours. After cooling, the resulting precipitate was collected by filtration, washed with chilled acetonitrile and this was added to concentrated hydrochloric acid-methanol (1:1, 5 ml) and stirred for 40 minutes at elevated temperature. The reacting mixture was collected by filtration, washed with chilled water sufficiently and recrystallized from chloroform-methanol-concentrated aqueous ammonia (10:10:3) to give the title compound (0.076 g) as pale yellow prisms, mp 268°-270° C. (decompd.). Analysis (%) for C18 H20 FN3 O3.2/3H2 O, Calcd. (Found): C, 60.49 (60.50); H, 6.02 (6.05); N, 11.76 (11.61). |
Yield | Reaction Conditions | Operation in experiment |
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With hydrogenchloride In methanol; dimethyl sulfoxide | 13 Example 13 STR31 2.8 g (10 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are heated at 140° in 30 ml of dimethyl sulphoxide with 2.5 g (11 mmol) of 1-(6-hydroxy-2,2-dimethyl-1,3-dioxepan-5-yl)-piperazine and 2.25 g (20 mmol) of 1,4-diazabicyclo[2.2.2]octane for 4 hours, the reaction mixture is concentrated, the resulting oil is diluted with 20 ml of methanol and the pH is brought to 5 with 2N hydrochloric acid. The precipitate which has separated out is recrystallized from glycol monomethyl ether/methanol. 0.5 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-7-[4-(6-hydroxy-2,2-dimethyl-1,3-dioxepan-5-yl)-1-piperazinyl]-4-oxo-3-quinolinecarboxylic acid of melting point 255°-262° (with decomposition) is obtained, and is dissolved in 10 ml of 2N hydrochloric acid, with warming, to split off the protective group. |
Yield | Reaction Conditions | Operation in experiment |
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With hydrogenchloride In water; dimethyl sulfoxide | 11 Example 11 STR29 2.1 g (10 mmol) of 1-cinnamyl-piperazine and 2.2 g of 1,4-diazabicyclo[2.2.2]octane are added to 2.8 g (10 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 35 ml of dimethyl sulphoxide, and the mixture is heated at 140° for 5 hours. It is concentrated under a high vacuum, the residue is stirred with 50 ml of water and the pH is brought to 6 with 2N hydrochloric acid. The precipitate which has separated out is filtered off with suction, washed with water and boiled up with methanol. 1.7 g of 7-(4-cinnamyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 230°-234° (with decomposition) are obtained. |
Yield | Reaction Conditions | Operation in experiment |
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In methanol; water; dimethyl sulfoxide; | STR25 1.3 g of <strong>[20327-23-5]1-cyclopropylpiperazine</strong> and 2.2 g (20 mmol) of 1,4-diazabicyclo[2.2.2]octane are added to 2.8 g (10 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 25 ml of dimethyl sulphoxide, and the mixture is heated at 140 for 5 hours. 40 ml of water are added to the suspension and the precipitate is filtered off with suction, washed with water and boiled up with 20 ml of methanol. 1.2 g of 1-cyclopropyl-7-(4-cyclopropyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 226-229 (with decomposition) are obtained. |
Yield | Reaction Conditions | Operation in experiment |
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86% | With sodium hydroxide; potassium carbonate; acetic acid; triethylamine In 5,5-dimethyl-1,3-cyclohexadiene; water; isopropyl alcohol | 2 Example 2 Example 2 A mixture of 380 g of xylene (mixture of isomers), 110 g of ethyl N,N-dimethylaminoacrylate and 77.4 g of triethylamine was initially charged, and 160 g of 2,4-dichloro-5-fluorobenzoyl chloride were added dropwise at 70° C. over a period of 60 minutes. The mixture was subsequently stirred at 70° C. for 2 hours and cooled to room temperature. At room temperature, 51 g of acetic acid were then added, and the mixture was again heated to 70° C. At 70° C., 45 g of cyclopropylamine were then added dropwise. 100 ml of water were added to the reaction mixture which was stirred for 15 minutes, and the organic phase that formed was separated off. The organic phase was metered into a mixture of 89 g of potassium carbonate and 190 g of xylene (mixture of isomers) at from 140 to 142° C. The water of reaction that was liberated was separated off via a water separator. After all the water had been separated off, the mixture was cooled to 80° C. and, at a pressure of 40 mbar, xylene was distilled off. 80 g of 45% strength aqueous sodium hydroxide solution and 350 g of water were then added, and the remaining xylene was distilled off. After addition of 180 g of acetic acid and 100 g of water, the product was filtered off with suction and the solid was washed 3 times with 150 ml of water each time and 3 times with 200 ml of isopropanol each time. Drying under reduced pressure at 60° C. gave 170 g of 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid. This corresponds to a yield of 86% of theory. |
Yield | Reaction Conditions | Operation in experiment |
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76% | With nitronium tetrafluoborate In N,N-dimethyl-formamide at 100℃; for 8h; Green chemistry; | |
75% | With nitric acid at 0℃; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
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51% | In N,N-dimethyl-formamide at 80℃; for 24h; | |
In N,N-dimethyl-formamide at 80℃; |
Yield | Reaction Conditions | Operation in experiment |
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70% | With potassium carbonate In N,N-dimethyl-formamide at 70℃; |
Yield | Reaction Conditions | Operation in experiment |
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68% | Stage #1: bis(2-oxa-6-azaspiro[3.3]heptan-6-ium) ethanedioate With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 20℃; for 0.166667h; Inert atmosphere; Stage #2: 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid In dimethyl sulfoxide at 130℃; for 5.5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
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62% | Stage #1: 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester hemioxylate With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 20℃; for 0.25h; Inert atmosphere; Stage #2: 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid In dimethyl sulfoxide at 130℃; for 5.5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
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1: 22% 2: 15% | Stage #1: 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid; ethylenediamine In ISOPROPYLAMIDE at 0 - 120℃; for 11h; Stage #2: With hydrogenchloride In water at 85℃; for 1h; charcoal; | 4.5.1. 6-(2-Amino-ethylamino)-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (3a) and 7-[(2-aminoethyl)amino]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (3b) To the vigorously stirred solution of 1,2-diaminoethane (24 mL, 0.36 mol) in N,N-dimethylacetamide (600 mL) 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid 2 (50.0 g, 0.18 mol) was added in portions. Resulting heterogeneous mixture was stirred at 120 °C for 8 h, at rt for 2 h, and at 0 °C for 1 h. Formed precipitate was collected on filter, washed with water (2 × 200 mL), cold ethanol (2 × 200 mL) and dried at 110 °C. To the solution of crude product in 6% HCl (500 mL) was added charcoal and stirred at 85 °C for 1 h. Charcoal was filtered off, filtrate was cooled to 35-40 °C. Precipitate was collected on filter yielding hydrochloride salt of product 3a (6.40 g, 22%). Mother liquors were cooled at 4 °C and stirred overnight. Second precipitate was collected on filter, washed with water (100 mL) and ethanol (100 mL) and dried at 110 °C yielding product 3b (4.18, 15%).CommentCompound 3a: MS(m/z): calcd MH+ 322.76; found: 322.00.CommentHRMS calcd for C15H16ClN3O3 (M+H)+ 322.0958; found 322.0919.Comment1H NMR (500 MHz, DMSO): δ 8.61 (1H, 2-CH, s), 8.28 (1H, 8-CH, s), 7.45 (1H, 5-CH, s), 6.29 (1H, X1-NH, t), 3.84 (1H, 11-CH, m), 3.54 (2H, L6-CH2, dq), 3.09 (2H, L5-CH2, t), 1.30 (2H, 15-CH2, dq), 1.17 (2H, 16-CH2, dq).Comment13C NMR (75 MHz, DMSO): δ 176.76 (4-CO), 166.22 (12-CO), 146.21 (2-CH), 142.66 (6-C), 132.72 (9-C), 126.99 (10-C), 125.59 (7-C), 119.44 (8-CH), 106.47 (3-C), 103.03 (5-CH), 40.55 (L6-CH2), 37.40 (L5-CH2), 36.00 (11-CH), 7.54 (15, 16-CH).CommentIR (KBr) νmax/cm-1: 3381, 3088, 3010, 2976, 1723, 1606, 1549, 1496, 1450, 1356, 1336, 1268, 1233, 1191, 1090, 1063, 1032, 1010, 960, 887, 855, 804, 770, 691, 613.CommentCompound 3b: MS(m/z): calcd 306.31; found: 306.03.CommentHRMS calcd for C15H16FN3O3 (M+H)+ 306.1254; found 306.1213.Comment1H NMR (500 MHz, DMSO): δ 8.57 (1H, 2-CH, s), 7.79 (1H, 5-CH, d), 7.16 (1H, 8-CH, d), 3.75 (1H, 11-CH, m), 3.33 (2H, L6-CH2, m), 2.84 (2H, L5-CH2, t), 1.31 (2H, 15-CH2, dq), 1.14 (2H, 16-CH2, m).Comment13C NMR (125 MHz, DMSO): δ 176.22 (4-CO), 166.71 (12-CO), 151.24 (10-C), 149.21 (2-CH), 147.39 (7-C), 140.91 (9-C), 113.93 (6-C), 109.10 (5-CH), 109.02 (3-C), 96.86 (2-CH), 46.16 (L6-CH2), 40.22 (L5-CH2), 36.17 (11-CH), 7.50 (15, 16-CH2).CommentIR (KBr) νmax/cm-1: 3399, 3317, 2964, 2963, 2130, 1622, 1561, 1524, 1477, 1393, 1367, 1311, 1294, 1239, 1172, 1114, 1038, 984, 951, 893, 825, 787, 732. |
Yield | Reaction Conditions | Operation in experiment |
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37% | With triethylamine In dimethyl sulfoxide at 115℃; for 6h; | 3 4.3 7,7′-((2S,2′S)-[2,2′-Bimorpholine]-4,4′-diyl)bis(1-cyclopro-pyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid) 8a A mixture of quinolone carboxylic acid 1a (334 mg, 1.184 mmol), (2S,2′S)-bimorpholine 7a (102 mg, 0.592 mmol), triethylamine (496 μL, 3.553 mmol) and DMSO (0.5 mL) was heated at 115 °C in the CEM Discover microwave reactor for 6 h. The reaction mixture was cooled to room temperature and MeOH (1 mL) was added. The precipitate was filtered and dried at reduced pressure, affording the product 8a as off-white solid (yield 146 mg, 37%), mp 317-323 °C. |
Yield | Reaction Conditions | Operation in experiment |
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57% | at 115℃; for 1.5h; Microwave irradiation; | 4 4.2 General procedure for MW-assisted amination of quinolone carboxylic acid 1a General procedure: A mixture of quinolone carboxylic acid 1a (0.30 mmol), cyclic amine (1.50 mmol) and DMPU (0.5 M solution) was heated at fixed temperature, at 115 °C (power value ranging from 7 to 10 W) in the CEM Discover microwave reactor for 1.5 h. The reaction mixture was cooled to room temperature and EtOAc (1 mL) was added. The precipitate was filtered and dried at reduced pressure affording the aminated quinolone as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
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63% | Stage #1: 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid With boric acid; acetic anhydride; zinc(II) chloride at 110 - 115℃; for 8h; Stage #2: 2-piperidin-4-yl-1<i>H</i>-benzoimidazol-5-ylamine With triethylamine In acetonitrile at 25 - 30℃; for 8h; |
Yield | Reaction Conditions | Operation in experiment |
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19 g | Stage #1: 2,4-dichloro-alpha(elhoxymethlene)-5-fluoro-beta-oxo-benzene propanoic acid ethyl ester; Cyclopropylamine In dichloromethane at 10 - 20℃; for 1h; Stage #2: With sodium hydride In 1,2-dimethoxyethane; mineral oil at 80 - 85℃; for 3h; Inert atmosphere; Stage #3: With water; sodium hydroxide In tetrahydrofuran for 2h; Reflux; | 7-Chloro-6-fluoro-1-cyclopropyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (7) To a solution of 4 (80 g) in methylene chloride (800 mL), cyclopropylamine (44.0 g) was added with cooling below 10° C. The mixture was stirred at room temperature for 1 h and evaporated to a dry mixture. To the dry mixture in dimethoxyethane (800 mL), a 60% sodium hydride-in-oil suspension (12.0 g) was added slowly with cooling and stirring. The mixture was heated at 80-85° C. for 3 h under nitrogen atmosphere. It was cooled and water (5 L) was added and the precipitate was filtered and washed with water and dried. The ester was suspended in tetrahydrofuran (800 mL). A solution of sodium hydroxide (20.0 g) in water (500 mL) was added and the mixture was refluxed for 2 h. It was cooled and acidified with acetic acid and the precipitate was filtered. The solid was washed with water and acetone. wt=19.0 g of (7). m.p.=235-240° C. [0125] Anal. calcd. for: C13H9NFClO3. Theory: C, 55.43; H, 3.22; N, 4.97; F, 6.77; Cl, 12.58. Found: C, 55.42; H, 3.26; N, 4.95; F, 5.92; Cl, 12.31. |
Yield | Reaction Conditions | Operation in experiment |
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With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 2h; | 1.2.5 The synthesis of compounds 5a-5g and 12a-12g General procedure: To the solution of 4/11 (1 mmol), quinoline acids (1.1 mmol) and DMAP (12 mg, 0.1 mmol) in CH2Cl2 (15mL) was added DCC (0.4 g, 2 mmol) and the solution was stirred for 2 h at room temperature. Then, DCU was filtered off and the solution was concentrated under vacuum to get the crude compounds 5a-5g/12a-12g respectively, which were used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
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With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 2h; | 1.2.5 The synthesis of compounds 5a-5g and 12a-12g General procedure: To the solution of 4/11 (1 mmol), quinoline acids (1.1 mmol) and DMAP (12 mg, 0.1 mmol) in CH2Cl2 (15mL) was added DCC (0.4 g, 2 mmol) and the solution was stirred for 2 h at room temperature. Then, DCU was filtered off and the solution was concentrated under vacuum to get the crude compounds 5a-5g/12a-12g respectively, which were used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
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98% | With potassium carbonate In d<SUB>7</SUB>-N,N-dimethylformamide at 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
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95% | With thionyl chloride for 8h; Reflux; | 3.1 4-Chlorobutyl 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (2) A mixture of 1 (1.5 g, 5.3 mmol) and SOCl2 (4 mL, 54 mmol)in 25 mL of dry THF was stirred under reflux for 8 h. Aftercooling to room temperature, THF and excess SOCl2 wereevaporated under reduced pressure. The solid residue waspurified by column chromatography using MeOH-CHCl3(10:90) as eluent to afford the title compound as colorlesscrystals. Yield 1.5 g (95 %); m.p. 167-169 °C. - IR (film):v = 3084, 2988, 2927, 2856, 1727, 1615, 1541, 1455 cm-1. - 1HNMR (400 MHz, CDCl3, 25 °C, TMS): δ = 1.17 (m, 2H) and 1.38(m, 2H), (2′-H/3′-H), 1.94-2.01 (m, 4H, 11-H + 12-H), 3.49 (m,1H, 1′-H), 3.65 (t, J = 8 Hz, 2H, 13-H), 4.37 (t, J = 8 Hz, 2H,10-H), 8.01 (s, 1H, 8-H), 8.15 (d, 3JH-F = 10 Hz, 1H, 5-H), 8.56(s, 1H, 2-H). - 13C NMR (100 MHz, CDCl3): δ = 8.3 (C-2′/C-3′), 26.1 (C-11), 29.3 (C-12), 34.8 (C-1′), 44.7 (C-13), 64.2 (C-10),110.6 (C-3), 113.8 (d, 2JC-F = 20 Hz, C-5), 119.0 (C-8), 127.0 (d,2JC-F = 17.5 Hz, C-7), 128.7 (d, 3JC-F = 5 Hz, C-4a), 137.2 (C-8a),148.9 (C-2), 156.6 (d, 1JC-F = 260 Hz, C-6), 165.3 (C-9), 172.7(C-4). - HRMS (ESI): m/z = 372.05879 (calcd. 372.05695for C17H17Cl2FNO3, [M+H]+). - C17H16Cl2FNO3 (372.2): calcd.C 54.86, H 4.33, N 3.76; found C 54.79, H 4.42, N 3.62. |
Yield | Reaction Conditions | Operation in experiment |
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90% | With palladium diacetate; triphenylphosphine; silver carbonate In dimethyl sulfoxide at 130℃; for 12h; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
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Stage #1: 4'-O-demethylpodophyllotoxin; 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid With dicyclohexyl-carbodiimide In dichloromethane at 45℃; for 2.1h; Inert atmosphere; Stage #2: With dmap In dichloromethane at 25℃; for 24h; Inert atmosphere; | 4 Example 4 4-0- (fluoroquinolonic acid-1) -4-deoxy-4'-demethyl formo podophyllotoxin(Compound 4) (1) Synthesis of 4-0- (fluoroquinolonic acid-1) -4-deoxy-4'-demethyl table podophyllotoxin: 400 mg of 4'-demethylephrine ghost white toxin and 281 mg of fluorine Norquinone was dried in vacuo at 45 ° C for 2 hours. Under nitrogen protection, the dried 4'-demethylepipodophyllotoxin and flunoxolenic acid and 208 mg of dicyclohexylcarbodiimide were added to a four-necked flask, followed by the addition of 10 mL of dried methylene chloride, Reaction for 6 min, adding 40 mg of 4-dimethylamino R to pyridine to the reaction system and reacting at 25 ° C for 24 h. After completion of the reaction, the reaction solution was filtered with a filter paper to remove insoluble matter, 100 ml of deionized water was added, the organic phase was left, and the organic phase was washed twice with methylene chloride. The organic layer was combined with Dried over anhydrous sodium sulfate overnight, spin dry the crude product. |
Yield | Reaction Conditions | Operation in experiment |
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91% | With nano iron oxide on ZrO2 coated sulfonic acid; In water; for 0.3h;Reflux; | General procedure: A mixture of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1a (1 mmol) and Nethylpiperazine2y (1.5 mmol) and n-FZSA (0.06 g) as catalystin H2O (5 ml) were heated under reflux for the appropriatetime. The reaction was monitored by TLC. After appropriatetime, the catalyst was separated using an externalmagnet and washed with hot ethanol (5 mL). The reactionmixture was then cooled to room temperature. The precipitatedsolid was collected by filtration, and recrystallized fromethanol 96% to give desired compound in high yields. |
84% | at 150℃;Microwave irradiation; | General procedure: A mixture of 6-chloro-4-cyclopropyl-7-fluoro-1-oxo-1,4-dihydronaphthalene-2-carboxylic acid 1a (1 g, 3.5 mmol) with N-ethylpiperazine 2c (0.6 g, 5.25mmol) was loaded in a small flask fitted with a micro condenser, placed in the microwave reactor and irradiated for 25 min at 150C under solvent free conditions. The reaction progress was monitored by TLC. Upon completion of the process, addition of hot absolute ethanol (10 mL) to the reaction mixture was followed by filtration. The filtrate was concentrated and stored at room temperature for precipitation. The solid was filtered off and recrystallized from absolute ethanol to give compound 3c. |
Yield | Reaction Conditions | Operation in experiment |
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With nitric acid; acetic acid at 0 - 10℃; for 2h; | 1.a (a) the preparation of 6-fluoro -7-chloro- 8-nitro- 1,4-dihydro-4-oxoquinoline-3-carboxylicacid The 56.0g 6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (preparation method reference EuropeanJournalofOrganicChemistry, 2006,4398) dissolved in 300 ml glacial acetic acid, stir. 0-5 °C slowly dripping 42.0 ml of nitric acid (d= 1.52) glacial acetic acid solution of 200 ml. Reaction liquid 0-10 °C lower heat insulating stirring 2 hours. After the reaction, the low-temperature, add 600 ml ice water, precipitating a large amount of solid product, filtering. The filter cake is washed with water and normal heptane washing two times, drying under vacuum 8 hours to obtain 50.0g6-fluoro-7-chloro-8-nitro -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid of the crude product. Does not need to be refined, is directly used for the feeding of the next. |
Yield | Reaction Conditions | Operation in experiment |
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67% | In dimethyl sulfoxide at 110℃; for 4h; | 10 Example 10:1-cyclopropyl-7- (diethylamino) -6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid(Compound 675) At room temperature, diethylamine (1.48g, 20mmol),7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (2.82 g, 10 mmol)Dissolved in 15mL of dimethyl sulfoxide, gradually heated to 110 ° C, and reacted for 4h.Reduce the temperature to room temperature, and add water (20 mL) and ethyl acetate (3 * 15 mL) to the above reaction system.extraction. Combine the organic layers, and wash the organic layers with water (2 * 15mL) in order.It was washed with saturated brine (15 mL) and dried over anhydrous magnesium sulfate. Desolvate under reduced pressure, column chromatography(Eluent: mixed solution of ethyl acetate, petroleum ether and formic acid (volume ratio 1.5: 1: 0.01))The product was obtained 2.13 g with a yield of 67%. |
32% | In dimethyl sulfoxide at 140℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
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78.5% | With [Bmim]OH ionic liquid In acetonitrile at 80℃; for 1.33333h; Microwave irradiation; | 2 Example 2 1-cyclopropyl-7-(diethoxyphosphoryl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (IIb) 2.0 mmol of the intermediate I 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 2.2mmol diethyl phosphanate, 60ml acetonitrile and 0.8mmol [Bmim]OH ionic liquid were added to a 100ml three-necked flask and placed in microIn the wave synthesizer, the reaction was carried out for 80 min under the conditions of a power of 700 W and a temperature of 80 ° C. The reaction was completed, filtered, and concentrated under reduced pressure to obtain a crude material.The product was separated and purified by column chromatography to give the object product as white solid (IIb), yield 78.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | In dimethyl sulfoxide; at 115℃; for 3h;Microwave irradiation; | General procedure: A mixture of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Q1a) (500 mg, 1.8 mmol, 1 eq), the corresponding cyclic amine (8.9 mmol, 5 eq) and DMSO (3.6 mL) was heated by microwave irradiation at 115 C for 3 h. The resultant mixture was concentrated by freeze drying, and to the residue was added EtOAc (30 mL). The precipitate was isolated by vacuum filtration and washed with EtOAc, water and Et2O to afford the Boc-protected aminated quinolone. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | In dimethyl sulfoxide at 115℃; for 3h; Microwave irradiation; | General Procedure B6: Microwave-assisted amination of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Q1a). General procedure: A mixture of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Q1a) (500 mg, 1.8 mmol, 1 eq), the corresponding cyclic amine (8.9 mmol, 5 eq) and DMSO (3.6 mL) was heated by microwave irradiation at 115 C for 3 h. The resultant mixture was concentrated by freeze drying, and to the residue was added EtOAc (30 mL). The precipitate was isolated by vacuum filtration and washed with EtOAc, water and Et2O to afford the Boc-protected aminated quinolone. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | Stage #1: ethanol With sodium at 20℃; for 3h; Reflux; Stage #2: 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid In N,N-dimethyl-formamide at 90℃; for 5h; | 1 Example 1: 1-cyclopropyl-7-ethoxy-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Compound 1) At room temperature, adding sodium wire in portions to 2.30 g (50 mmol) of ethanol 0.46g (20mmol), Heat and reflux for 3 h. Add 15 mL of N,N-dimethylformamide to the above solution in turn, 2.82 g (10 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, gradually heated to 90 ° C, the reaction was 5h. At room temperature, 20 mL of water was added to the above reaction system. Extract with ethyl acetate (3 x 15 mL). Combine the organic layers, the organic layer was washed with 15 mL of water and 15 mL of saturated brine. Dry over anhydrous magnesium sulfate. Desolvation under reduced pressure, column chromatography (eluent: ethyl acetate, a mixture of petroleum ether and formic acid (1:1:0.01)) gave 1.86 g of product in a yield of 64%. |
64% | Stage #1: ethanol With sodium In N,N-dimethyl-formamide at 20℃; for 3h; Reflux; Stage #2: 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid In N,N-dimethyl-formamide at 90℃; for 5h; | 8.1 First step reaction:1-cyclopropyl-7-ethoxy-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid At room temperature,To ethanol(2.30g, 0.05mol)Adding sodium wire in batches(0.46 g, 0.02 mol), heated and refluxed for 3 h. Add 15ml to the above solution in orderN,N-dimethylformamide,7-Chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (2.82 g, 0.01 mol),Gradually heated to 90 ° C, the reaction was 5h.At room temperature, water (20 mL) was added to the above reaction system.Extract with ethyl acetate (3*15 mL). The organic layers were combined and washed with water (1*15 ml).Wash with saturated saline (1*10ml),Dry over anhydrous magnesium sulfate. Decomposition under reduced pressure,Column chromatography (eluent: ethyl acetate,a mixture of petroleum ether and formic acid (1:1:0.01))1.86g,The yield was 64%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Stage #1: propan-1-ol With sodium at 20℃; for 4h; Reflux; Stage #2: 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid In N,N-dimethyl-formamide at 90℃; for 5h; | 2 Example 2: 1-cyclopropyl-6-fluoro-4-oxo-7-propoxy-1,4-dihydroquinoline-3-carboxylic acid (Compound 2) At room temperature, 0.46 g (20 mmol) of sodium silk was added portionwise to 3.00 g (50 mmol) of propanol. Heat and reflux for 4 h.Add 15 mL of N,N-dimethylformamide to the above solution in turn, 2.82 g (10 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, gradually heated to 90 ° C, the reaction was 5h. After cooling to room temperature, 20 mL of water and ethyl acetate (3 × 15 mL) were added to the above reaction mixture. The organic layers were combined, and the organic layer was washed with 15 mL of water. It was washed with 15 mL of saturated brine and dried over anhydrous magnesium sulfate. Desolvation under reduced pressure, column chromatography (eluent: ethyl acetate, a mixture of petroleum ether and formic acid (1:1:0.01)) gave 2.01 g of a product, yield 66%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | In N,N-dimethyl-formamide at 20 - 110℃; for 6h; | 3 Example 3: 7-tert-butoxy-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Compound 7) At room temperature, 2.24 g (20 mmol) of potassium t-butoxide, 2.82 g (10 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was dissolved in 15 mL of N,N-dimethylformamide. Gradually heat to 110 ° C, reaction for 6 h. After cooling to room temperature, 20 mL of water and ethyl acetate (3 × 15 mL) were added to the above reaction mixture. The organic layers were combined, and the organic layer was washed with 15 mL of water. It was washed with 15 mL of saturated brine and dried over anhydrous magnesium sulfate. Desolvation under reduced pressure, column chromatography (eluent: ethyl acetate, a mixture of petroleum ether and formic acid (1:1:0.01)) gave 1.78 g of product in a yield of 56%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | Stage #1: 2,2,2-trifluoroethanol With sodium at 20℃; for 5h; Reflux; Stage #2: 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid In N,N-dimethyl-formamide at 90℃; for 5h; | 4 Example 4: 1-cyclopropyl-6-fluoro-4-oxo-7-(2,2,2-trifluoroethoxy)-1,4-dihydroquinoline-3-carboxylic acid(Compound 8) At room temperature, 0.46 g (20 mmol) of sodium silk was added portionwise to 4.00 g (40 mmol) of trifluoroethanol.Heat and reflux for 5 h. Add 15 mL of N,N-dimethylformamide to the above solution in turn,2.82 g (10 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, gradually heated to 90 ° C, the reaction was 5h. At room temperature, 20 mL of water was added to the above reaction system. Extract with ethyl acetate (3 x 15 mL). The organic layers were combined, and the organic layer was washed with 15 mL of water. It was washed with 15 mL of saturated brine and dried over anhydrous magnesium sulfate. Desolvation under reduced pressure, column chromatography (eluent: ethyl acetate, a mixture of petroleum ether and formic acid (1:1:0.01)) gave 2.13 g of product, yield 62%. |
62% | Stage #1: 2,2,2-trifluoroethanol With sodium In N,N-dimethyl-formamide at 20℃; for 3h; Reflux; Stage #2: 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid In N,N-dimethyl-formamide at 90℃; for 5h; | 9.1 First step reaction: 1-cyclopropyl-6-fluoro-4-oxo-7-(2,2,2-trifluoroethoxy)-1,4-dihydroquinoline-3-carboxylic acid Adding sodium wire in portions to trifluoroethanol (4.00 g, 0.04 mol) at room temperature(0.46 g, 0.02 mol), heated and refluxed for 5 h. Add to the above solution15ml N,N-dimethylformamide,7-Chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (2.82 g, 0.01 mol),Gradually heated to 90 ° C, the reaction was 5h. Down to room temperature,Water (20 mL) and ethyl acetate (3*15 mL) were added to the mixture.The organic layers were combined, washed with water (1*15 ml), and washed with saturated brine (1*10 ml).Dry over anhydrous magnesium sulfate. Desolvation under reduced pressure, column chromatography (eluent: ethyl acetate,A mixture of petroleum ether and formic acid (1:1:0.01))2.13 g, yield 62%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | At room temperature, 0.46 g (20 mmol) of sodium silk was added portionwise to 2.32 g (40 mmol) of <strong>[16545-68-9]cyclopropanol</strong>. Heat and reflux for 6 h. Add 15 mL of N,N-dimethylformamide to the above solution in turn, 2.82 g (10 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, gradually heat to 100 C, reaction for 6 h. After cooling to room temperature, 20 mL of water and ethyl acetate (3 × 15 mL) were added to the above reaction mixture. The organic layers were combined, and the organic layer was washed with 15 mL of water. It was washed with 15 mL of saturated brine and dried over anhydrous magnesium sulfate. Desolvation under reduced pressure, column chromatography (eluent: ethyl acetate, a mixture of petroleum ether and formic acid (1:1:0.01)) gave 1.57 g of product in a yield of 52%. | |
52% | Adding sodium wire in portions to <strong>[16545-68-9]cyclopropanol</strong> (2.32 g, 0.04 mol) at room temperature(0.46 g, 0.02 mol), heated and refluxed for 6 h.To the above solution, 15 ml of N,N-dimethylformamide was sequentially added,7-Chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (2.82 g, 0.01 mol),Gradually heated to 90 C, the reaction was 5h. Down to room temperature,Water (20 mL) was added to the above reaction system.Extract with ethyl acetate (3*15 mL).The organic layers were combined, washed with water (1*15 ml), and washed with saturated brine (1*10 ml).Dry over anhydrous magnesium sulfate. Decomposition under reduced pressure,Column chromatography (eluent: ethyl acetate, petroleum ether and formic acid mixture (1:1:0.01))Product1.57 g, yield 52%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | In N,N-dimethyl-formamide at 90℃; for 6h; | 11.1 First step reaction: 1-cyclopropyl-6-fluoro-7-methylthio-4-oxo-1,4-dihydroquinoline-3-carboxylic acid Sodium methyl mercaptan (1.40 g, 0.02 mol),7-Chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (2.82 g, 0.01 mol)Soluble in 15ml N,N-dimethylformamide,Gradually heated to 90 ° C,Reaction for 6 h. Down to room temperature,Water (20 mL) was added to the above reaction system.Extract with ethyl acetate (3*15 mL). Combine the organic layers,Washed (1*15ml), washed with saturated saline (1*10ml),Dry over anhydrous magnesium sulfate. Desolvation under reduced pressure, column chromatography (eluent: ethyl acetate,A mixture of petroleum ether and formic acid (1:1:0.01))1.64 g, yield 56%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With palladium diacetate; triphenylphosphine; silver carbonate In dimethyl sulfoxide at 130℃; for 2h; | 1 Example 1: 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (281.5 mg, 1 mmol), Ag2CO3 (275 mg, 1 mmol),Pd (OAc) 2 (22.4mg, 0.1mmol), bis (2,4,6-trimethylphenyl) disulfide (453mg, 1.5mmol), PPh3 (52.4mg, 0.2mmol), dissolved in DMSO ( 8 mL), and then the reaction temperature was raised to 130 ° C for 12 hours.After the reaction was completed, the temperature was lowered to room temperature, and then 25 mL of CH2Cl2 was added to the reaction system, and then 20 mL of water was added.After drying over anhydrous sodium sulfate, the solvent was distilled off, and the residue was separated by a chromatography column (PE / EA, 10: 1 to 2: 1) to obtain the target product.7-chloro-1-cyclopropyl-6-fluoro-3- (2,4,6-trimethylphenylthio) quinolin-4 (1H) -one, yield 88%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | Stage #1: 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid; 1,4-diaminobutane In N,N-dimethyl acetamide at 120℃; for 8h; Stage #2: With hydrogenchloride; pyrographite In water at 85℃; for 1h; | 1 Example 1: General synthesis method of compound 3-5 General procedure: Quinolone 1 (1 eq) was added to a vigorously stirred N,N-dimethylacetamide (240 mL) solution of compound 2 (diamine with 4-6 carbon atoms) (2eq) dissolved in vigorously. The mixture was stirred at 120°C for 8 hours. After the reaction was monitored by TLC, it was stirred at room temperature for 1 hour, and then 200 mL of distilled water was added and stirred overnight. The formed precipitate was suction filtered, washed with water (2×100 mL), cold ethanol (2×100 mL) and dried at 60°C. The crude product was added to 100 mL of 0.6% HCl solution, and a spoon of activated carbon was added and stirred at 85° C. for 1 h. The filtrate was placed at room temperature and the solid was slowly precipitated out. Compound 3-5 was obtained by suction filtration. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | To a stirred solution of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3- carboxylic acid (0.420 g, 1.492 mmol, 1.0 equiv) in DMF (10 mL) was added HATU (1.20 g, 2.985 mmol, 2.0 equiv) at RT and stirred for 10 minutes. Then <strong>[118753-66-5]tert-butyl 4-aminopiperazine-1-carboxylate</strong> (0.300 g, 1.492 mmol, 1.0 equiv) was added followed by the addition of DIPEA (0.8 mL, 4.472 mmol, 3.0 equiv). The resulting reaction mixture was allowed to stir at RT for overnight. Product formation was confirmed by LCMS. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL × 2). The combined organic layer was washed with water (50 mL × 5 ), dried over anhydrous sodium sulfate and concentrated under reduced pressure.The crude product which was enriched by flash chromatography (0-5 % MeOH in DCM as an eluent) to obtain tert- butyl 4-(7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxamido)piperazine-1- carboxylate (0.150 g, 22 % Yield) as an off-white solid. LCMS 465.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; | 7 Synthesis of trans-7-chloro-N-(4-(2-(4-chloro-3-fluorophenoxy)acetamido)cyclohexyl)-1- cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxamide To a solution of trans-N-(4-aminocyclohexyl)-2-(4-chloro-3-fluorophenoxy)acetamide 2,2,2-trifluoroacetate (0.100 g, 0.252 mmol, 1.0 equiv) in DMF (3 mL) was added 7-chloro-1- cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.078 g, 0.278 mmol, 1.1 equiv) and HATU (0.192 g, 0.505 mmol, 2.0 equiv) at RT. The reaction mixture was stirred for 10 minutes and then DIPEA (0.5 mL, 3.19 mmol, 3.0 equiv) was added. The resultant reaction mixture was allowed to stir at RT for overnight. Progress of the reaction was monitored by LCMS. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (100 mL × 2). Combined organic layer was washed with water (50 mL × 4), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product which was purified by flash chromatography (0-5% MeOH in DCM as an eluent) to obtain trans-7-chloro-N-(4-(2-(4-chloro-3- fluorophenoxy)acetamido)cyclohexyl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3- carboxamide (Compound 32 - 0.080 g, 56% Yield) as a white solid. LCMS 564.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) G^9.69 (d, J=7.45 Hz, 1 H) 8.68 (s, 1 H) 8.38 (d, J=6.14 Hz, 1 H) 8.12 (d, J=9.21 Hz, 1 H) 7.50 (t, J=8.99 Hz, 1 H) 7.07 (d, J=10.09 Hz, 1 H) 6.85 (d, J=9.21 Hz, 1 H) 4.51 (s, 2 H) 3.77 (br. s., 2 H) 3.68 (br. s., 1 H) 1.96 (br. s., 2 H) 1.80 (br. s., 2 H) 1.34 - 1.50 (m, 3 H) 1.31 (d, J=5.70 Hz, 3 H) 1.11 (br. s., 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; | 8 Synthesis of trans-7-chloro-N-(4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)-1-cyclopropyl- 6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxamide To a solution of trans-N-(4-aminocyclohexyl)-2-(4-chlorophenoxy)acetamide 2,2,2- trifluoroacetate (0.100 g, 0.264 mmol, 1.0 equiv) in DMF (3 mL) was added 7-chloro-1-cyclopropyl- 6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.082 g, 0.290 mmol, 1.1 equiv) and HATU (0.201 g, 0.528 mmol, 2.0 equiv) at RT. The reaction mixture was stirred for 10 minutes and then DIPEA (0.13 mL, 0.800 mmol, 3.0 equiv) was added. The resultant reaction mixture was allowed to stir at RT for overnight. Progress of the reaction was monitored by LCMS. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (100 mL × 2). Combined organic layer was washed with water (50 mL × 4), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product which was purified by flash chromatography (0-5% MeOH in DCM as an eluent) to obtain trans-7-chloro-N-(4-(2-(4- chlorophenoxy)acetamido)cyclohexyl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3- carboxamide (Compound 112 - 0.045 g, 31% Yield) as a white solid. LCMS 546.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) d9.69 (d, J=7.45 Hz, 1 H) 8.69 (s, 1 H) 8.38 (d, J=6.14 Hz, 1 H) 8.13 (d, J=8.77 Hz, 1 H) 7.96 (d, J=7.89 Hz, 1 H) 7.35 (m, J=8.33 Hz, 2 H) 6.98 (m, J=8.77 Hz, 2 H) 4.46 (s, 2 H) 3.77 (br. s., 3 H) 3.38 (d, J=6.58 Hz, 1 H) 1.95 (d, J=10.09 Hz, 2 H) 1.79 (br. s., 2 H) 1.25 - 1.47 (m, 4 H) 1.00 - 1.19 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; | 1 Synthesis of 7-chloro-N-(1-(3-(4-chloro-3-fluorophenoxy)-2-hydroxypropyl)piperidin-4-yl)-1- cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxamide To a stirred solution of 1-(4-aminopiperidin-1-yl)-3-(4-chloro-3-fluorophenoxy)propan- 2-ol 2,2,2-trifluoroacetate (0.200 g, 0.480 mmol, 1.0 equiv) and 7-chloro-1-cyclopropyl-6-fluoro-4- oxo-1,4-dihydroquinoline-3-carboxylic acid (0.136 g, 0.480 mmol, 1.0 equiv) in DMF (5 mL) was added HATU (0.366 g, 0.960 mmol, 2.0 equiv) followed by the addition of DIPEA (0.3 mL) at RT. The resulting reaction mixture was allowed to stir at RT for overnight. Product formation was confirmed by LCMS. The reaction mixture was diluted with water (100 mL). The resulting solid was filtered off, washed with water (25 mL × 2) and dried under vacuum. The crude product was purified by reversed phase HPLC to obtain 7-chloro-N-(1-(3-(4-chloro-3-fluorophenoxy)-2- hydroxypropyl)piperidin-4-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxamide (Compound 1 -0.050 g, 18 % Yield) as an off-white solid. LCMS 566.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 9.80 (d, J=7.45 Hz, 1 H), 8.69 (s, 1 H), 8.39 (d, J=6.14 Hz, 1 H), 8.14 (d, J=9.21 Hz, 1 H), 7.46 (t, J=8.99 Hz, 1 H), 7.08 (dd, J=11.84, 2.63 Hz, 1 H), 6.85 (dd, J=8.77, 1.75 Hz, 1 H), 4.91 (br. s., 1 H), 4.02 (d, J=6.58 Hz, 1 H), 3.73 - 3.97 (m, 3 H), 3.33 (br. s., 3 H), 2.76 (br. s., 2 H), 2.19 - 2.48 (m, 4 H), 1.85 (d, J=8.77 Hz, 2 H), 1.42 - 1.58 (m, 2 H), 1.31 (d, J=6.14 Hz, 2 H), 1.12 (br. s., 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid With N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #2: 1-(tert-butoxycarbonyl)-4-aminopiperidine With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; | 2.1; 6.1 Step 1 - Synthesis of tert-butyl 4-(7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxamido)piperidine-1-carboxylate To a stirred solution of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3- carboxylic acid (0.705 g, 2.50 mmol, 1.0 equiv) in DMF (10 mL) was added HATU (1.90 g, 5.00 mmol, 2.0 equiv) at RT and stirred for 10 minutes. Then tert-butyl 4-aminopiperidine-1-carboxylate (0.500 g, 1.492 mmol, 1.0 equiv) was added followed by the addition of DIPEA (1.4 mL, 7.50 mmol, 3.0 equiv). The resulting reaction mixture was allowed to stir at RT for overnight. Product formation was confirmed by LCMS. The reaction mixture was diluted with water (100 mL). The resulting solid was filtered off, washed with water (25 mL × 2) and dried under vacuum to obtain tert-butyl 4-(7- chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxamido)piperidine-1-carboxylate (1.00 g, 87 % Yield) as an off-white solid. LCMS 464.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) 9.81 (d, J=7.45 Hz, 1 H), 8.69 (s, 1 H), 8.39 (d, J=6.14 Hz, 1 H), 8.13 (d, J=9.21 Hz, 1 H), 3.99 (d, J=7.89 Hz, 1 H), 3.67 - 3.84 (m, 3 H), 3.01 (br. s., 2 H), 1.86 (d, J=9.21 Hz, 2 H), 1.41 (s, 7 H), 1.36 (br. s., 1 H), 1.31 (d, J=6.58 Hz, 2 H), 1.12 (br. s., 2 H). |
Yield | Reaction Conditions | Operation in experiment |
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82% | Stage #1: 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid With methanol; sodium tetrahydroborate at 0 - 20℃; Stage #2: With toluene-4-sulfonic acid In methanol for 3.5h; Reflux; | 7 Preparation of 7-chloro- 1-cyclopropyl-6-fluoro- 1,2,3, 4-tetrahydroquinoiin-4-one To a cooled solution of 7-chloro-1-cydopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (10.0 g, 1.0 eq.) in anh. MeOH (150.0 mL) NaBH4(6.0 g, 4.5 eq.) was added portionwise over 1h. The mixture was allowed to reach RT and was stirred overnight. Afterwards / toluenesulfonic acid monohydrate (0.67 g, 0.10 eq.) was added and the reaction mixture was heated at reflux for 3.5h. Subsequently, the mixture was allowed to reach RT and the solvent was removed in vacuo. The residue was diluted with water and extracted with DCM. Combined organic layers was dried over anh. MgS04and concentrated under reduced pressure. FCC (SiHP; Hex : EtOAc) afforded the product (6.98 g, yield 82%) as a yellow solid. ESI-MS: 240 [M + H]+.1H NMR (400 MHz, DMSO- d6) d 7.55 (d, 7= 9.3 Hz, 1H), 7.39 (d, 7= 6.2 Hz, 1H), 3.52 (dd, 7= 7.5, 6.3 Hz, 2H), 2.61 (dd, 7 =7.5, 6.3 Hz, 2H), 2.47 - 2.41 (m, 1H), 0.96 - 0.86 (m, 2H), 0.76 - 0.66 (m, 2H). |
82% | Stage #1: 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid With sodium tetrahydroborate In methanol at 20℃; Stage #2: With toluene-4-sulfonic acid In methanol for 3.5h; Reflux; | 7 Example 7.7-Amino-1-cyclopropyl-6-fluoro-3-([(3S)-1-(6-methylpyridin-3-yl)piperidin-3-yl][(2- methylpyridin-4-yl)methyl]amino}methyl)-1,4-dihydroquinolin-4-one Preparation of 7-chloro-1-cyclopropyl-6-fluoro-1,2,3,4-tetrahydroquinolin-4-one To a cooled solution of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (10.0 g, 1.0 eq.) in anh. MeOH (150.0 mL) NaBH4 (6.0 g, 4.5 eq.) was added portionwise over 1h. The mixture was allowed to reach RT and was stirred overnight. Afterwards p-tol- uenesulfonic acid monohydrate (0.67 g, 0.10 eq.) was added and the reaction mixture was heated at reflux for 3.5h. Subsequently, the mixture was allowed to reach RT and the solvent was removed in vacuo. The residue was diluted with water and extracted with DCM. Combined organic layers was dried over anh. MgSO4 and concentrated under reduced pressure. FCC (SiHP; Hex : EtOAc) afforded the product (6.98 g, yield 82%) as a yellow solid. ESI-MS: 240 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.55 (d, J = 9.3 Hz, 1H), 7.39 (d, J = 6.2 Hz, 1H), 3.52 (dd, J = 7.5, 6.3 Hz, 2H), 2.61 (dd, J = 7.5, 6.3 Hz, 2H), 2.47 - 2.41 (m, 1H), 0.96 - 0.86 (m, 2H), 0.76 - 0.66 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With acid functionalized multi-walled carbon nanotubes modified with CeO2 nanoparticles In water; isopropyl alcohol for 1.5h; Reflux; | General procedure for the synthesis of compounds 2, 3,and 4 in the presents of (MWCNTs)-COOH/CeO2 General procedure: Raw materials and (MWCNTs)-COOH/CeO2 (7 mol%) weremixed and reacted in isopropanol 70% (compound 2) ormethanol (compound 3, 4) (10 ml) under reflux conditions.The completion of the reaction was determined by TLCusing n-hexane: ethyl acetate (2:1) and appeared by a UVlamp (254 & 366 nm). In the end, the reaction mixture wascentrifuged and the catalyst was filtered and washed withethanol (35 ml) and water (35 ml), dried at 100 C for2 h, and reused for the same reaction. The rest of the reactionmixture was evaporated, and the crude product waspurified by recrystallization from methanol or short-columnchromatography on silica gel (n-hexane: ethyl acetate/2:1).The products were determined by elemental analysis, NMR,and FT-IR spectra. |
Tags: 86393-33-1 synthesis path| 86393-33-1 SDS| 86393-33-1 COA| 86393-33-1 purity| 86393-33-1 application| 86393-33-1 NMR| 86393-33-1 COA| 86393-33-1 structure
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