| 76% |
With sulfuric acid; nitric acid; In water; at -10℃; for 1.08333h; |
3,4-Dihydro-2 (lH)-quinolinone (1.0 g, 6.70 mmol) is dissolved in 20 mL of concentrated sulfuric acid at-10C, and then 5 mL of water is added slowly to the solution. After 5 minutes, 61% nitric acid (0.5 mL, 6.70 mmol) is added dropwise to the solution. The reaction mixture turns from yellow to dark red, and eventually solidifies. After 1 hour, water (50 mL) is added slowly at-10C and precipitate appears. The solution is poured into a separatory funnel, extracted with ethyl acetate (20 mL x 2) and washed with saline (20 mL). The organic layers are collected and dried over MgS04. Solvent is removed and the title compound is obtained as a pale yellow solid (1.0 g, 76%) ; 1H NMR (300 MHz, DMSO) 8 10.66 (s, 1H), 8.08-8. 01 (m, 2H), 6.96 (d, 1H), 2.98 (t, 2H), 2.49 (dd, 2H). |
| 76% |
With sulfuric acid; nitric acid; In water; at -10℃; for 1.08333h; |
Step 1: Preparation of 6-nitro-3,4-dihydro-1H-quinolin-2-one 3,4-Dihydro-2(1H)-quinolinone (1.0 g, 6.70 mmol) is dissolved in 20 ML of concentrated sulfuric acid at -10 C., and then 5 ML of water is added slowly to the solution.After 5 minutes, 61% nitric acid (0.5 ML, 6.70 mmol) is added dropwise to the solution.The reaction mixture turns from yellow to dark red, and eventually solidifies.After 1 hour, water (50 ML) is added slowly at -10 C. and precipitate appears.The solution is poured into a separatory funnel, extracted with ethyl acetate (20 ML*2) and washed with saline (20 ML).The organic layers are collected and dried over MgSO4.Solvent is removed and the title compound is obtained as a pale yellow solid (1.0 g, 76%); 1H NMR (300 MHz, DMSO) delta 10.66 (s, 1H), 8.08-8.01 (m, 2H), 6.96 (d, 1H), 2.98 (t, 2H), 2.49 (dd, 2H). |
| 76% |
With sulfuric acid; nitric acid; at -20 - 20℃; for 4.5h; |
3,4-Dihydroquinolin-2(1H)-one (20.0 g, 136.05 mmol) was added to conc. sulfuric acid (200 ml) and cooled to -20 C., and fuming nitric acid (4 ml, 95.24 mmol) was then added carefully over a period of 30 minutes. The resulting reaction mixture was stirred at -20 C. for 2 h and at room temperature for a further 2 h and then slowly diluted with ice-water. The aqueous phase was then repeatedly extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 6-nitro-3,4-dihydroquinolin-2(1H)-one (20.0 g, 76% of theory) was isolated as a colorless solid. 6-Nitro-3,4-dihydroquinolin-2(1H)-one (8.52 g, 44.38 mmol) was dissolved under argon in abs. N,N-dimethylformamide (150 ml), the mixture was cooled to 0 C. and fine potassium carbonate powder (7.40 g, 52.26 mmol) was added. After 15 min of stirring at a temperature of 0 C., n-propyl iodide (2 equiv, 88.771 mmol) was added. The resulting reaction mixture was stirred at room temperature for 24 h and, after cooling to room temperature, water and ethyl acetate were added. The aqueous phase was then repeatedly extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), gave 6-nitro-1-propyl-3,4-dihydroquinolin-2(1H)-one (8.40 g, 87% of theory) as a colorless solid. In the next step, 6-nitro-1-propyl-3,4-dihydroquinolin-2(1H)-one (5.0 g, 24.27 mmol) was dissolved in an ethanol/water mixture (ratio 1:1, 50 ml), and ammonium chloride (12.96 g, 242.72 mmol) and iron powder (4.07 g, 72.82 mmol) were added. The resulting reaction mixture was stirred at a temperature of 80 C. for 2 h and, after cooling to room temperature, concentrated. Ethyl acetate and water were added to the residue and the aqueous phase was then repeatedly extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient) gave 6-amino-1-propyl-3,4-dihydroquinolin-2(1H)-one (4.0 g, 94% of theory) as a colorless solid. 1H-NMR (400 MHz, d6-DMSO delta, ppm) 6.79 (d, 1H), 6.45 (m, 1H), 6.42 (m, 1H), 4.85 (br. s, 2H, NH2), 3.75 (m, 2H), 2.68 (m, 2H), 2.43 (m, 2H), 1.52 (m, 2H), 0.85 (t, 3H). Trimethyl phosphite (1 equiv, 8.07 mmol) and 2,4-dimethylbenzyl bromide (1 equiv, 8.07 mmol) were added to a multi-necked flask which had been dried by heating and then stirred together under continuous nitrogen flow at a temperature of 100 C. for 10 h. After complete conversion, without further purification, distilled POCl3 (1 equiv) was added to the resulting crude product and the mixture was stirred under argon at a temperature of 60 C. for 1.5 h. After complete conversion, the methyl (2,4-dimethylbenzyl)phosphonochloridate obtained was, without further purification, directly reacted in the next step. In a round-bottom flask which had been dried by heating, under argon, 6-amino-1-propyl-3,4-dihydroquinolin-2(1H)-one (668 mg, 3.27 mmol) was dissolved in abs. tetrahydrofuran (2 ml) and slowly added dropwise under argon to a solution, cooled to -20 C., of methyl (2,4-methylbenzyl)phosphonochloridate (1065 mg, 3.27 mmol) in abs. tetrahydrofuran (10 ml) in a round-bottom flask which had been dried beforehand by heating. The resulting reaction mixture was stirred at -20 C. for 10 minutes, triethylamine (0.91 ml, 6.54 mmol) was then added and the mixture was subsequently stirred at room temperature for 2 h. The reaction mixture was then filtered, the filter cake was washed with tetrahydrofuran and the filtrate was concentrated under reduced pressure. Column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient) gave methyl N-[1-(n-propylmethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]-P-(2,4-dimethylbenzyl)phosphonamidate (57 mg, 4% of theory) as a colorless solid. 1H-NMR (400 MHz, CDCl3 delta, ppm) 7.00 (m, 1H), 6.95 (m, 1H), 6.88 (m, 1H), 6.85-6.83 (m, 2H), 6.80 (m, 1H), 6.69 (m, 1H), 4.88 (br. s, 1H, NH), 3.86 (m, 2H), 3.76 (d, 3H), 3.32/3.26 (d, 2H), 2.83-2.78 (m, 2H), 2.64-2.59 (m, 2H), 2.26/2.13 (s, 6H), 1.71-1.63 (m, 2H), 0.96 (t, 3H). |
| 69% |
With nitric acid; acetic acid; at 20℃; for 2h; |
3,4-Dihydroquinolin-2(1H)-one (1.54 g, 7.66 mmol) was added to conc. acetic acid (10 mL) and then cautiously admixed with fuming nitric acid (0.42 mL, 10.12 mmol). The resulting reaction mixture was stirred at room temperature for 2 h and then diluted with ice-water. The aqueous phase was then repeatedly extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 6-nitro-3,4-dihydroquinolin-2(1H)-one (1.09 g, 69% of theory) was isolated as a colorless solid. 6-Nitro-3,4-dihydroquinolin-2(1H)-one (1.30 g, 6.77 mmol) was dissolved under argon in abs. N,N-dimethylformamide (20 mL) and admixed with fine potassium carbonate powder (2.80 g, 20.29 mmol). After stirring at room temperature for 5 min, 2-bromoethyl ethyl ether (1.49 g, 8.79 mmol) and potassium iodide (17 mg, 0.10 mmol) were added. The resulting reaction mixture was stirred at 100 C. for 1.5 h and, after cooling to room temperature, water and ethyl acetate were added. The aqueous phase was then repeatedly extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 1-(ethoxyethyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (650 mg, 36% of theory) was isolated as a colorless solid. 1H-NMR (400 MHz, CDCl3 delta, ppm) 8.14 (dd, 1H), 8.05 (d, 1H), 7.45 (d, 1H), 4.14 (t, 2H), 3.70 (t, 2H), 3.50 (q, 2H), 3.01 (m, 2H), 2.72 (m, 2H), 1.16 (t, 3H). In the next step, 1-(ethoxyethyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (650 mg, 2.46 mmol) was added together with tin(II) chloride dihydrate (2.22 g, 9.38 mmol) to abs. ethanol (10 mL) and the mixture was stirred under argon at a temperature of 40 C. for 5 h. After cooling to room temperature, the reaction mixture was poured onto ice-water and then adjusted to pH 12 with 6 N NaOH. The aqueous phase was then repeatedly extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 6-amino-1-(ethoxyethyl)-3,4-dihydroquinolin-2(1H)-one (620 mg, 97% of theory) was isolated as a colorless solid. 6-Amino-1-(ethoxyethyl)-3,4-dihydroquinolin-2(1H)-one (150 mg, 0.58 mmol) was dissolved together with (4-chlorophenyl)methanesulfonyl chloride (143 mg, 0.63 mmol) in abs. acetonitrile (7 mL) in a baked-out round-bottom flask under argon, then pyridine (0.09 mL, 1.15 mmol) was added and the mixture was stirred at room temperature for 6 h. The reaction mixture was then concentrated under reduced pressure, the remaining residue was admixed with dil. HCl and dichloromethane, and the aqueous phase was extracted repeatedly with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), N-[1-(ethoxyethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]-1-(4-chloromethylphenyl)methanesulfonamide (139 mg, 62% of theory) was isolated as a colorless solid. 1H-NMR (400 MHz, CDCl3 delta, ppm) 7.34 (d, 2H), 7.23 (m, 3H), 6.95-6.943 (m, 2H), 6.23 (s, 1H, NH), 4.30 (s, 2H), 4.08 (m, 2H), 3.68 (m, 2H), 3.53 (q, 2H), 2.87 (m, 2H), 2.66 (m, 2H), 1.18 (t, 3H). |
| 60% |
With sulfuric acid; nitric acid; In water; at -10 - 0℃; for 0.25h; |
To a solution of 3,4-dihydroquinolin-2(lH)-one (1 g) in H2S04 (20 niL) at -10C, water (5 mL) was added dropwise with stirring. To this solution, concentrated HNO3 (0.5 mL) was added dropwise with stirring, while cooling to a temperature of 0C. The resulting solution was stirred for 15 min at -10C. After completion, the mixture was quenched by adding ice water (50 mL). The resulting solution was extracted with EtOAc (5 x 50 mL). The combined organic layers were concentrated under reduced pressure and the resulting crude product was purified by column chromatography over silica gel using EtOAc in hexane as eluent. The product eluted at 50-70% EtOAc in hexane. The fractions with pure product were concentrated to obtain 6-nitro-3,4-dihydroquinolin- 2(lH)-one as light brown solid (0.9 g, 69%). 1H NMR (CDC13, 400 MHz): delta 8.549 (brs 1H), 8.116 (brs, 2H), 6.879 (t, 1H), 3.095 (t, 2H), 2.720 (t, 2H). |
|
With KNO3; sulfuric acid; |
(a) 6-Nitro-1,3,4-trihydroquinolin-2-one. To a round-bottomed flask equipped with magnetic stirring was added 3,4-dihydro-2(1H)-quinolinone (1.47 g, 10 mmol, Aldrich) and 96% H2SO4 (8.3 mL). The mixture was stirred until all of the material was dissolved, then cooled to 0 C. and treated with KNO3 (1.2 g, 11.7 mmol) in portions. The reaction mixture was allowed to warm to 25 C. and stirred at that temperature overnight. The mixture was basified to pH 9 with 35% NaOH, resulting in a precipitate. The solid was collected by filtration, washed with water and dried in vacuo at 50 C. to provide the title product as a yellow solid. MS (ESI, pos. ion) m/z: 193 (M+1). |
|
With sulfuric acid; nitric acid; In water; at 0℃; for 0.333333h; |
Reaction step 1. Preparation of 6-nitro-3,4-dihydroquinolin-2(lH)-one, 4 Cone. H2S04 (1000 mL) was added to water (250 mL) at 0 C with stirring, then 3,4- dihydroquinolin-2(lH)-one, 3 (50.0 g, 350 mmol) was added portionwise. After that, HNO3 (68%, 25 mL) was added dropwise over a period of 10 min at 0 C and the reaction mixture was stirred for 10 min. The progress of the reaction was monitored by TLC (TLC system: 10 % MeOH/dichloromethane, Rf value: 0.5) [0082] After completion of the reaction, the reaction mixture was poured into ice cold water and filtered, washing with ethyl acetate. The crude product was dried under vacuum to afford 6-nitro-3,4-dihydroquinolin-2(lH)-one, 4 as a pale yellow solid. |
|
With sulfuric acid; nitric acid; In water; at 0℃; for 0.25h; |
H2SO4 (20 mL) and 3,4-dihydro-2(1H)-quinolinone (6.8 mmol) to stirred solution of water (5 mL) and HNO3 (0.5 mL) was added at 0 C. The water produced as a result was stirred for 15 minutes at 0 C. After the reaction is complete, the mixture is quenched with water (50 mL). The precipitate was collected by filtration and washed with H2O. The crude residue generated as a result was purified by silica gel flash column chromatography to generate the J1. |
|
With sulfuric acid; nitric acid; at 0 - 10℃; for 3h; |
15.1 g of compound II and 30.4 Ml of H2SO4 (78%) were placed in a 250 mL reaction flask, stirred, and cooled to 0 to 5 C with an ice salt bath, and 31.5 mL of H 2 SO 4 (78%) and 9.2 mL (01186 mol) of HNO 3 (65) were added dropwise. %) of the mixture, control the drop accelerationDegree, keep the reaction temperature below 10 C, remove the ice bath after the addition is completed, continue to react for 3h, pour the reaction solution into ice water, let it stand, filter it by suction, wash it twice with water, dry the filter cake, and use acetone Crystallization, 17.6 g of a pale yellow solid product 6-nitro-3,4-dihydro-2(1H)quinolinone (III), yield 8912%; mp 203-204 C;First, 7.63 g of reduced iron powder and 2.75 mL of concentrated hydrochloric acid (36%) were added to the reaction flask, stirred and 150 mL of ethanol (95%) was added, and then the temperature was raised to reflux. After cooling, 7.9 g of the compound was added in portions.III, reheating to reflux, after 2.5h reaction, stop the reaction, heat filtration, and rinse the iron mud in the bottle with hot ethanol for 2 to 3 times, concentrate the filtrate, add a small amount of water, and put it in the refrigerator to cool, a large amount of solids are precipitated. Then, suction filtration, the obtained filter cake was dried to obtain 618 g of pale yellow crystal 6-amino-3,4-dihydro-2(1H)quinolinone (IV), yield 9916%, mp 174-175 C; The mass spectrum obtained by mass spectrometry has a peak of 162 which is consistent with the mass of the product, and the peaks of the fragments are also consistent;Dissolve 1.4 g of sodium nitrite in 3.71 mL of water; then pour 4.3 mL of concentrated sulfuric acid (98%) and 617 mL of water into the reaction flask, add 2.95 of the starting compound IV with stirring, stir until it is a paste, and cool with an ice salt bath until 0 to 5 C, add a pre-formed aqueous solution of sodium nitrite, control the dropAcceleration, so that the reaction temperature does not exceed 10 C; after the addition is completed, the ice bath is removed, heated to reflux with a preheated oil bath, the reaction is stopped for 40 min, the reaction is stopped, 10 mL of water is added, cooled, suction filtered, dried to give 216 g shallow Yellow solid 1, yield 86.7% |
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