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CAS No. : | 52980-28-6 | MDL No. : | MFCD01314279 |
Formula : | C12H11NO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | YBEOYBKKSWUSBR-UHFFFAOYSA-N |
M.W : | 217.22 | Pubchem ID : | 220876 |
Synonyms : |
|
Num. heavy atoms : | 16 |
Num. arom. heavy atoms : | 10 |
Fraction Csp3 : | 0.17 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 60.66 |
TPSA : | 59.16 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) : | -6.21 cm/s |
Log Po/w (iLOGP) : | 1.83 |
Log Po/w (XLOGP3) : | 1.99 |
Log Po/w (WLOGP) : | 1.7 |
Log Po/w (MLOGP) : | 0.98 |
Log Po/w (SILICOS-IT) : | 2.78 |
Consensus Log Po/w : | 1.86 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.7 |
Solubility : | 0.428 mg/ml ; 0.00197 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.86 |
Solubility : | 0.301 mg/ml ; 0.00138 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -4.1 |
Solubility : | 0.0174 mg/ml ; 0.0000802 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.88 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P301+P312-P302+P352-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H320-H335 | 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 |
---|---|---|
80% | at 0 - 80℃; for 16 h; | Ex mple 2: Synthesis of 4-Oxo-l,4-dihydroquinoline-3-carboxylic acid (3): (0084) (0085) To a suspension of ethyl 4-oxo- l,4-dihydroquinoline-3-carboxylate (2) (0.5 g, 2.30 mmol) in THF (10 mL), a solution of aqueous 1 M LiOH (aq) (4.60 mL, 4.60 mmol) was added drop wise at 0 °C, and then the reaction mixture was heated at 80 °C for 16h. Reaction mass was evaporated to dryness, dissolved in H20 (5 mL), washed with diethyl ether (2x5 mL).The aqueous layer was acidified with 1 M HC1 (aq),compound thus precipitated was filtered, dried under vacuum to give desired compound as off-white solid. Yield: (0.35g; 80percent) 1H NMR (400MHz ,DMSO-d6) δ = 15.36 (brs, 1H), 13.43 (brs, 1H), 8.91 (s, 1H), 8.31 (d, J = 8.3 Hz, 1H), 7.98 - 7.75 (m, 2H), 7.62 (t, J = 7.6 Hz, 1H). |
75% | With sodium hydroxide In ethanol for 5 h; Reflux | General procedure: A suspension of ester 3e–k (2 mmol) in 4percent NaOHhydroalcoholic solution (5 ml) was refluxed until no startingmaterial could be detected by Thin Layer Chromatography(5 h). After cooling, the mixture was completely acidifiedby adding concentrated HCl and the solid obtained wascollected by filtration, washed with water, and crystallizedfrom ethanol to afford compound 4e–k. 4-Oxo-1,4-dihydroquinoline-3-carboxylic acid (4e) Starting from 3e (1 g); Yield (white powder): 600 mg(75 percent); m.p. 280 °C (decomposed); IR (KBr) νmax1400–1600 (aromatic), 1717 (carbonyl), 2790–3260 (acidicOH) cm−1; 1H-NMR (DMSO-d6, 500 MHz) δ = 7.59–7.63 (1H, t, J = 7.2 Hz, H6), 7.83 (1H, d, J = 8.2 Hz, H8), 7.90(1H, t, J = 7.0 Hz, H7), 8.30 (1H, d, J = 7.3 Hz, H5), 8.90(1H, s, H2), 13.42 (1H, br s, enolic OH), 15.34 (1H, br s,carboxylic OH); 13C-NMR (DMSO-d6, 60 MHz) δ = 105.3(C, C-3), 119.7 (CH, C-9), 123.6 (CH, C-7), 125.6 (CH,C-6), 125.9 (C, C-5), 133.9 (CH, C-8), 138.5 (C,C-10), 158.9 (CH, C-2), 167.2 (C,COOH), 178.5 (C, C=O);LC-MS (ESI) m/z 212.1 (M+Na+); Anal. Calcd. forC10H7NO3: C, 63.49; H, 3.73; N, 7.40. Found: 63.62; H,3.96; N, 7.69. |
7.5 g | at 80 - 85℃; for 3 h; | In a clean round bottom flask, ethyl 4-oxo-l, 4-dihydroquinoline-3-carboxylate (10.0 gm) was charged to a solution of sodium hydroxide (3.7 gm) in 13.0 ml water. The reaction mass was heated for 3.0 hr at 80-85 C and then cooled to 25-30. To this was added 0.10 gm of activated charcoal and filtered. The pH was adjusted using con HCL and the product was filtered and washed with water. The wet cake slurried in methanol at 25 -30 C and filtered. The product was dried under vacuum at 50.0 C to get 7.50 gm of title productPurity by HPLC - 99.75 percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | In diphenylether; for 0.5h;Reflux; | General procedure: Anilinomethylenemalonates 8a-c (3 g, 10.83 mmol) were refluxed for 30 min in diphenyl ether (30 mL), leading to crude oxoquinolines 9a-c which were recrystallized from dimethylformamide [20,21,26,27]. |
75% | With ortho-chlorobenzoic acid; at 250℃; for 2h;Microwave irradiation; | General procedure: A diphenyl ether solution of 2e-k (4 mmol) containingcatalytic 2-chlorobenzoic acid was heated by microwaveirradiation (250 C) for 1-2 h. After cooling, the reactionmixture was filtered and the precipitate 3e-k was washedwith n-hexane and water. Ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate (3e) Starting from 2e (5 g); Yield (cream powder): 3 g (75 %); m.p. 261-262 C; IR (KBr) numax 1400-1600 (aromatic), 1695(carbonyl), 3150 (N-H) cm-1; LC-MS (ESI) m/z 218.1 (M+H+), 240.1 (M+Na+); Calcd. for C12H11NO3: C, 66.35; H,5.10; N, 6.45. Found: 66.47; H, 5.22; N, 6.27. |
In diphenylether;Reflux; | General procedure: The quinolone derivatives 1 were prepared by treating the appropriate aniline (100 mmol) with diethyl ethoxymethylenemalonate (100 mmol) under reflux in ethanol (5 mL) for 2-10 h to obtain the enamine derivatives that were then cyclized in refluxing diphenyl ether for 30 min-6 h [29]. These quinolones (13 mmol) were refluxed in thionyl chloride (20 mL), for 17 h, affording the corresponding chloro-derivatives 2a-g [22]. Reaction of 2a-g (4 mmol) with 2-hydrazinobenzothiazole (8 mmol) in toluene (30 mL), for 3 h, followed by a 2 h reflux in acetic acid gave the corresponding 2-(benzo[d]thiazol-2-yl)-8-substituted-2H-pyrazolo[4,3-c]quinolin-3(5H)-ones 3a-g as solids which were collected by filtration under vacuum, washed with water and subsequent purified by washing with hot ethyl alcohol. |
In diphenylether; ethanol; at 228 - 232℃; for 3.5h;Inert atmosphere; | Procedure for the preparation of ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate (25) Compound 23 (4.77 g, 47.7 mmol) was added dropwise to compound 22 (10 g, 46.3 mmol) with subsurface N2 flow to drive out ethanol below 30 C. for 0.5 hours. The solution was then heated to 100-110 C. and stirred for 2.5 hours. After cooling the mixture to below 60 C., diphenyl ether was added. The resulting solution was added dropwise to diphenyl ether that had been heated to 228-232 C. for 1.5 hours with subsurface N2 flow to drive out ethanol. The mixture was stirred at 228-232 C. for another 2 hours, cooled to below 100 C. and then heptane was added to precipitate the product. The resulting slurry was stirred at 30 C. for 0.5 hours. The solids were then filtrated, and the cake was washed with heptane and dried in vacuo to give compound 25 as brown solid. 1H NMR (DMSO-d6; 400 MHz) delta 12.25 (s), delta 8.49 (d), delta 8.10 (m), delta 7.64 (m), delta 7.55 (m), delta 7.34 (m), delta 4.16 (q), delta 1.23 (t). | |
In diphenylether; at 228 - 232℃; for 3.5h;Inert atmosphere; | Compound 23 (4.77 g, 47.7 mmol) was added dropwise to Compound 22 (10 g, 46.3 mmol) with subsurface N2 flow to drive out ethanol below 30 C for 0.5 hours. The solution was then heated to 100-110 C and stirred for 2.5 hours. After cooling the mixture to below 60 C, diphenyl ether was added. The resulting solution was added dropwise to diphenyl ether that had been heated to 228-232 C for 1.5 hours with subsurface N2 flow to drive out ethanol. The mixture was stirred at 228-232 C for another 2 hours, cooled to below 100 C and then heptane was added to precipitate the product. The resulting slurry was stirred at 30 C for 0.5 hours. The solids were then filtered, and the cake was washed with heptane and dried in vacuo to give Compound 25 as a brown solid. 1H NMR (DMSO-d6; 400 MHz) delta 12.25 (s), delta 8.49 (d), delta 8.10 (m), delta 7.64 (m), delta 7.55 (m), delta 7.34 (m), delta 4.16 (q), delta 1.23 (t). | |
In diphenylether; for 1h;Reflux; | General procedure: Substituted aniline 1 (0.01 mol) and diethylethoxy methylene malonate 2 (0.01 mol) were mixed and heated at 125-130 0C for 2 h. Ethanol was evaporated off from the resulting mixture ofethyl anilinomethylene malonate 3. The crude solid was filtered on sintered funnel, dried and recrystallized from n-hexane. The malonate 3 (0.01mol) was refluxed with diphenylether (50 mL) for 1h to give 1,4-dihydro-4-oxoquinoline-3-carboxylicacid ethyl ester 4. After 1 h the solution was cooled and the resulting precipitate was filtered off, washed with n-hexane, and dried. The solid was recrystallized from DMF to give substituted-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethylester 4. | |
In diphenylether; ethanol; at 228 - 232℃; for 3.5h;Inert atmosphere; | [00324] Compound 23 (4.77 g, 47.7 mmol) was added dropwise to compound 22 (10 g, 46.3mmol) with subsurface N2 flow to drive out ethanol below 30 oc for 0.5 hours. The solution wasthen heated to 100-110 oc and stirred for 2.5 hours. After cooling the mixture to below 60 C,diphenyl ether was added. The resulting solution was added dropwise to diphenyl ether that hadbeen heated to 228-232 oc for 1.5 hours with subsurface N2 flow to drive out ethanol. Themixture was stirred at 228-232 oc for another 2 hours, cooled to below 100 oc and then heptanewas added to precipitate the product. The resulting slurry was stirred at 30 oc for 0.5 hours. Thesolids were then filtrated, and the cake was washed with heptane and dried in vacuo to give compound 25 as brown solid. 1H NMR (DMSO-d6; 400 MHz) 8 12.25 (s), 8 8.49 (d), 8 8.10(m), 8 7.64 (m), 8 7.55 (m), 8 7.34 (m), 8 4.16 (q), 8 1.23 (t). | |
5 g | With phosphorus pentoxide-methanesulfonic acid; at 80 - 85℃; for 10h; | In a clean round bottom flask, charge Diethyl (anilinomethylene) malonate (10 .0 gm) and eaton's reagent (40.0 ml).The reaction mass was heated to 80-85 C for 10.0 hr and cooled to 25- 30 C .To the reaction mass sodium carbonate solution was added at 25-30C and the product was filtered and washed with water and filtered. The wet cake was dissolved in acetone (80.0 ml) and water by heating to, 45-50 C (10.0 ml) to obtain suspension. The solution was maintained for 1.0 hr, cooled to 25-30C and filtered. The product was dried at 50 -55C for 24.0 hr to get 5.0 gm title compound. Purity by HPLC - 99.32 % |
In diphenylether; at 228 - 232℃; for 3.5h;Inert atmosphere; | [00339] Compound 23 (4.77 g, 47.7 mmol) was added dropwise to compound 22 (10 g, 46.3 mmol) with subsurface N2 flow to drive out ethanol below 30 C for 0.5 hours. The solution was then heated to 100-1 10 C and stirred for 2.5 hours. After cooling the mixture to below 60 C, diphenyl ether was added. The resulting solution was added dropwise to diphenyl ether that had been heated to 228-232 C for 1.5 hours with subsurface N2 flow to drive out ethanol. The mixture was stirred at 228-232 C for another 2 hours, cooled to below 100 C and then heptane was added to precipitate the product. The resulting slurry was stirred at 30 C for 0.5 hours. The solids were then filtrated, and the cake was washed with heptane and dried in vacuo to give compound 25 as brown solid. NMR (DMSO-d6; 400 MHz) delta 12.25 (s), delta 8.49 (d), 5 8.10 (m), 5 7.64 (m), delta 7.55 (m), delta 7.34 (m), delta 4.16 (q), delta 1.23 (t). | |
In diphenylether; at 228 - 232℃; for 3.5h;Inert atmosphere; | Compound 23 (4.77 g, 47.7 mmol) was added dropwise to Compound 22 (10 g, 46.3 mmol) with subsurface N2 flow to drive out ethanol below 30 C. for 0.5 hours. The solution was then heated to 100-110 C. and stirred for 2.5 hours. After cooling the mixture to below 60 C., diphenyl ether was added. The resulting solution was added dropwise to diphenyl ether that had been heated to 228-232 C. for 1.5 hours with subsurface N2 flow to drive out ethanol. The mixture was stirred at 228-232 C. for another 2 hours, cooled to below 100 C. and then heptane was added to precipitate the product. The resulting slurry was stirred at 30 C. for 0.5 hours. The solids were then filtrated, and the cake was washed with heptane and dried in vacuo to give Compound 25 as a brown solid. 1H NMR (DMSO-d6; 400 MHz) delta 12.25 (s), delta 8.49 (d), delta 8.10 (m), delta 7.64 (m), delta 7.55 (m), delta 7.34 (m), delta 4.16 (q), delta 1.23 (t). | |
12.4 g | In diphenylether; at 260℃; for 4h; | To <strong>[54535-22-7]diethyl 2-((phenylamino)methylene)malonate</strong> from the previous step (max 0.1 mol) was added Ph20 (500 mL). In three batches the reaction mixture was heated to 260 C for 4 h. Upon cooling to room temperature a white precipitate formed which was collected by filtration, washed with toluene and dried under vacuum to give thetitle product (12.4 g, 57% over two steps) as a white powder.HRMS m/z (El) 217.07352, calculated for C,2H,,NO3 217.07334; ?H NIVIR (500 IVIHz, DMSO) 12.32 (s, 1H, NH), 8.55 (s, 1H, aromatic), 8.19 - 8.13 (m, 1H, aromatic), 7.74 - 7.67 (m, 1H, aromatic), 7.62 (d, J= 8.1, 1H, aromatic), 7.42 (t, J=7.1, 1H, aromatic), 4.22 (q, J= 7.1, 2H, CH2CH3), 1.28 (t, J= 7.1, 3H, CH2CH3); ?3CNIVIR (126 MFIz, DMSO) 173.40 (CO), 164.80 (CO), 144.87 (aromatic), 138.95(aromatic), 132.37 (aromatic), 127.25 (aromatic), 125.60 (aromatic), 124.66(aromatic), 118.77 (aromatic), 109.76 (aromatic), 59.54 (CH2CH3), 14.32 (CH2CH3). |
With Eaton?s reagent; at 80 - 90℃; | Step b :4-hydroxyquinoline 3- carboxylic acid ethyl ester A clean and dry I liter round bottom flask, fitted with mechanical stirrer and thermo pocket was charged 2-Phenylaminotnethylene malonic acid diethyl ester (100 g) and Eaton's reagent (400 ml) at room temperature. The reaction mass was heated to 80-90 C. and maintained under stirring for 4-6 hours at the same temperature. After completion, the reaction mass was cooled to 5-10 C. and was treated with aqueous sodium carbonate solution at 0-10 C. and stirred for 60-90 minutes at the same temperature. The resultant solid was filtered, washed with water (until the water filtrate showed neutral pH) and dried at 45-50 for 6-8 hours to obtain 4-hydroxyquinoline 3-carboxylic acid ethyl ester (70-80 g) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With N-ethyl-N,N-diisopropylamine In chloroform for 20h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With N-ethyl-N,N-diisopropylamine In chloroform for 20h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With N-ethyl-N,N-diisopropylamine In chloroform for 20h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.71% | With potassium carbonate In N,N-dimethyl-formamide at 25 - 80℃; for 4h; | 76; 77 Preparation of ethyl 1-ethyl-4-oxo-quinoline-3-carboxylate To a mixture of ethyl 4-oxo-1H-quinoline-3-carboxylate (2.00 g, 9.21 mmol, 1 eq) in DMF (20 mL) was added K2CO3 (2.54 g, 18.41 mmol, 2 eq) and iodoethane (4.31 g, 27.62 mmol, 2.21 mL, 3 eq) at 25°C, the resulting mixture was stirred at 80°C for 4 h. Then the reaction mixture was cooled to 25°C, poured into iced sat. NH4Cl (20 mL), and the aqueous phase was extracted with EtOAc (15 mL x 3). The combined organic phase was washed with brine (15 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/4 to 0/1) to give ethyl 1-ethyl-4-oxo-quinoline-3-carboxylate (1.80 g, 7.34 mmol, 79.71% yield) as a yellow solid.1H NMR (CDCl3, 400 MHz) d 8.57 (dd, J = 8.0, 1.2 Hz, 1H), 8.52 (s, 1H), 7.72-7.68 (m, 1H), 7.48-7.43 (m, 2H), 4.41 (q, J = 7.2 Hz, 2H), 4.27 (q, J = 7.2 Hz, 2H), 1.56 (t, J = 7.2 Hz, 3H), 1.43 (t, J = 7.2 Hz, 3H). |
With thallium (I) ethoxide 1.) ethanol, Rt, 2 h; 2.) without solvent, 70 - 80 deg C, 4 h; Yield given. Multistep reaction; | ||
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 10h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With N-ethyl-N,N-diisopropylamine In chloroform for 20h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With triethylamine In chloroform at 50℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere; Stage #2: methyl iodide In N,N-dimethyl-formamide at 60℃; for 8h; | |
78% | Stage #1: ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate With sodium hydride In N,N-dimethyl-formamide at 20℃; Inert atmosphere; Stage #2: methyl iodide In N,N-dimethyl-formamide at 60℃; for 4h; Inert atmosphere; | |
70% | Stage #1: ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate With potassium carbonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere; Stage #2: methyl iodide In N,N-dimethyl-formamide at 60℃; for 1h; | 7.1.3. Synthesis of ethyl-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (6) Ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (5)(1.15 mmol) and DMF (5 mL) were placed in a round bottom flask.Then, K2CO3 (1.72 mmol)was added, and the reactionwas stirred atroom temperature in argon atmosphere. At that time, CH3I(2.30 mmol) was introduced dropwise. The reaction was stirred at60 C for 1 h. After, the mixture was diluted with water andextracted with DCM (3 15 mL). The combined organic layers weredried over anhydrous Na2SO4, and the solvent was evaporatedunder reduced pressure. The crude product was crystallised fromDCM (70% yield). 1H NMR (400 MHz, CDCl3) d: 8.53 (1H, dd, J 8.0,1.6, 0.6 Hz, H5), 8.46 (1H, s, H2), 7.70 (1H, dd, J 8.6, 7.2,1.6 Hz, H7),7.49e7.39 (2H, m, H8, H6) 4.40 (2H, q, J 7.1 Hz, CH2), 3.88 (3H, s,NCH3), 1.42 (3H, t, J 7.1 Hz, CH3). |
With thallium (I) ethoxide 1.) ethanol, Rt, 2 h; 2.) without solvent, 70 - 80 deg C, 4 h; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With mesitylenesulfonylhydroxylamine; potassium carbonate In N,N-dimethyl-formamide at 20 - 25℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In diphenylether at 120℃; for 25h; | |
80% | Stage #1: aniline; diethyl 2-ethoxymethylenemalonate In neat (no solvent) at 120℃; for 1h; Inert atmosphere; Stage #2: With Eaton′s reagent In neat (no solvent) at 130℃; for 1h; Inert atmosphere; | |
80% | at 120℃; for 2h; | 7.1.2. Synthesis of ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylate(5) A mixture of aniline (10.73 mmol) and DEEMM (10.73 mmol)was heated at 120 C for 1 h. After cooling the solid obtained wasdissolved in diphenyl ether (32 mL). The reaction was refluxed for2 h. After cooling, diethyl ether (25 mL) was added and the solidwas filtered and recrystallized from DMF (yield 80%). 1H NMR(400 MHz, DMSO-d6) d: 12.31 (1H, s, NH), 8.55 (1H, s, H2), 8.16 (1H,dd, J 7.6, 1.5, 0.6 Hz, H5), 7.71 (1H, dd, J 7.6, 6.9, 1.5 Hz, H7), 7.62(1H, dd, J 7.6,1.5, 0.6 Hz, H8), 7.42 (1H, dd, J 7.6, 6.9 Hz, H6), 4.22(2H, q, J 7.1 Hz, CH2), 1.29 (3H, t, J 7.1 Hz, CH3). |
58% | With Dowtherm A for 0.5h; Reflux; | 3-Carbethoxy-4-quinolone Aniline (10.0 mL, 110 mmol) and diethyl ethoxymethylene malonate (21.99 mL, 110mmol) were heated in refluxing Dowtherm A (100 mL) for 30 minutes. After cooling,the reaction mixture was diluted with hexanes (150 mL) and vacuum filtered, rinsingwith further hexanes (200 mL), followed by acetone (100 mL). The product wasobtained as grayish beige, powdery solid (13.87 g, 58%). |
Stage #1: aniline; diethyl 2-ethoxymethylenemalonate at 100℃; Stage #2: With PPA | ||
In diphenylether at 110 - 260℃; for 3h; Neat (no solvent); | 84.1 31.7 g (147 mmol) of 2-Ethoxyrnethylene-malonic acid diethyl ester and 13.7 g(147 mmol) of aniline were stirred neat at 11O0C for Ih, then 300 mL of diphenyl ether was added and the temperature of the oil bath was raised to 2600C for 2 h. The solution was then cooled down to rt, diluted with 600 mL of hexanes and filtered. The solids were washed with 200 mL of hexanes and dried to yield 23.7 g of the product as a light brown powder. LC- MSD, m/z for Ci2HnNO3 [M+H]+ = 218.2, HPLC retention time: 2.5 min | |
In diphenylether at 30 - 232℃; Inert atmosphere; | 1; 2 Compound 23 (4.77 g, 47.7 mmol) was added dropwise to compound 22 (10 g, 46.3 mmol) with subsurface N2 flow to drive out ethanol below 30 0C for 0.5 hours. The solution was then heated to 100-110 0C and stirred for 2.5 hours. After cooling the mixture to below 60 0C, diphenyl ether was added. The resulting solution was added dropwise to diphenyl ether that had been heated to 228-232 0C for 1.5 hours with subsurface N2 flow to drive out ethanol. The mixture was stirred at 228-232 0C for another 2 hours, cooled to below 100 °C and then heptane was added to precipitate the product. The resulting slurry was stirred at 30 0C for 0.5 hours. The solids were then filtrated, and the cake was washed with heptane and dried in vacuo to give compound 25 as brown solid. 1H NMR (DMSOd6; 400 MHz) δ 12.25 (s), δ 8.49 (d), δ 8.10 (m), δ 7.64 (m), δ 7.55 (m), δ 7.34 (m), δ 4.16 (q), δ 1.23 (t). | |
In diphenylether; ethanol at 30 - 232℃; Inert atmosphere; | 1 Compound 23 (4.77 g, 47.7 mmol) was added dropwise to compound 22 (10 g, 46.3 mmol) with subsurface N2 flow to drive out ethanol below 30 0C for 0.5 hours. The solution was then heated to 100-110 0C and stirred for 2.5 hours. After cooling the mixture to below 60 0C, diphenyl ether was added. The resulting solution was added dropwise to diphenyl ether that had been heated to 228-232 0C for 1.5 hours with subsurface N2 flow to drive out ethanol. The mixture was stirred at 228-232 °C for another 2 hours, cooled to below 100 0C and then heptane was added to precipitate the product. The resulting slurry was stirred at 30 0C for 0.5 hours. The solids were then filtrated, and the cake was washed with heptane and dried in vacuo to give compound 25 as brown solid. 1H NMR (DMSOd6; 400 MHz) δ 12.25 (s), δ 8.49 (d), δ 8.10 (m), δ 7.64 (m), δ 7.55 (m), δ 7.34 (m), δ 4.16 (q), δ 1.23 (t). | |
Multi-step reaction with 2 steps 1: ethanol / 3 h / 30 - 110 °C / Inert atmosphere 2: diphenylether; ethanol / 3.5 h / 228 - 232 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: ethanol / 3 h / 30 - 110 °C / Inert atmosphere 2: diphenylether / 3.5 h / 228 - 232 °C / Inert atmosphere | ||
Stage #1: aniline; diethyl 2-ethoxymethylenemalonate In ethanol at 30 - 110℃; for 3h; Inert atmosphere; Stage #2: With diphenylether In ethanol at 228 - 232℃; for 3.5h; Inert atmosphere; | 1a Example 1a: Ethyl 4oxo-1,4-dihydroqu inoline-3-carboxyIate (25) Compound 23 (4.77 g, 47.7 mmol) was added dropwise to Compound 22 (10 g, 46.3 mmol) with subsurface N2flow to drive out ethanol below 30 °C for 0.5 hours. The solution was then heated to 100-110 °C and stirred for 2.5 hours. After cooling the mixture to below 60 °C, diphenyl ether was added. The resulting solution was added dropwise to diphenyl ether that had been heated to 228-232 °C for 1.5 hours with subsurface N2flow to drive out ethanol. The mixture was stirred at 228-232 °C for another 2 hours, cooled to below 100 °C and then heptane was added to precipitate the product. The resulting slurry was stirred at 30 °C for 0.5 hours. The solids were then filtered, and the cake was washed with heptane and dried in vacuo to give Compound 25 as a brown solid. NMR (DMSO-dg; 400 MHz) δ 12.25 (s), δ 8.49 (d), δ 8.10 (m), δ 7.64 (m), δ 7.55 (m), 5 7.34 (m), δ 4.16 (q), δ 1.23 (t). | |
Multi-step reaction with 2 steps 1: 2 h / 125 - 130 °C 2: diphenylether / 1 h / Reflux | ||
Multi-step reaction with 2 steps 1: ethanol / 3 h / Reflux 2: diphenylether / 0.5 h / Reflux | ||
Multi-step reaction with 2 steps 1: 3 h / 20 - 55 °C 2: Eaton′s reagent / 10 h / 80 - 85 °C | ||
Stage #1: aniline; diethyl 2-ethoxymethylenemalonate In toluene for 5h; Reflux; Stage #2: In Petroleum ether at 280℃; for 3h; | Preparation of Compounds 1-4 A mixture of aniline (10mmol), EMME (11mmol), and toluene (30mL) was refluxed in a 250-ml round-bottom flask for 5h. It was then cooled and washed with 3 (N) 100 mL H2SO4. Toluene was distilled off afterward. The mixture was scratched vigorously to get solid anil product. This product (5g) was refluxed with biphenyl-oxide (50mL) for 2h at 280°C. It was then cooled and stirred for an hour after addition of a small amount (100mL)of petroleum ether. Compounds 1-4 were obtained by filtration on Buchnerfunnel. | |
Multi-step reaction with 2 steps 1: 140 - 150 °C 2: Eaton’s reagent / 80 - 90 °C | ||
Stage #1: aniline; diethyl 2-ethoxymethylenemalonate In ethanol for 2h; Reflux; Stage #2: In diphenylether at 270℃; | ||
Multi-step reaction with 2 steps 1: ethanol / 6 h / Reflux 2: diphenylether / 0.33 h / Reflux | ||
Multi-step reaction with 2 steps 1: ethanol / 3 h / Reflux; Inert atmosphere 2: diphenylether / 2 h / Reflux | ||
Stage #1: aniline; diethyl 2-ethoxymethylenemalonate In ethanol Reflux; Stage #2: In diphenylether at 250℃; | ||
Multi-step reaction with 2 steps 1: 2 h / 120 °C 2: Eaton′s reagent / 3 h / 100 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With triphenylphosphine In tetrahydrofuran Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.4% | With pyridine at 125℃; for 30h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | at 120℃; for 24h; Heating; | |
53.1% | With pyridine at 125℃; for 30h; | |
30% | In diphenylether at 210℃; for 1h; | 3.2.3. General Procedure for the Synthesis of Oxoquinolines 10-18 General procedure: Oxoquinolines 9a-c(8 mmol) were reacted with the appropriate amine (8 mmol) in diphenyl ether(30 mL) at 210 °C under magnetic stirring for 1 h. The resulting mixture was poured into petroleum ether. The obtained solid was filtered and recrystallized from dichloromethane/petroleum ether (1/1) to yield the derivatives listed below [28-30]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; for 17h;Reflux; | General procedure: The quinolone derivatives 1 were prepared by treating the appropriate aniline (100 mmol) with diethyl ethoxymethylenemalonate (100 mmol) under reflux in ethanol (5 mL) for 2-10 h to obtain the enamine derivatives that were then cyclized in refluxing diphenyl ether for 30 min-6 h [29]. These quinolones (13 mmol) were refluxed in thionyl chloride (20 mL), for 17 h, affording the corresponding chloro-derivatives 2a-g [22]. Reaction of 2a-g (4 mmol) with 2-hydrazinobenzothiazole (8 mmol) in toluene (30 mL), for 3 h, followed by a 2 h reflux in acetic acid gave the corresponding 2-(benzo[d]thiazol-2-yl)-8-substituted-2H-pyrazolo[4,3-c]quinolin-3(5H)-ones 3a-g as solids which were collected by filtration under vacuum, washed with water and subsequent purified by washing with hot ethyl alcohol. | |
With trichlorophosphate; for 1h;Reflux; Inert atmosphere; Schlenk technique; | General procedure: A solution of compounds 3a-d (1.0 mmol) in POCl3 (6 mL) was refluxed for 1 h. The mixture was evaporated in vacuo and the residue was extracted with methylene chloride, crushed ice and aqueous NH3.The organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography (SiO2, EA: n-Hex) to get key intermediates 4a-d. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: 1,4-dibromo-butane; ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate With sodium hydride In N,N-dimethyl-formamide Stage #2: With sodium iodide In acetonitrile for 24h; Heating; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Stage #1: ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate; 1,3-dibromo-propane With sodium hydride In N,N-dimethyl-formamide Stage #2: With sodium iodide In acetonitrile for 24h; Heating; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 20℃; for 6h; | |
75% | Stage #1: ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate With sodium hydride In N,N-dimethyl-formamide at 20℃; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 90℃; for 6h; | |
75% | With sodium hydride In N,N-dimethyl-formamide at 90℃; for 3h; |
64% | Stage #1: ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate With potassium carbonate In N,N-dimethyl-formamide at 40℃; for 0.0833333h; Inert atmosphere; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 80℃; for 4.5h; | 20 Compound 85. Synthesis of ethyl 1 -benzyl-4-oxo- 1 ,4-dihydroquinoline-3 -carboxylate 7 Ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate 6 (3.00 g, 13.811 mMol) was stirred in DMF (120 mL) with potassium carbonate (4.77 g, 34.527 mMol) at 40°C under an atmosphere of nitrogen. After 5 minutes benzyl bromide (8.2 mL, 69.054 mMol) wasadded dropwise and the temperature raised to 80°C. After 4.5 hours, t.l.c. analysis (dichloromethane : acetone, 4 : 1) showed the presence of one UV-active product (Rf 0.87) and complete consumption of the starting material (Rf 0.10). The reaction mixture was filtered and the filtrate was concentrated in vacuo, pre-absorbed on silica and purified by flash-column chromatography (ethyl acetate : cyclohexane, 3 : 7, to 1: 1, to 7 : 1, to ethyl acetate) to afford ethyl 1-benzyl-4-oxo-1,4-dihydroquinoline-3- carboxylate 7 (2.70 g, 64%) as a white/pale yellow crystalline solid. M.p. 150-158°C (ethyl acetate/cyclohexane; melted over the range); HRMS (El): found 307.12088 [M] C19H17N03 requires 307.12029; Vmax (thin film): 3109, 3048 (w, ArC-H), 2979, 2935, 2904, 2871 (m, alkyl C-H), 1722 (s, C=O ketone), 1692 (s, C=O ester,conjugated with C=C), 1622, 1610 (s, C=C conjugated with C=Os), 1234 (s, C-N stretch) cm’; 6H (CD3CN, 500 MHz): 1.36 (3H, t, JCH3,CH2 7.1 Hz, CH3), 4.31 (2H, q, JCH2,CH3 7.1 Hz, CH2), 5.52 (2H, s, CH2-Bn), 7.25-7.29 (2H, m, 2 x ArHs (Bn)), 7.32-7.40 (3H, m, 3 x ArHs (Bn)), 7.43 (1 H, ddd, JHB,HA 8.0 Hz, JHB,HC 7.1 Hz,JHB,HD 1.0 Hz, HB), 7.51 (1 H, d, JHD,HC 8.6 Hz, HD), 7.62 (1 H, ddd, JHC,HD 8.6 Hz,JHC,HB 7.0 Hz, JHC,HA 1.6 Hz, Hc), 8.38 (1H, dd, JHA,HB 8.5 Hz, JHA,HC 1.6 Hz, HA),8.74 (1H, s, HE); 6c (CD3CN, 125 MHz): 14.1 (CH3), 57.0 (CH2 (Bn)), 60.5 (CH2),111.1 (O=C-C-C=O), 117.8 (ArC’), 125.3 (ArCB), 127.1 (ArCA), 126.9, 128.5, 129.4(5 x ArCs (Bn) & ArCq-C=O), 132.8 (ArCC), 136.0 (Cq (Bn)), 139.8 (ArCq-NH),150.5 (ArCE), 165.2 (COOEt), 174.2 (C0). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | Stage #1: ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate With sodium hydride In N,N-dimethyl-formamide at 20℃; Stage #2: 1-bromo-butane In N,N-dimethyl-formamide at 90℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Stage #1: ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate With sodium hydride In N,N-dimethyl-formamide at 20℃; Stage #2: 1-Bromopentane In N,N-dimethyl-formamide at 90℃; for 3h; | |
93% | With sodium hydride In N,N-dimethyl-formamide at 90℃; for 3h; | |
With sodium hydride In N,N-dimethyl-formamide at 90℃; for 16h; |
Stage #1: ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.5h; Stage #2: 1-Bromopentane In N,N-dimethyl-formamide; mineral oil at 20℃; for 12h; | 1.1.1 General procedure: Compound 7-9 was dissolved in N,N-dimethylformamide (DMF), sodium hydride (NaH, 60%) was added, and the mixture was stirred at room temperature for 30 minutes. Subsequently, 1-bromopentane (10) was added to this solution and reacted at room temperature for 12 hours. After the reaction, the reaction was quenched by adding saturated ammonium chloride solution, the organic phase was separated, the aqueous phase was extracted three times with dichloromethane, merged into the organic phase, washed with saturated ammonium chloride aqueous solution and saturated brine in turn, and then with anhydrous sulfuric acid The sodium was dried, the sodium sulfate was removed by filtration, and the crude product was obtained by concentration. The crude product is separated by column chromatography (200-300 mesh silica gel, eluent is n-hexane: ethyl acetate=2:1) to obtain pure intermediate 11-13. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | Stage #1: ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate With sodium hydride In N,N-dimethyl-formamide at 20℃; Stage #2: 1-bromo-hexane In N,N-dimethyl-formamide at 90℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With toluene-4-sulfonic acid Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With lithium hydroxide monohydrate; In tetrahydrofuran; water; at 20℃; | General procedure: The ethyl 4(1H)-oxo-quinolone-3-carboxylate (1?2 mmol) was dissolved in 5 mL MeOH. LiOH·H2O (3.0equiv), dissolved in 1?2 mL H2O, was added to the reaction mixture. The reaction mixture was stirredat ambient temperature overnight or monitored by TLC analysis. After the starting material was fullyconsumed (judged by TLC-analysis), the reaction volume was reduced to one third of its initialvolume. The solution was acidified to pH 2?3 (pH-paper) with 1 M HCl. The resulting white solutionwas centrifuged and the liquid carefully removed. The remaining solid was washed with water andcentrifuged twice, leaving a pure off-white solid. |
80% | With water; lithium hydroxide; at 0 - 80℃; for 16h; | Ex mple 2: Synthesis of 4-Oxo-l,4-dihydroquinoline-3-carboxylic acid (3): (0084) (0085) To a suspension of ethyl 4-oxo- l,4-dihydroquinoline-3-carboxylate (2) (0.5 g, 2.30 mmol) in THF (10 mL), a solution of aqueous 1 M LiOH (aq) (4.60 mL, 4.60 mmol) was added drop wise at 0 C, and then the reaction mixture was heated at 80 C for 16h. Reaction mass was evaporated to dryness, dissolved in H20 (5 mL), washed with diethyl ether (2x5 mL).The aqueous layer was acidified with 1 M HC1 (aq),compound thus precipitated was filtered, dried under vacuum to give desired compound as off-white solid. Yield: (0.35g; 80%) 1H NMR (400MHz ,DMSO-d6) delta = 15.36 (brs, 1H), 13.43 (brs, 1H), 8.91 (s, 1H), 8.31 (d, J = 8.3 Hz, 1H), 7.98 - 7.75 (m, 2H), 7.62 (t, J = 7.6 Hz, 1H). |
75% | With sodium hydroxide; In ethanol; for 5h;Reflux; | General procedure: A suspension of ester 3e-k (2 mmol) in 4% NaOHhydroalcoholic solution (5 ml) was refluxed until no startingmaterial could be detected by Thin Layer Chromatography(5 h). After cooling, the mixture was completely acidifiedby adding concentrated HCl and the solid obtained wascollected by filtration, washed with water, and crystallizedfrom ethanol to afford compound 4e-k. 4-Oxo-1,4-dihydroquinoline-3-carboxylic acid (4e) Starting from 3e (1 g); Yield (white powder): 600 mg(75 %); m.p. 280 C (decomposed); IR (KBr) numax1400-1600 (aromatic), 1717 (carbonyl), 2790-3260 (acidicOH) cm-1; 1H-NMR (DMSO-d6, 500 MHz) delta = 7.59-7.63 (1H, t, J = 7.2 Hz, H6), 7.83 (1H, d, J = 8.2 Hz, H8), 7.90(1H, t, J = 7.0 Hz, H7), 8.30 (1H, d, J = 7.3 Hz, H5), 8.90(1H, s, H2), 13.42 (1H, br s, enolic OH), 15.34 (1H, br s,carboxylic OH); 13C-NMR (DMSO-d6, 60 MHz) delta = 105.3(C, C-3), 119.7 (CH, C-9), 123.6 (CH, C-7), 125.6 (CH,C-6), 125.9 (C, C-5), 133.9 (CH, C-8), 138.5 (C,C-10), 158.9 (CH, C-2), 167.2 (C,COOH), 178.5 (C, C=O);LC-MS (ESI) m/z 212.1 (M+Na+); Anal. Calcd. forC10H7NO3: C, 63.49; H, 3.73; N, 7.40. Found: 63.62; H,3.96; N, 7.69. |
With hydrogenchloride; water; at 85 - 90℃; for 6.5h;Product distribution / selectivity; | Compound 25 (1.0 eq) was suspended in a solution of HCl (10.0 eq) and H2O (11.6 vol). The slurry was heated to 85 - 90 0C, although alternative temperatures are also suitable for this hydrolysis step. For example, the hydrolysis can alternatively be performed at a temperature of from about 75 to about 100 C. In some instances, the hydrolysis is performed at a temperature of from about 80 to about 95 0C. In others, the hydrolysis step is performed at a temperature of from about 82 to about 93 C (e.g., from about 82.5 to about 92.5 C or from about 86 to about 89 0C). After stirring at 85 - 90 0C for approximately 6.5 hours, the reaction was sampled for reaction completion. Stirring may be performed under any of the temperatures suited for the hydrolysis. The solution was then cooled to 20 - 25 0C and filtered. The reactor/cake was rinsed with H2O (2 vol x 2). The cake was then washed with 2 vol H2O until the pH >; 3.0. The cake was then dried under vacuum at 60 0C to give compound 26. | |
Compound 25 (11.3 g, 52 mmol) was added to a mixture of 10% NaOH (aq) (10 mL) and ethanol (100 mL). The solution was heated to reflux for 16 hours, cooled to 20-25 0C and then the pH was adjusted to 2-3 with 8% HCl. The mixture was then stirred for 0.5 hours and filtered. The cake was washed with water (50 mL) and then dried in vacuo to give compound 26 as a brown solid. 1H NMR (DMSO-d6; 400 MHz) delta 15.33 (s), delta 13.39 (s), delta 8.87 (s), delta 8.26 (m), delta 7.87 (m), delta 7.80 (m), delta 7.56 (m). | ||
Procedure for the preparation of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (26) Method 2Compound 25 (11.3 g, 52 mmol) was added to a mixture of 10% NaOH (aq) (10 mL) and ethanol (100 mL). The solution was heated to reflux for 16 hours, cooled to 20-25 C. and then the pH was adjusted to 2-3 with 8% HCl. The mixture was then stirred for 0.5 hours and filtered. The cake was washed with water (50 mL) and then dried in vacuo to give compound 26 as a brown solid. 1H NMR (DMSO-d6; 400 MHz) delta 15.33 (s), delta 13.39 (s), delta 8.87 (s), delta 8.26 (m), delta 7.87 (m), delta 7.80 (m), delta 7.56 (m). | ||
With water; sodium hydroxide; In ethanol; for 16h;Reflux; | Compound 25 (11.3 g, 52 mmol) was added to a mixture of 10% NaOH (aq) (10 mL) and ethanol (100 mL). The solution was heated to reflux for 16 hours, cooled to 20-25 C and then the pH was adjusted to 2-3 with 8% HC1. The mixture was then stirred for 0.5 hours and filtered. The cake was washed with water (50 mL) and then dried in vacuo to give Compound 26 as a brown solid. 1H NMR (DMSO-d6; 400 MHz) delta 15.33 (s), delta 13.39 (s), delta 8.87 (s), delta 8.26 (m), delta 7.87 (m), delta 7.80 (m), delta 7.56 (m). | |
With hydrogenchloride; water; at 85 - 90℃; | Compound 25 (1.0 eq) was suspended in a solution of HQ (10,0 eq) and H20 (1 1.6 vol). The slum'' was heated to 85 - 90 C, although alternative temperatures are also suitable for this hydrolysis step. For example, the hydrolysis can alternatively be performed at a temperature of from about 75 to about 100 C. in some instances, fee hydrolysis is performed at a temperature of from about 80 to about 95 C. In others, the hydrolysis step is performed at a temperature of from about 82 to about 93 C (e.g., from about 82.5 to about 92.5 C or from about 86 to about 89 C). After stirring at 85 - 90 C for approximately 6.5 hours, fee reaction was sampled for reaction completion. Stirring may be performed under any of the temperatures suited for the hydrolysis. The solution was then cooled to 20 - 25 C and filtered. The reactor/cake was rinsed wife H2?> (2 vol x 2), The cake was then washed with 2 vol 0 until fee pH > 3.0, The cake was then dried under vacuum at 60 C to give Compound 26. | |
With water; sodium hydroxide; In ethanol; for 16h;Reflux; | Method 1[00326] Compound 25 (1.0 eq) was suspended in a solution ofHCl (10.0 eq) and H20 (11.6vol). The slurry was heated to 85 - 90 C, although alternative temperatures are also suitable forthis hydrolysis step. For example, the hydrolysis can alternatively be performed at a temperatureof from about 75 to about 100 C. In some instances, the hydrolysis is performed at atemperature of from about 80 to about 95 C. In others, the hydrolysis step is performed at atemperature of from about 82 to about 93 oc (e.g., from about 82.5 to about 92.5 oc or fromabout 86 to about 89 C). After stirring at 85 - 90 oc for approximately 6.5 hours, the reactionwas sampled for reaction completion. Stirring may be performed under any of the temperaturessuited for the hydrolysis. The solution was then cooled to 20 - 25 oc and filtered. Thereactor/cake was rinsed with H20 (2 vol x 2). The cake was then washed with 2 vol H20 untilthe pH 2: 3.0. The cake was then dried under vacuum at 60 octo give compound 26.Method 2[00327] Compound 25 (11.3 g, 52 mmol) was added to a mixture of 10% NaOH (aq) (10 mL)and ethanol (100 mL). The solution was heated to reflux for 16 hours, cooled to 20-25 oc andthen the pH was adjusted to 2-3 with 8% HCl. The mixture was then stirred for 0.5 hours andfiltered. The cake was washed with water (50 mL) and then dried in vacuo to give compound 26as a brown solid. 1H NMR (DMSO-d6; 400 MHz) 8 15.33 (s), 8 13.39 (s), 8 8.87 (s), 8 8.26 (m),8 7.87 (m), 8 7.80 (m), 8 7.56 (m). | |
7.5 g | With water; sodium hydroxide; at 80 - 85℃; for 3h; | In a clean round bottom flask, ethyl 4-oxo-l, 4-dihydroquinoline-3-carboxylate (10.0 gm) was charged to a solution of sodium hydroxide (3.7 gm) in 13.0 ml water. The reaction mass was heated for 3.0 hr at 80-85 C and then cooled to 25-30. To this was added 0.10 gm of activated charcoal and filtered. The pH was adjusted using con HCL and the product was filtered and washed with water. The wet cake slurried in methanol at 25 -30 C and filtered. The product was dried under vacuum at 50.0 C to get 7.50 gm of title productPurity by HPLC - 99.75 % |
Compound 25 (11.3 g, 52 mmol) was added to a mixture of 10% NaOH (aq) (10 mL) and ethanol (100 mL). The solution was heated to reflux for 16 hours, cooled to 20-25 C. and then the pH was adjusted to 2-3 with 8% HCl. The mixture was then stirred for 0.5 hours and filtered. The cake was washed with water (50 mL) and then dried in vacuo to give Compound 26 as a brown solid. 1H NMR (DMSO-d6; 400 MHz) delta 15.33 (s), delta 13.39 (s), delta 8.87 (s), delta 8.26 (m), delta 7.87 (m), delta 7.80 (m), delta 7.56 (m). | ||
With hydrogenchloride; In water; at 85 - 90℃; | Method 1 [00341] Compound 25 (1.0 eq) was suspended in a solution of HC1 (10.0 eq) and H20 (1 1.6 vol). The slurry was heated to 85 - 90 C, although alternative temperatures are also suitable for this hydrolysis step. For example, the hydrolysis can alternatively be performed at a temperature of from about 75 to about 100 C. In some instances, the hydrolysis is performed at a temperature of from about 80 to about 95 C. In others, the hydrolysis step is performed at a temperature of from about 82 to about 93 C (e.g., from about 82.5 to about 92.5 C or from about 86 to about 89 C). After stirring at 85 - 90 C for approximately 6.5 hours, the reaction was sampled for reaction completion. Stirring may be performed under any of the temperatures suited for the hydrolysis. The solution was then cooled to 20 - 25 C and filtered. The reactor/cake was rinsed with H20 (2 vol x 2). The cake was then washed with 2 vol H20 until the pH > 3.0. The cake was then dried under vacuum at 60 C to give compound 26. | |
With sodium hydroxide; at 90 - 100℃; | Step c : 4-Oxo 1,4-dihydroquinoline- 3-carboxylic acid 4-hydroxyquinoline 3- carboxylic acid ethyl ester (100 g) was suspended in 2N sodium hydroxide solution at room temperature and was heated to 90-100 C. and maintained for 2-4 hours. After completion, the reaction mass was cooled to room temperature and filtered to remove undissolved material. The obtained filtrate was acidified to pH 3-4 with 2N Hydrochloric acid at 25-30 C. The resultant solid was filtered, washed with water and dried at 50 C. until constant weight was observed to obtain the title compound (55-65 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium hydride In N,N-dimethyl-formamide at 90℃; for 3h; | |
With potassium carbonate In N,N-dimethyl-formamide at 100℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With sodium hydride In N,N-dimethyl-formamide at 90℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium hydride In N,N-dimethyl-formamide at 90℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With sodium hydride In N,N-dimethyl-formamide at 90℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With sodium hydride In N,N-dimethyl-formamide at 90℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With sodium hydride In N,N-dimethyl-formamide at 90℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: NaH / dimethylformamide / 20 °C 1.2: 75 percent / dimethylformamide / 6 h / 90 °C 2.1: 75 percent / aq. NaOH / ethanol / 3 h / Heating | ||
Multi-step reaction with 2 steps 1: lithium hydroxide; water / tetrahydrofuran / 24 h / 0 - 80 °C 2: N-ethyl-N,N-diisopropylamine / acetonitrile / 0 - 80 °C | ||
Multi-step reaction with 2 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 0.08 h / 40 °C / Inert atmosphere 1.2: 4.5 h / 80 °C 2.1: sodium hydroxide; water / acetone / 5.5 h / 20 - 70 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
PREPARATION I Freshly distilled aniline (46.5 g) and diethyl ethoxymethylene malonate (108 g) were heated together on a steam bath for two hours. The ethanol formed in the reaction was then evaporated off under vacuum to give the intermediate diethyl (anilinomethylene)malonate, m.p. 48 C. The above intermediate was then cyclised by adding it to 1200 ml of boiling diphenyl ether, the reaction being carried out under a nitrogen atmosphere. Boiling and efficient stirring was continued until evolution of ethanol ceased (about twenty five minutes). The reaction mixture was cooled to room temperature, causing precipitation of a buff solid, and stirred for half an hour with an equal volume of n-hexane. Filtration, washing of the solid with more hexane and drying gave the compound ethyl 4(1H)-quinolone-3-carboxylate, which was recrystallized from DMF/H2 O, m.p. 266 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With palladium 10% on activated carbon; hydrazine hydrate In ethanol at 23℃; for 0.5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: ethanol / Reflux 2: diphenylether / Reflux | ||
Multi-step reaction with 2 steps 1: ethanol / Reflux 2: Dowtherm A / Reflux | ||
Multi-step reaction with 2 steps 1: 2 h / 125 - 130 °C 2: diphenylether / Reflux |
Multi-step reaction with 2 steps 1: toluene / Reflux 2: diphenylether / 280 °C / Reflux | ||
Multi-step reaction with 2 steps 1: ethanol / 3 h / 30 - 110 °C / Inert atmosphere 2: ethanol; diphenylether / 3.5 h / 228 - 232 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: neat (no solvent) / 4 h / 120 °C 2: Eaton’s reagent / 3.5 h / 100 °C | ||
Multi-step reaction with 2 steps 1: 1 h / 100 °C 2: diphenylether / 2 h / 240 °C | ||
Multi-step reaction with 2 steps 1: 2.5 h / 100 - 110 °C / Inert atmosphere 2: diphenylether / 3.5 h / 228 - 232 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: 2 h / 140 - 150 °C 2: diphenylether / 3.5 h / 228 - 232 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: 16.5 h / 120 - 130 °C 2: diphenylether / 4 h / 260 °C | ||
Multi-step reaction with 2 steps 1: 1 h / 120 °C 2: ortho-chlorobenzoic acid / 2 h / 250 °C / Microwave irradiation | ||
Multi-step reaction with 2 steps 1.1: neat (no solvent) / 6 h / 20 - 165 °C 1.2: 20 - 115 °C 2.1: diphenylether / 228 - 232 °C | ||
Multi-step reaction with 2 steps 1: 100 °C 2: Dowtherm A / 2 h / 250 °C | ||
Multi-step reaction with 2 steps 1: ethanol / 1 h / Reflux; Inert atmosphere; Schlenk technique 2: diphenylether / 0.75 h / 250 °C / Inert atmosphere; Schlenk technique | ||
Multi-step reaction with 2 steps 1: ethanol / 1 h / Reflux; Inert atmosphere; Schlenk technique 2: diphenylether / 0.75 h / 250 °C / Schlenk technique; Inert atmosphere | ||
Multi-step reaction with 2 steps 1: 3 h / 30 - 110 °C / Inert atmosphere 2: diphenylether / 3.5 h / 228 - 232 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: ethanol / 2.5 h / Reflux 2: 2 h / 250 °C / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: ethanol / Reflux 2: diphenylether / Reflux | ||
Multi-step reaction with 2 steps 1: ethanol / Reflux 2: Dowtherm A / Reflux | ||
Multi-step reaction with 2 steps 1: 2 h / 125 - 130 °C 2: diphenylether / Reflux |
Multi-step reaction with 2 steps 1: toluene / Reflux 2: diphenylether / 280 °C / Reflux | ||
Multi-step reaction with 2 steps 1: ethanol / 3 h / 30 - 110 °C / Inert atmosphere 2: ethanol; diphenylether / 3.5 h / 228 - 232 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: neat (no solvent) / 4 h / 120 °C 2: Eaton’s reagent / 3.5 h / 100 °C | ||
Multi-step reaction with 2 steps 1: 1 h / 100 °C 2: diphenylether / 2 h / 240 °C | ||
Multi-step reaction with 2 steps 1: 2.5 h / 100 - 110 °C / Inert atmosphere 2: diphenylether / 3.5 h / 228 - 232 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: 2 h / 140 - 150 °C 2: diphenylether / 3.5 h / 228 - 232 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: 16.5 h / 120 - 130 °C 2: diphenylether / 4 h / 260 °C | ||
Multi-step reaction with 2 steps 1: 1 h / 120 °C 2: ortho-chlorobenzoic acid / 2 h / 250 °C / Microwave irradiation | ||
Multi-step reaction with 2 steps 1.1: neat (no solvent) / 6 h / 20 - 165 °C 1.2: 20 - 115 °C 2.1: diphenylether / 228 - 232 °C | ||
Multi-step reaction with 2 steps 1: 100 °C 2: Dowtherm A / 2 h / 250 °C | ||
Multi-step reaction with 2 steps 1: ethanol / 1 h / Reflux; Inert atmosphere; Schlenk technique 2: diphenylether / 0.75 h / 250 °C / Inert atmosphere; Schlenk technique | ||
Multi-step reaction with 2 steps 1: ethanol / 1 h / Reflux; Inert atmosphere; Schlenk technique 2: diphenylether / 0.75 h / 250 °C / Schlenk technique; Inert atmosphere | ||
Multi-step reaction with 2 steps 1: 3 h / 30 - 110 °C / Inert atmosphere 2: diphenylether / 3.5 h / 228 - 232 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: ethanol / 2.5 h / Reflux 2: 2 h / 250 °C / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 48h; | 1.1. General procedures for the syntheses of ethyl 1-[(diisopropoxyphosphoryl)methyl]-4-oxo-1,4-dihydroquinoline-3-carboxylates 3a-3k General procedure: The appropriate oxoquinoline derivative 5 (1.75 mmol) was stirred for 15 minutes in the presence of 750.0 mg of K2CO3 and 5.0mL of DMF, followed by the addition of diisopropyl(tosylmethoxy)phosphonate 4 (3.50 mmol). The reaction mixture was additionally stirred for 48 h at 80 °C. Afterwards, the resulting mixture was poured into water (30 mL) and extracted with methylene chloride (3 x 20 mL). The combined organic extracts were washed with water (3 x 20 mL), dried over anhydrous magnesium sulfate, filtered and evaporated, giving rise to ethyl 1-[(diisopropoxyphosphoryl)methyl]-4-oxo-1,4-dihydroquinoline-3-carboxylates 3a-3k which were purified by crystallization from ethyl ether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With hydrazine hydrate In ethanol; water at 55℃; | |
With hydrazine hydrate In ethanol for 12h; Reflux; | Preparation of substituted-1,4-dihydro-4-oxoquinoline-3-carbohydrazide derivatives 5 General procedure: Substituted-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester 4 (0.01 mol) wasrefluxed for 12 h with hydrazine monohydrate (0.01mol) in absolute ethanol ( 9 mL) to give substituted-4-oxo-1,4-dihydroquinoline-3-carbohydrazide 5.The excess solvent was evaporated off and theresulting mixture was poured into crushed ice. Thesolid separated was filter on sintered funnel,washed with water and dried. The crude solid waspurified by recrystallized from Dioxane: ethanol togive 5 as white solid. Purity of the compound waschecked on silica gel TLC plates. TLC was run inchloroform-methanol (9:1) as eluent. | |
With hydrazine hydrate In ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In diphenylether at 210℃; for 1h; | 3.2.3. General Procedure for the Synthesis of Oxoquinolines 10-18 General procedure: Oxoquinolines 9a-c(8 mmol) were reacted with the appropriate amine (8 mmol) in diphenyl ether(30 mL) at 210 °C under magnetic stirring for 1 h. The resulting mixture was poured into petroleum ether. The obtained solid was filtered and recrystallized from dichloromethane/petroleum ether (1/1) to yield the derivatives listed below [28-30]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In diphenylether at 210℃; for 1h; | 3.2.3. General Procedure for the Synthesis of Oxoquinolines 10-18 General procedure: Oxoquinolines 9a-c(8 mmol) were reacted with the appropriate amine (8 mmol) in diphenyl ether(30 mL) at 210 °C under magnetic stirring for 1 h. The resulting mixture was poured into petroleum ether. The obtained solid was filtered and recrystallized from dichloromethane/petroleum ether (1/1) to yield the derivatives listed below [28-30]. |
In diphenylether at 210℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In diphenylether at 210℃; for 1h; | 3.2.3. General Procedure for the Synthesis of Oxoquinolines 10-18 General procedure: Oxoquinolines 9a-c(8 mmol) were reacted with the appropriate amine (8 mmol) in diphenyl ether(30 mL) at 210 °C under magnetic stirring for 1 h. The resulting mixture was poured into petroleum ether. The obtained solid was filtered and recrystallized from dichloromethane/petroleum ether (1/1) to yield the derivatives listed below [28-30]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In diphenylether at 210℃; for 1h; | 3.2.3. General Procedure for the Synthesis of Oxoquinolines 10-18 General procedure: Oxoquinolines 9a-c(8 mmol) were reacted with the appropriate amine (8 mmol) in diphenyl ether(30 mL) at 210 °C under magnetic stirring for 1 h. The resulting mixture was poured into petroleum ether. The obtained solid was filtered and recrystallized from dichloromethane/petroleum ether (1/1) to yield the derivatives listed below [28-30]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | In diphenylether at 210℃; for 1h; | 3.2.3. General Procedure for the Synthesis of Oxoquinolines 10-18 General procedure: Oxoquinolines 9a-c(8 mmol) were reacted with the appropriate amine (8 mmol) in diphenyl ether(30 mL) at 210 °C under magnetic stirring for 1 h. The resulting mixture was poured into petroleum ether. The obtained solid was filtered and recrystallized from dichloromethane/petroleum ether (1/1) to yield the derivatives listed below [28-30]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In diphenylether at 210℃; for 1h; | 3.2.3. General Procedure for the Synthesis of Oxoquinolines 10-18 General procedure: Oxoquinolines 9a-c(8 mmol) were reacted with the appropriate amine (8 mmol) in diphenyl ether(30 mL) at 210 °C under magnetic stirring for 1 h. The resulting mixture was poured into petroleum ether. The obtained solid was filtered and recrystallized from dichloromethane/petroleum ether (1/1) to yield the derivatives listed below [28-30]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | In diphenylether at 210℃; for 1h; | 3.2.3. General Procedure for the Synthesis of Oxoquinolines 10-18 General procedure: Oxoquinolines 9a-c(8 mmol) were reacted with the appropriate amine (8 mmol) in diphenyl ether(30 mL) at 210 °C under magnetic stirring for 1 h. The resulting mixture was poured into petroleum ether. The obtained solid was filtered and recrystallized from dichloromethane/petroleum ether (1/1) to yield the derivatives listed below [28-30]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | In diphenylether at 210℃; for 1h; | 3.2.3. General Procedure for the Synthesis of Oxoquinolines 10-18 General procedure: Oxoquinolines 9a-c(8 mmol) were reacted with the appropriate amine (8 mmol) in diphenyl ether(30 mL) at 210 °C under magnetic stirring for 1 h. The resulting mixture was poured into petroleum ether. The obtained solid was filtered and recrystallized from dichloromethane/petroleum ether (1/1) to yield the derivatives listed below [28-30]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With N-ethyl-N,N-diisopropylamine In acetonitrile at 0 - 80℃; for 22h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: diethyl 2-ethoxymethylenemalonate; toluene at 100 - 110℃; for 2.5h; Inert atmosphere; Stage #2: In diphenylether at 228 - 232℃; for 3.5h; | 1a Example 1a Ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate (25) Compound 23 (4.77 g, 47.7 mmol) was added dropwise to Compound 22 (10 g, 46.3 mmol) with subsurface N2 flow to drive out ethanol below 30° C. for 0.5 hours. The solution was then heated to 100-110° C. and stirred for 2.5 hours. After cooling the mixture to below 60° C., diphenyl ether was added. The resulting solution was added dropwise to diphenyl ether that had been heated to 228-232° C. for 1.5 hours with subsurface N2 flow to drive out ethanol. The mixture was stirred at 228-232° C. for another 2 hours, cooled to below 100° C. and then heptane was added to precipitate the product. The resulting slurry was stirred at 30° C. for 0.5 hours. The solids were then filtered, and the cake was washed with heptane and dried in vacuo to give Compound 25 as a brown solid. 1H NMR (DMSO-d6; 400 MHz) δ 12.25 (s), δ 8.49 (d), δ 8.10 (m), δ 7.64 (m), δ 7.55 (m), δ 7.34 (m), δ 4.16 (q), δ 1.23 (t). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 20℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 20℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With sodium hydride In tetrahydrofuran at 0℃; for 5h; Inert atmosphere; Reflux; | 4 General procedure for the synthesis of derivatives 17b, 17d, 17f General procedure: A well stirred solution of the appropriate 4-hydroxy-quinoline (4.6 mmol) in anhydrous THF (60 mL) was cooled at 0 °C and treated with NaH (9.2 mmol, 0.36 g) under argon atmosphere. Methyl 4-(bromomethyl)benzoate (9.2 mmol, 2.1 g) was then added into the suspension and the mixture was refluxed for 5 h and monitored by TLC (SiO2) using ethyl acetate/ethanol 10:1 as eluent. When the starting material disappeared, the reaction was cooled at 0 °C and saturated solution of NH4Cl was added till all the excess of NaH was neutralized. The organic solvent was then removed under reduced pressure, and the aqueous residue was extracted with ethyl acetate (3 x 25 mL). The organic phase was then washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The raw material was then purified with a column chromatography using ethyl acetate/ethanol 10:1 as eluent, to obtain the required alkylated quinolinone. 4.1.4 Ethyl 1-(4-(methoxycarbonyl)benzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (17f) Starting material, ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate (20, 1.2 g); 17f was obtained as a white solid (88% yield); 176-177 °C; crystallized from ethanol; IR ν 1717 (C=O quinolinone), 1678 (C=O ester), 1645 (ester) cm-1. 1H NMR (DMSO-d6) δ 1.30 (t, 3H, J = 7.2 Hz, CH3CH2), 3.82 (s, 3H, OCH3), 4.27 (q, 4H, J = 7.2 Hz, CH2CH3), 5.79 (s, 2H, CH2 benzyl), 7.37 (d, 2H, Jo = 8.0 Hz, benzene H), 7.42 (t, 1H, J5-6 = J6-7 = 8.0 Hz, quinolinone C6-H), 7.53 (d, 1H, J7-8 = 8.4 Hz, quinolinone C8-H), 7.66 (t, 1H, J7-8 = J6-7 = 8.0 Hz, quinolinone C7-H), 7.94 (d, 2H, Jo = 8.0 Hz, benzene H), 8.26 (d, 1H, J5-6 = 8.0 Hz, quinolinone C5-H), 8.97 (s, 1H, quinolinone C2-H). Anal. (C21H19NO5) calc. C, 69.03; H, 5.24; N, 3.83; found C, 69.21; H, 5.13; N, 3.70. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With nitronium tetrafluoborate In acetonitrile at 20℃; for 0.0833333h; regioselective reaction; | General Procedure of Nitration Reaction (Compounds 1a-8h) General procedure: A mixture 4-quinolone-3-carboxylate (1mmol) in 5 ml dry acetonitrile was taken in a 25-ml round-bottom flask. Then, 2 mmol (0.266g) of NTFB (nitronium tetrafluroborate) was added into it at a time. The reaction mixture was stirred at room temperature for 5 min. The progress of reaction was monitored by TLC, and upon completion the reaction mixture was poured into the ice water and a yellow solid appeared. The yellow solid material was collected and dried completely. The crude material was further purified by the silica-gel column chromatography using ethyl acetate and petroleum ether as an eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With potassium carbonate In N,N-dimethyl-formamide at 40 - 80℃; for 18h; | 35 Ethyl 1 -(2-fluorobenzyl)-4-oxo- 1 ,4-dihydroquinoline-3 -carboxylate To a suspension of ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (lg, 4.60 mmol) and K2C03 (1.20 g, 8.60 mmol) in DMF (7 mL) at 40 °C was added 2-fluorobenzylbromide (2.02 mL, 16.75 mmol) dropwise. The reaction mixture was stirred at 80 °Cfor 18 h. Solvent was removed under reduced pressure and the product purified byflash chromatography using a gradient of 0-20% MeOH in EtOAc to give the titleproduct (1.106 g, 74%) as a white powder.HRIVIS m/z (El) 325.11090, calculated for C19H16NO3F 325.11087. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium carbonate In N,N-dimethyl-formamide at 40 - 80℃; for 18h; | 36 Compound 148Ethyl 4-oxo- 1 -(4-(trifluoromethoxy)benzyl)- 1 ,4-dihydroquinoline-3 -carboxylate To a suspension of ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (lg, 4.60 mmol)and K2C03 (1.20 g, 8.60 mmol) in DMF (7 mL) at 40 °C was added 4-trifluoromethoxybenzyl bromide (2.68 mL, 16.75 mmol) dropwise. The reactionmixture was stirred at 80 °C for 18 h. Solvent was removed under reduced pressureand the product purified by flash chromatography using a gradient of 0-20% MeOH in EtOAc to give the title product (1.56 g, 87%) as a white powder.HRIVIS m/z (El) 391.10268, calculated for C2oH,6NO4F3 391.10259. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium carbonate In N,N-dimethyl-formamide at 40 - 80℃; for 18h; | 37 Ethyl 1 -ethyl-4-oxo- 1 ,4-dihydroquinoline-3 -carboxylate To a suspension of ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (lg, 4.60 mmol)and K2C03 (1.20 g, 8.60 mmol) in DMF (7 mL) at 40 °C was added bromoethane(1.25 mL, 16.75 mmol) dropwise. The reaction mixture was stirred at 80 °C for 18 h.Solvent was removed under reduced pressure and the product purified by flashchromatography using a gradient of 0-20% MeOH in EtOAc to give the title product(921 mg, 82%) as a white powder.HRIVIS m/z (El) 245.10481, calculated for C,4H,5NO3 245.10464; ‘H NIVIR (500IVIHz, CDC13) 8.53 (s, 1H, aromatic), 8.51 (dd, J = 8.1, 1.6, 1H, aromatic), 7.66(ddd, J= 8.6, 7.1, 1.6, 1H, aromatic), 7.45 (d, J= 8.5, 1H, aromatic), 7.43 -7.38 (m,1H, aromatic), 4.37 (q, J= 7.1, 2H, CH2CH3), 4.26 (q, J= 7.3, 2H, CH2CH3), 1.52 (t,J 7.3, 3H, CH2CH3), 1.38 (t, J= 7.1, 3H, CH2CH3); ‘3C NIVIR (126 MHz, CDC13)174.40 (CO), 166.22 (CO), 148.85 (aromatic), 138.82 (aromatic), 132.88 (aromatic),129.29 (aromatic), 128.28 (aromatic), 125.31 (aromatic), 115.76 (aromatic), 111.08 (aromatic), 61.15 (CH2CH3), 49.11 (CH2CH3), 14.71 (CH2CH3), 14.62 (CH2CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With potassium carbonate In N,N-dimethyl-formamide at 40 - 80℃; for 18h; | 38 Compound 150Ethyl 1 -(3 -chlorobenzyl)-4-oxo- 1 ,4-dihydroquinoline-3 -carboxylate To a suspension of ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (lg, 4.60 mmol)and K2C03 (1.20 g, 8.60 mmol) in DMF (7 mL) at 40 °C was added 3-chlorobenzylbromide (2.2 mL, 16.75 mmol) dropwise. The reaction mixture was stirred at 80 °C for 18 h. Solvent was removed under reduced pressure and the product purified by flash chromatography using a gradient of 0-20% MeOH in EtOAc to give the title product (805 mg, 51%) as a white powder.HRIVIS m/z (El) 341.08162, calculated for C19H16NO335Cl 341.08132; ‘HNMR (500 IVIHz, CDC13) 8.62 (s, 1H, aromatic), 8.52 (dd, J = 8.1, 1.5, 1H, aromatic), 7.55 (ddd, J= 8.6, 7.1, 1.6, 1H, aromatic), 7.43 - 7.37 (m, 1H, aromatic), 7.30 - 7.25 (m, 3H, aromatic), 7.15 (s, 1H, aromatic), 7.03 -6.98 (m, 1H, aromatic), 5.38 (s, 2H, BnCH 2), 4.39 (q, J= 7.1, 2H, CH2CH3), 1.40 (t, J= 7.1, 3H, CH2CH3); ‘3C NIVIR (126IVIHz, CDC13) 174.50 (CO), 165.99 (CO), 149.96 (aromatic), 139.18 (aromatic),136.59 (aromatic), 135.63 (aromatic), 133.08 (aromatic), 130.91 (aromatic), 129.24 (aromatic), 129.08 (aromatic), 128.23 (aromatic), 126.40 (aromatic), 125.65(aromatic), 124.29 (aromatic), 116.56 (aromatic), 111.57 (aromatic), 61.37 (Bn-CH2),57.02 (CH2CH3), 14.63 (CH2CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With potassium carbonate; In N,N-dimethyl-formamide; at 40 - 80℃; for 18.0h; | To a suspension of ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (lg, 4.60 mmol) and K2C03 (1.20 g, 8.60 mmol) in DMF (7 mL) at 40 C was added 4-methoxybenzyl chloride (2.28 mL, 16.75 mmol) dropwise. The reaction mixture was stirred at 80 C for 18 h. Solvent was removed under reduced pressure and the product purified by flash chromatography using a gradient of 0-20% MeOH in EtOAc to give the titleproduct (960 mg, 62%) as a white powder.HRIVIS m/z (El) 337.13145, calculated for C2oH,9NO4 337.13086; ?H NIVIR (500IVIHz, CDC13) 8.68 (s, 1H, aromatic), 8.51 (dd, J = 8.2, 1.6, 1H, aromatic), 7.56(ddd, J= 8.7, 7.2, 1.6, 1H, aromatic), 7.43 - 7.37 (m, 2H, aromatic), 7.28 (d, J= 8.5,1H, aromatic), 7.10 (d, J = 8.7, 1H, aromatic), 6.85 (dd, J = 8.7, 3.5, 2H, aromatic),5.37 (s, 2H, Bn-CH2), 4.39 (q, J= 7.1, 2H, CH2CH3), 3.75 (s, 3H, O-CH3), 1.40 (t, J7.1, 3H, CH2CH3); ?3C NIVIR (126 IVIFIz, CDC13) 174.54 (CO), 166.20 (CO), 159.97(aromatic), 149.87 (aromatic), 139.41 (aromatic), 132.97 (aromatic), 130.46(aromatic), 129.11 (aromatic), 128.83 (aromatic), 128.04 (aromatic), 127.90(aromatic), 126.13 (aromatic), 125.55 (aromatic), 116.84 (aromatic), 114.93(aromatic), 114.12 (aromatic), 61.34 (Bn-CH2), 57.31 (CH2CH3), 55.52 (O-CH3),14.62 (CH2CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With potassium carbonate; In N,N-dimethyl-formamide; at 40 - 80℃; for 18h; | To a suspension of ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (lg, 4.60 mmol) and K2C03 (1.20 g, 8.60 mmol) in DMF (7 mL) at 40 C was added 3,5- dimethylbenzyl bromide (3.33 g, 16.75 mmol) dropwise. The reaction mixture wasstirred at 80 C for 18 h. Solvent was removed under reduced pressure and the product purified by flash chromatography using a gradient of 0-20% MeOH in EtOAc to give the title product (850 mg, 55%) as a white powder.HRIVIS m/z (El) 335.15192, calculated for C2,H2,NO3 335.15160; ?H NIVIR (500 IVIHz, CDC13) 8.61 (s, 1H, aromatic), 8.54 (d, J= 8.0, 1H, aromatic), 7.55 (t, J= 7.7,1H, aromatic), 7.39 (t, J= 7.5, 1H, aromatic), 7.34 (d, J= 8.5, 1H, aromatic), 6.94 (s,1H, aromatic), 6.75 (s, 2H, aromatic), 5.32 (s, 2H, Bn-CH2), 4.41 (q, J = 7.1, 2H,CH2CH3), 2.26 (s, 6H 2 x aromatic-CH3), 1.42 (t, J = 7.1, 3H, CH2CH3); ?3C NIVIR(126 IVIFIz, CDC13) 174.56 (CO), 166.08 (CO), 149.96 (aromatic), 139.34(aromatic), 139.20 (aromatic), 134.24 (aromatic), 132.73 (aromatic), 130.32(aromatic), 129.26 (aromatic), 127.93 (aromatic), 125.27 (aromatic), 123.83(aromatic), 116.70 (aromatic), 111.11 (aromatic), 61.10 (Bn-CH2), 57.59 (CH2CH3), 21.36 (aromatic-CH3), 14.52 (CH2CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With potassium carbonate In N,N-dimethyl-formamide at 40 - 80℃; for 18h; | 41 Compound 153Ethyl 1 -(2-chlorobenzyl)-4-oxo- 1 ,4-dihydroquinoline-3 -carboxylate To a suspension of ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (lg, 4.60 mmol) and K2C03 (1.20 g, 8.60 mmol) in DMF (7 mL) at 40 °C was added 2-chlorobenzylbromide (2.16 mL, 16.75 mmol) dropwise. The reaction mixture was stirred at 80 °C for 18 h. Solvent was removed under reduced pressure and the product purified by flash chromatography using a gradient of 0-20% MeOH in EtOAc to give the title product (452 mg, 29%) as a white powder.HRIVIS m/z (El) 341.08157, calculated for C19H16NO335Cl 341.08132; ‘HNMR (500IVIHz, CDC13) 8.61 (s, 1H, aromatic), 8.51 (dd, J = 8.1, 1.5, 1H, aromatic), 7.57(ddd, J= 8.6, 7.1, 1.6, 1H, aromatic), 7.46 (dd, J= 8.0, 0.9, 1H, aromatic), 7.41 - 7.36(m, 1H, aromatic), 7.32-7.25 (m, 1H, aromatic), 7.22 (d, J= 8.6, 1H, aromatic), 7.14(td, J= 7.7, 1.1, 1H, aromatic), 6.78 (d, J= 7.1, 1H, aromatic), 5.49 (s, 2H, Bn-CH2),4.37 (q, J 7.1, 2H, CH2CH3), 1.38 (t, J 7.1, 3H, CH2CH3); ‘3C NIVIR (126 MHz,CDC13) 174.96 (CO), 165.88 (CO), 150.05 (aromatic), 139.29 (aromatic), 136.94(aromatic), 133.23 (aromatic), 132.57 (aromatic), 131.89 (aromatic), 130.92(aromatic), 130.32 (aromatic), 130.04 (aromatic), 128.13 (aromatic), 127.88(aromatic), 127.49 (aromatic), 125.67 (aromatic), 116.59 (aromatic), 61.33 (Bn-CH2),55.11 (CH2CH3), 14.61 (CH2CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triethylamine In 1,4-dioxane; water at 20℃; for 18h; | 44 Compound 1561 -tert-Butyl 3-ethyl 4-oxoquinoline- 1,3 (41])-dicarboxylate To a suspension of ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (500 mg, 2.30 mmol) in 1:1 H20/1,4-dioxane (4 mL) was added Et3N, (700 tL, 5.02 mmol) followed by di-tert-butyl dicarbonate (750 mg, 3.44 mmol). The reaction mixture was stirred at room temperature for 18 h. Water (25 mLO and EtOAc were added to the reaction mixture and the layers separated. The aqueous layer was extracted withEtOAc (2 x 50 mL) and the combined organic fractions were dried over Mg504, filtered and evaporated to give the title product (691 mg, 95%) as a white powder.HRIVIS m/z (El) 3 17.12627, calculated for C,7H,9NO5 3 17.12577. ‘HNIVIR (500 IVIHz, CDC13) 9.12 (s, 1H, aromatic), 8.47 (d, J= 8.8, 1H, aromatic), 8.43 (dd, J= 8.0, 1.7, 1H, aromatic), 7.65 (ddd, J= 8.8, 7.1, 1.8, 1H, aromatic), 7.44 (ddd, J = 8.0, 7.1, 0.9, 1H, aromatic), 4.39 (q, J = 7.1, 2H, CH2CH3), 1.68 (s, 9H,C(CH3)3), 1.39 (t, J = 7.1, 3H, CH2CH3); ‘3C NIVIR (126 IVIHz, CDC13) 175.11(CO), 165.04 (CO), 149.45 (CO), 145.22 (aromatic), 137.72 (aromatic), 133.07(aromatic), 128.22 (aromatic), 127.59 (aromatic), 126.27 (aromatic), 119.96(aromatic), 113.58 (aromatic), 88.12 (C(CH3)3), 61.54 (CH2CH3), 28.09 (C(CH3)3),14.53 (CH2CH3). |
74% | With triethylamine In N,N-dimethyl-formamide at 20℃; for 0.916667h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.6% | In ethanol for 6h; Reflux; | 17 Compound 26 (31.1 g, 0.1 mol), compound 6 (26 g, 0.12 mol) was added to 300 mL of anhydrous ethanol in 500 mL of a three-necked flask. The reaction mixture was heated under reflux for 6 h and then cooled, 500 mL of n-hexane was added, , Filter, filter cake and then added to the isopropyl alcohol 300mL, the temperature to reflux, all dissolved. The insoluble material was filtered and the mixture was stirred at room temperature for 1 h and filtered to give a white solid, which was compound 7, yield 36.5 g and 75.6% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.3% | In toluene at 120 - 230℃; for 4.5h; Autoclave; | 12 To the high pressure autoclave, Compound 5 (2-(sodium oxymethylene)diethyl malonate) (21 g, 0.1 mol), Toluene 200mL, Aniline (10.2 g, 0.11mol), Stirred and mixed, Slowly warming to 120 °C, Insulation mixing 1.5h, And then slowly warming to 230 °C, the insulation stirring 3h, The pressure during the reaction was maintained at 1.5 to 2.0 atmospheres, After the reaction was cooled, the mixture was concentrated until dry, Then, 120 mL of n-hexane was added, stirred at room temperature for 2 h, The resulting solid was filtered, dried, That is, compound 6, yield 17.9g, yield 82.3%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: hydrogen / tetrahydrofuran / 6 h / 20 °C / 760.05 Torr 2: toluene / 6 h / 100 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.56 g | With <i>N</i>,<i>N</i>-dimethyl-formamide dimethyl acetal In ethyl acetate for 0.666667h; | 4 Example 4: Synthesis of Ethyl 4-oxo-l,4-dihydroquinoline-3-carboxylate (2) Experimental procedure :( Continues process) Example 4: Synthesis of Ethyl 4-oxo-l,4-dihydroquinoline-3-carboxylate (2): (0092) Indole-3-acetic acid ester 1(3 g, 14.77 mmol) was dissolved in acetone: water (50 mL, 2: 1), and loaded in syringe. Pump is used to pump this solution in syringe to a Tee junction where other inlet of Tee junction was connected to ozone generator where stream of 03 was passed to the Tee junction at 0 °C. Outlet of Tee junction was connected to the continuous flow reactor where reaction takes place. Outlet of the flow reactor is connected to 2-neck round bottom flask. Flow rate of substrate 1(1.0 mL/min) and O3/O2(1000 mL/min) gas was kept to have 2 sec residence time for overall reaction. One neck is used to evacuate excesses 03 for quenchingand from other neck product was transferred to the other round bottom flask under stirring where water (0.1 mL/min) and ethyl acetate (1.0 niL) was pumped. The mixed solution was then pumped to the separating funnel for layer separation. Ethylacetate layer was then pumped(0.4 mL/min) to another Tee junction where other inlet of Tee junction was connected to the syringe filled with DMF-DMA in ethylacetate (0.4mL/min; 10% v/v). Outlet of Tee connected to the continuous flow reactor to maintain the 40 min residence time.Reaction mass, collected from at the outlet of the flow reactor, was evaporated to give dark brown syrup. This crude material was added dropwise into cold H20 (75 mL) under stirring. The precipitates thus formed were filtered, washed with H20 (50 mL), dried to give off-white solid (yield: 1.56 g; 54%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With phosphorus(V) oxybromide at 120℃; for 8h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In diphenylether at 220℃; for 2h; Inert atmosphere; | 1 Example 1 Synthesis of 3-(2-benzothiazolyl)-4(1H)-quinolinone (Compound 3a). Compound 1 o-aminothiophenol was added to the round bottom flask in turn under electromagnetic stirring.Compound 2a and diphenyl ether, heated to 220 ° C with an electric heating jacket under nitrogen protection,The reaction was refluxed for 2 h; cooled to room temperature, a large amount of solid was precipitated, suction filtered, washed with petroleum ether, and then washed with dichloromethane, and the solid was placed in a vacuum oven at 60 ° CAfter drying for 3 h, compound 3a was obtained. 3a yield: 92%; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate; 1-Bromo-2-bromomethyl-benzene With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 2h; Stage #2: With tetrabutylammomium bromide; palladium diacetate In N,N-dimethyl-formamide at 20 - 80℃; for 3h; Inert atmosphere; | Phenanthridinone Derivatives 7 and 9; General Procedure General procedure: A mixture of the appropriate quinolone 1 (1 mmol), 2-bromobenzylbromide 5 or 8 (1.5 mmol), and K2CO3 (2 mmol) in anhydDMF (3 mL) was stirred at 80 °C for 2 h, then cooled to r.t. TBAB(1.5 equiv), K2CO3 (1.5 equiv), and Pd(OAc)2 (10 mol %) wereadded to the reaction vessel under argon, and the mixture washeated at 80 °C for 3 h. When the reaction was complete, themixture was cooled and diluted with H2O then extracted withEtOAc. The combined organic extracts were washed with H2Oand brine, dried (Na2SO4), filtered, and concentrated. Theresidue was purified by column chromatography [silica gel,CHCl3-MeOH (9:1)]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate; 2-bromo-5-fluorobenzyl bromide With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 2h; Stage #2: With tetrabutylammomium bromide; palladium diacetate In N,N-dimethyl-formamide at 20 - 80℃; for 3h; Inert atmosphere; | Phenanthridinone Derivatives 7 and 9; General Procedure General procedure: A mixture of the appropriate quinolone 1 (1 mmol), 2-bromobenzylbromide 5 or 8 (1.5 mmol), and K2CO3 (2 mmol) in anhydDMF (3 mL) was stirred at 80 °C for 2 h, then cooled to r.t. TBAB(1.5 equiv), K2CO3 (1.5 equiv), and Pd(OAc)2 (10 mol %) wereadded to the reaction vessel under argon, and the mixture washeated at 80 °C for 3 h. When the reaction was complete, themixture was cooled and diluted with H2O then extracted withEtOAc. The combined organic extracts were washed with H2Oand brine, dried (Na2SO4), filtered, and concentrated. Theresidue was purified by column chromatography [silica gel,CHCl3-MeOH (9:1)]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: 2-bromo-5-chlorobenzyl bromide; ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 2h; Stage #2: With tetrabutylammomium bromide; palladium diacetate In N,N-dimethyl-formamide at 20 - 80℃; for 3h; Inert atmosphere; | Phenanthridinone Derivatives 7 and 9; General Procedure General procedure: A mixture of the appropriate quinolone 1 (1 mmol), 2-bromobenzylbromide 5 or 8 (1.5 mmol), and K2CO3 (2 mmol) in anhydDMF (3 mL) was stirred at 80 °C for 2 h, then cooled to r.t. TBAB(1.5 equiv), K2CO3 (1.5 equiv), and Pd(OAc)2 (10 mol %) wereadded to the reaction vessel under argon, and the mixture washeated at 80 °C for 3 h. When the reaction was complete, themixture was cooled and diluted with H2O then extracted withEtOAc. The combined organic extracts were washed with H2Oand brine, dried (Na2SO4), filtered, and concentrated. Theresidue was purified by column chromatography [silica gel,CHCl3-MeOH (9:1)]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: 2-bromo-5-methoxybenzyl bromide; ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 2h; Stage #2: With tetrabutylammomium bromide; palladium diacetate In N,N-dimethyl-formamide at 20 - 80℃; for 3h; Inert atmosphere; | Phenanthridinone Derivatives 7 and 9; General Procedure General procedure: A mixture of the appropriate quinolone 1 (1 mmol), 2-bromobenzylbromide 5 or 8 (1.5 mmol), and K2CO3 (2 mmol) in anhydDMF (3 mL) was stirred at 80 °C for 2 h, then cooled to r.t. TBAB(1.5 equiv), K2CO3 (1.5 equiv), and Pd(OAc)2 (10 mol %) wereadded to the reaction vessel under argon, and the mixture washeated at 80 °C for 3 h. When the reaction was complete, themixture was cooled and diluted with H2O then extracted withEtOAc. The combined organic extracts were washed with H2Oand brine, dried (Na2SO4), filtered, and concentrated. Theresidue was purified by column chromatography [silica gel,CHCl3-MeOH (9:1)]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: 5-bromo-6-bromomethylbenzo[1,3]dioxole; ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 2h; Stage #2: With tetrabutylammomium bromide; palladium diacetate In N,N-dimethyl-formamide at 20 - 80℃; for 3h; Inert atmosphere; | Phenanthridinone Derivatives 7 and 9; General Procedure General procedure: A mixture of the appropriate quinolone 1 (1 mmol), 2-bromobenzylbromide 5 or 8 (1.5 mmol), and K2CO3 (2 mmol) in anhydDMF (3 mL) was stirred at 80 °C for 2 h, then cooled to r.t. TBAB(1.5 equiv), K2CO3 (1.5 equiv), and Pd(OAc)2 (10 mol %) wereadded to the reaction vessel under argon, and the mixture washeated at 80 °C for 3 h. When the reaction was complete, themixture was cooled and diluted with H2O then extracted withEtOAc. The combined organic extracts were washed with H2Oand brine, dried (Na2SO4), filtered, and concentrated. Theresidue was purified by column chromatography [silica gel,CHCl3-MeOH (9:1)]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Stage #1: 1-bromo-2-(bromomethyl)naphthalene; ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate With potassium carbonate In N,N-dimethyl-formamide at 80℃; Stage #2: With tetrabutylammomium bromide; palladium diacetate In N,N-dimethyl-formamide at 80℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In diphenylether at 210℃; | |
88% | In diphenylether at 210℃; for 0.166667h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In diphenylether at 220℃; for 2h; Inert atmosphere; | S1; 17 Example 17: Preparation of Compound 4a. Compound 1a, o-aminophenol, and diphenyl ether were sequentially added to a 50 mL single-mouth flask under electromagnetic stirring.The reaction was heated to reflux under nitrogen for 2 h (TLC monitoring reaction, developing solvent: V dichloromethane: V ethyl acetate: V methanol = 9:3:1),After completion of the reaction, a large amount of solid was precipitated, suction filtered, washed with petroleum ether (10 mL×5) to give a pale yellow solid (Comp. 4a).The yield was 90%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In diphenylether at 220℃; for 2h; Inert atmosphere; | S1; 1 Example 1: Preparation of Compound 3a. Compound 1a o-aminothiophenol and diphenyl ether were sequentially added to a 50 mL single-mouth flask under electromagnetic stirring.The reaction was heated to reflux under nitrogen for 2 h (TLC monitoring reaction, developing solvent: V dichloromethane: V ethyl acetate: V methanol = 9:3:1),After completion of the reaction, a large amount of solid was precipitated, suction filtered, washed with petroleum ether (10 mL × 5) to give a pale yellow solid (Compound 3a).The yield was 90%. |
In diphenylether at 220℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: orthoformic acid triethyl ester; aniline; diethyl malonate at 130℃; for 24h; Stage #2: In diphenylether for 0.75h; Reflux; | 4 The preparation method comprises the following steps: In the first step, with stirring, diethyl malonate, triethyl orthoformate and aniline are used as raw materials.The three components are put into the reactor together, and the temperature is raised to 130 ° C to keep the reaction for 24 hours.Continue to add diphenyl ether reflux,After a large amount of solids are precipitated, the reaction is stopped to obtain a quinolone compound. Vacuum filtration,It was washed with petroleum ether, ethyl acetate and methanol, and dried to give a quinolone compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With ethanol; for 24h;Reflux; | General procedure: To the desired <strong>[13720-94-0]ethyl 4-chloro-quinoline-3-carboxylate</strong> derivative (1 - 2 mmol) was added 5 mL dryethanol. This solution was refluxed for 24 h or monitored by TLC analysis. The reaction mixture wascooled after the starting material was fully consumed (judged by TLC) and gave a white precipitation.The white solid was centrifuged, the liquid carefully removed and the solid was washed with EtOAcand centrifuged 2-3 times to leave a pure off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54.2% | With potassium carbonate In N,N-dimethyl-formamide at 80℃; Inert atmosphere; | 19.2 Step 2: Synthesis of 4-oxo-1-((tetrahydro-2H-pyran-4-yl) methyl) -1,4-dihydroquinoline-3-carboxylic acid ethyl ester Ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate (0.7 g, 3.22 mmol, 1.0 eq) was dissolved in DMF (4.5 mL), and 4- (bromomethyl) tetrahydro was added -2H-pyran (1.73 g, 9.66 mmol, 3.0 eq) and potassium carbonate (1.34 g, 9.66 mmol, 3.0 eq), and stirred at 80 ° C. overnight under nitrogen protection.The reaction was monitored by TLC. The reaction was concentrated under reduced pressure. Ethyl acetate (15 mL) and water (20 mL) were added. The layers were separated and the organic phase was concentrated. The crude product was purified by silica gel column chromatography (dichloromethane: methanol = 50: 1 30: 1 ) To obtain the product (550.3mg, yield: 54.2%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.8% | With thionyl chloride; at 85℃; | <strong>[13721-01-2]4-oxo-1,4-dihydroquinoline-3-carboxylic acid</strong> (1.08 g, 5.7 mmol, 1.0 eq) was dissolved in ethanol (15 mL), and socl2 (6.8 g, 57 mmol) was added dropwise with stirring. , 10.0 eq.), And reacted at 85 C. overnight.The reaction was monitored for completeness by TLC, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane: methanol = 60: 1 to 40: 1) to obtain the product (901.3 mg, yield: 72.8%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With potassium carbonate In acetonitrile at 160℃; for 0.75h; Sealed tube; Microwave irradiation; | 5.1.1. General procedure for the synthesis of compounds 8e11 bymicrowave catalyzed N-alkylation The 4-oxo-1,4-dihydroquinoline core structure 7 (1 g,4.6 mmol), the appropriate dibromoalkane (13.8 mmol), and K2CO3(1.28 g, 9.3 mmol) were weighted altogether in a 10e20 mL microwavevial and CH3CN (z12 mL) was added. The vial was sealed,shaken vigorously, and heated in the microwave irradiator at 160 Cfor 45 min. After cooling, the solvent was removed by rotaryevaporation and the corresponding residue was partitioned betweenH2O (20 mL) and CH2Cl2 (20 mL). The aqueous phase wasfurther extracted with CH2Cl2 (2 20 mL). The combined organiclayers were dried over Na2SO4 and evaporated under vacuumaffording a brownish oil as crude which was purified by chromatography(1:50) with CH2Cl2/AcOEt (4:1) as eluent to afford the titlecompound. 5.1.1.1. Ethyl 1-(6-bromohexyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate-8. Compound 7 was alkylated with 1,6-dibromohexane (2.1 mL) to afford 8 as an off-white solid. Yield,53%; mp: 76e78 C.1H NMR (500 MHz, CDCl3) d: 1.40 (t, 3H, J 7.1 Hz),1.40e1.47 (m,2H), 1.53 (quint, 2H, J 7.5 Hz), 1.87 (quint, 2H, J 7.0 Hz), 1.92(quint, 2H, J 7.5 Hz), 3.40 (t, 2H, J 7.0 Hz), 4.20 (t, 2H, J 7.5 Hz),4.41 (q, 2H, J 7.1 Hz), 7.43e7.46 (m, 2H), 7.70 (dt, 1H, J1 7.8 Hz,J2 1.5 Hz), 8.50 (s, 1H), 8.56 (d, 1H, J 7.8 Hz). HRMS-ESI forC18H22BrNO3 (m/z): [MH] calcd, 380.0856; found, 380.0852;[MNa] calcd, 402.0675; found, 402.0674. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With potassium carbonate In acetonitrile at 160℃; for 0.75h; Sealed tube; Microwave irradiation; | 5.1.1. General procedure for the synthesis of compounds 8e11 bymicrowave catalyzed N-alkylation General procedure: The 4-oxo-1,4-dihydroquinoline core structure 7 (1 g,4.6 mmol), the appropriate dibromoalkane (13.8 mmol), and K2CO3(1.28 g, 9.3 mmol) were weighted altogether in a 10e20 mL microwavevial and CH3CN (z12 mL) was added. The vial was sealed,shaken vigorously, and heated in the microwave irradiator at 160 Cfor 45 min. After cooling, the solvent was removed by rotaryevaporation and the corresponding residue was partitioned betweenH2O (20 mL) and CH2Cl2 (20 mL). The aqueous phase wasfurther extracted with CH2Cl2 (2 20 mL). The combined organiclayers were dried over Na2SO4 and evaporated under vacuumaffording a brownish oil as crude which was purified by chromatography(1:50) with CH2Cl2/AcOEt (4:1) as eluent to afford the titlecompound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With potassium carbonate In acetonitrile at 160℃; for 0.75h; Sealed tube; Microwave irradiation; | 5.1.1. General procedure for the synthesis of compounds 8e11 bymicrowave catalyzed N-alkylation General procedure: The 4-oxo-1,4-dihydroquinoline core structure 7 (1 g,4.6 mmol), the appropriate dibromoalkane (13.8 mmol), and K2CO3(1.28 g, 9.3 mmol) were weighted altogether in a 10e20 mL microwavevial and CH3CN (z12 mL) was added. The vial was sealed,shaken vigorously, and heated in the microwave irradiator at 160 Cfor 45 min. After cooling, the solvent was removed by rotaryevaporation and the corresponding residue was partitioned betweenH2O (20 mL) and CH2Cl2 (20 mL). The aqueous phase wasfurther extracted with CH2Cl2 (2 20 mL). The combined organiclayers were dried over Na2SO4 and evaporated under vacuumaffording a brownish oil as crude which was purified by chromatography(1:50) with CH2Cl2/AcOEt (4:1) as eluent to afford the titlecompound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With potassium carbonate In acetonitrile at 160℃; for 0.75h; Sealed tube; Microwave irradiation; | 5.1.1. General procedure for the synthesis of compounds 8e11 bymicrowave catalyzed N-alkylation General procedure: The 4-oxo-1,4-dihydroquinoline core structure 7 (1 g,4.6 mmol), the appropriate dibromoalkane (13.8 mmol), and K2CO3(1.28 g, 9.3 mmol) were weighted altogether in a 10e20 mL microwavevial and CH3CN (z12 mL) was added. The vial was sealed,shaken vigorously, and heated in the microwave irradiator at 160 Cfor 45 min. After cooling, the solvent was removed by rotaryevaporation and the corresponding residue was partitioned betweenH2O (20 mL) and CH2Cl2 (20 mL). The aqueous phase wasfurther extracted with CH2Cl2 (2 20 mL). The combined organiclayers were dried over Na2SO4 and evaporated under vacuumaffording a brownish oil as crude which was purified by chromatography(1:50) with CH2Cl2/AcOEt (4:1) as eluent to afford the titlecompound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | In diphenylether at 200℃; for 7h; | 1 Add 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester (100mg, 0.46mmol) to diphenyl ether (2.3mL), and the product VIII (141mg, 0.55mmol) of step (2) ) The reaction was carried out at 200° C. for 7 hours, and thin layer chromatography (TLC) monitoring was performed. After the reaction was completed, a brown precipitate was obtained.The reaction mixture was cooled to room temperature, filtered to obtain a solid, washed with ethyl acetate, ethanol, methanol, and dichloromethane, respectively, and fully dried to obtain compound 1.Yield: 66%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | Stage #1: ethyl 3-(2-((tert-butoxycarbonyl)amino)phenyl)-3-oxopropionate With boron trifluoride diethyl etherate In dichloromethane at 0 - 20℃; for 2h; Stage #2: <i>N</i>,<i>N</i>-dimethyl-formamide dimethyl acetal In toluene at 100℃; for 12h; | 4 Preparation of Class B Heterocyclic 4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester Add 0.5mmol of Intermediate Compound II to 4mL of dichloromethane, add 2.5mmol of boron trifluoride ether at 0°C, stir for 2h at room temperature, neutralize with saturated aqueous sodium bicarbonate solution, extract with DCM, dry, remove the solvent to obtain the crude product It was further dissolved in 2ml of toluene, 0.8mmol of N,N-dimethylformamide dimethyl acetal was added, and the reaction was carried out at 100°C for 12 hours. Cool to room temperature, filter, wash the obtained solid with 50% ethanol/water (5mL x 2), and dry under vacuum at 60°C to obtain Class B heterocyclic 4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl Esters, the yield is 46%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.7% | In N,N-dimethyl-formamide Alkaline conditions; | 1.1.3 Reaction formula 1.3 Potassium carbonate and commercial intermediate 17 were added to the N,N-dimethylformamide (DMF) solution of compound 16, and reacted at 70°C for 4 hours. After the reaction, the reaction was quenched by adding saturated ammonium chloride solution, the organic phase was separated, the aqueous phase was extracted three times with dichloromethane, merged into the organic phase, washed with saturated ammonium chloride aqueous solution and saturated brine in turn, and then with anhydrous sulfuric acid The sodium was dried, the sodium sulfate was removed by filtration, and the crude product was obtained by concentration. The crude product is separated by column chromatography (200-300 mesh silica gel, eluent is n-hexane: ethyl acetate=2:1) to obtain a pure final product 18. |
Tags: 52980-28-6 synthesis path| 52980-28-6 SDS| 52980-28-6 COA| 52980-28-6 purity| 52980-28-6 application| 52980-28-6 NMR| 52980-28-6 COA| 52980-28-6 structure
A219655[ 26892-90-0 ]
Ethyl 4-hydroxyquinoline-3-carboxylate
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[ 77156-75-3 ]
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P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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