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CAS No. : | 3279-90-1 | MDL No. : | MFCD03839832 |
Formula : | C9H8BrNO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MQWZSSIUHXNNTM-UHFFFAOYSA-N |
M.W : | 226.07 | Pubchem ID : | 14373281 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.22 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 54.24 |
TPSA : | 29.1 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) : | -6.24 cm/s |
Log Po/w (iLOGP) : | 1.95 |
Log Po/w (XLOGP3) : | 2.03 |
Log Po/w (WLOGP) : | 1.76 |
Log Po/w (MLOGP) : | 2.17 |
Log Po/w (SILICOS-IT) : | 2.76 |
Consensus Log Po/w : | 2.13 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.89 |
Solubility : | 0.291 mg/ml ; 0.00129 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.27 |
Solubility : | 1.22 mg/ml ; 0.00538 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -4.03 |
Solubility : | 0.0212 mg/ml ; 0.000094 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.64 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-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 |
---|---|---|
60% | Stage #1: With sodium azide; methanesulfonic acid In dichloromethane at 0 - 20℃; Stage #2: With sodium hydroxide In dichloromethane; water at 0℃; |
6-Bromo-3,4-dihvdroisoquinolin-l(2H)-one (1A):NaN3 (6.2 g, 94.78 mmol) was added to a solution of 5-bromo-l-indanone (10 g, 47.39 mmol) in 40 mL mixture of methane sulphonic acid and dichloromethane (1 : 1) in portion wise at 0 °C-5 °C. The resulting mixture was stirred for 8 h at room temperature. The reaction mixture was cooled to 0 °C in ice bath, neutralized with 5 percent aq. NaOH solution, and the aqueous layer with extracted with ethyl acetate (2x100 mL). The combined organic layer was washed with water and brine solution, dried over sodium sulphate, filtered and concentrated under vacuum. The residue was purified by silica gel flash column chromatography by eluting with 30 percent ethyl acetate in hexane to afford title compound (6.4 g, 60percent) as solid. 1H NMR (400 MHz, CDC13): δ 7.95 (d, J = 8.4 Hz, 1H), 7.5 (d, J = 8.4 Hz, 1H), 7.4 (s, 1H), 6.1 (bs, 1H), 3.6 (t, J = 6.8 Hz, 2H), 3.0 (t, J = 6.4 Hz, 2H). |
60% | With sodium azide; methanesulfonic acid In dichloromethane at 0 - 20℃; for 8 h; | 2-(i -Oxo-6-(4-(3-(3-(trilluoromethyl)phenyl)ureido) phenyl)-3,4-dihydroisoquinolin-2(i H)-yl)acetic acid6-Hromo-3,4-dihydroisoquinolin-i (2H)-one (iA)Procedures:10443] NaN3 (6.2 g, 94.78 mmol) was added to a solution of5-bromo-i-indanone(iO g, 47.39 mmol) in 40 mL of mixture of methane sulphonic acid and dichloromethane (i : i) in portion wise at 00 C.-5° C. The resulting mixture was stirred for 8 h at room temperature. The reaction mixture was cooled to0°C. in ice bath, neutralized with 5percent aq. NaOH, and aqueous layer was extracted with ethyl acetate (2x1 00 mE). The combined organic layer was washed with water and brine solution, dried over Na2SO4 and filtered. The filtrate was concentrated under vacuum and purified by silica gel flash column chromatography using 30percent ethyl acetate in hexane to afford title compound (6.4 g, 60percent) as solid. ö ‘H NMR (400 MHz, CDC13): ö 7.95 (d, J=8.4 Hz, 1H), 7.5 (d, J=8.4 Hz, 1H), 7.4 (s, 1H), 6.1 (bs, 1H), 3.6 (t, J=6.8 Hz, 2 |
25% | With sodium azide; methanesulfonic acid In chloroform at 0 - 10℃; for 2.5 h; Heating / reflux | 5-Bromoindan-1-one (44 g, 209 mmol) was dissolved in CHCl3 (750 mL) with vigorous stirring and cooled to 0° C. Methanesulfonic acid (135 mL, 2090 mmol) was added dropwise. Sodium azide (40.7 g, 625 mmol) was added in portions over 30 min such that the internal temperature did not exceed 10° C. The reaction mixture was heated to reflux temperature and stirred for 2 h. The reaction mixture was cooled to room temperature and poured onto ice (1 kg) with manual stirring. The mixture was neutralized with NH4OH. The layers were separated. The organic solution was dried over MgSO4, filtered and concentrated in vacuo. Column chromatography (EtOAc) provided, after removal of solvent in vacuo: (1) 6-bromo-2H-1,2,3,4-quinol-1-one (10.7 g, 25percent yield): 1H NMR (CDCl3, 300 MHz): 8.11 (br s, 1H), 7.32 (d, 1H, J=1), 7.29 (dd, 1H, J=8, 1), 6.23 (br s, 1H), 6.25 (br s, 1H), 2.98 (t, 2H, J=7), 2.65 (t, 2H, J=7); MS (APCI+): 267, 269 (C11H12BrN2O, M++H+CH3CN) and (2) 6-bromo-1H-1,2,3,4-tetrahydroisoquinolone (21.5 g, 46percent yield): 1H NMR (CDCl3, 300 MHz): 7.95 (d, 1H, J=8), 7.51 (dd, 1H, J=8, 1), 7.21 (t, 1H, J=1), 6.25 (br s, 1H), 3.59 (t, 2H, J=7), 3.01 (t, 2H, J=7); MS (APCI+): 267, 269 (C11H12BrN2O, M++H+CH3CN). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: With sodium hydride In N,N-dimethyl-formamide for 0.5 h; Inert atmosphere Stage #2: at 20℃; |
A. Synthesis of tert-butyl 2-(6-bromo-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate To a mixture of 95percent dry sodium hydride (834 mg, 33.0 mmol) in anhydrous N,N-dimethylformamide (30 mL) at room temperature was added a solution of 6-bromo-3,4-dihydroquinolin-2(1H)-one (6.780 g, 30.00 mmol) in anhydrous N,N-dimethylformamide (10 mL). The reaction mixture was stirred for 30 minutes under an atmosphere of dry N2, followed by addition of a solution of tert-butyl 2-bromoacetate (7.5 mL, 49.7 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at room temperature until the majority of the starting material was converted (confirmed by LCMS). The reaction mixture was quenched with methanol (40 mL), the mixture concentrated under reduced pressure, then diluted with ethyl acetate (150 mL). The organic phase was washed with water (100 mL), 30percent ammonium chloride (100 mL) and brine (100 mL), dried, and concentrated under reduced pressure. Ethyl ether (20 mL) was added, and the mixture sonicated, filtered, washed with ether (20 mL), and dried to afford tert-butyl 2-(6-bromo-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate (7.348 g, 21.6 mmol, 72percent). LCMS mz 285.9 (M-56+H), 363.9 (M+Na), anal HPLC>97percent in purity. 1H NMR (400 MHz; CDCl3) δ 7.30-7.40 (m, 2H); 7.50-6.70 (m, 1H); 4.54 (s, 2H); 2.92 (m, 2H); 2.69 (m, 2H), 1.44 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With Eosin Y; Selectfluor In acetonitrile at 25℃; for 1h; regioselective reaction; | |
95% | With sodium bromate; hydrogen bromide; acetic acid at 20℃; for 0.333333h; | |
92.1% | With N-Bromosuccinimide In N,N-dimethyl acetamide at 20℃; for 18h; Cooling with ice; Inert atmosphere; | 1.6 Step 6) 6 - bromo - 3, 4 - dihydroquinoline -2 (1H) - one synthesis of The 3, 4 - dihydroquinoline -2 (1H) - one (2.73g, 18 . 55mmol) dissolved in N, N - dimethylacetamide (30 ml) in, and in the ice water bath for slowly dripping N - bromosuccinimide (3.30g, 18 . 55mmol) of N, N - dimethylacetamide (10 ml) solution. In the reaction solution in the ice water bath to continue stirring 6 hours after the reaction temperature to the room temperature 12 hours. After the reaction, to the reaction mixture with water (50 ml), and ethyl acetate (50 ml × 3) extraction. The combined organic phase, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, the resulting residue by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=3/1) to obtain the title compound as white solid (3.86g, 92.1%). |
92% | With N-Bromosuccinimide In N,N-dimethyl-formamide at 0℃; for 2h; | |
90% | With N-Bromosuccinimide In N,N-dimethyl-formamide at 0℃; for 6h; | 1.1 Step 1: 6-Bromo-3,4-dihydroquinolin-2(1H)-one The compound 3,4-dihydro-2 (1H) -quinolinone (10.0 g, 67.95 mmol) was dissolved in N, N-dimethylformamide (100 mL).Cooled to 0 ° C,N-bromosuccinimide (12.7 g, 71.34 mmol) was added portionwise,The reaction was stirred for 6 hours under a slow temperature rise.The reaction solution was concentrated to dryness, and ethyl acetate was added thereto, followed by washing with sodium bicarbonate solution and brine. The organic phase was dried, filtered and concentrated to give 6-Bromo-3,4-dihydroquinolin-2(1H)-one (14 g) in 90% yield. |
89% | With N-Bromosuccinimide In N,N-dimethyl-formamide at 0℃; for 2h; | 1 To a solution of 3,4-dihydro-1H-quinolin-2-one (10.0 g, 67.9 mmol) in 100 ml dry DMF was added dropwise a solution of N-bromosuccinimide (12.7 g, 71.3 mmol) in 150 ml dry DMF at 0° C. The mixture was stirred at 0° C. for 2 h, then 400 ml water was added and the solution was extracted with ethyl acetate (3×150 ml). The organic phase was washed with water (2×200 ml), then dried over MgSO4 and evaporated, affording a yellow solid which was purified by washing with cold ether providing pure 6-bromo-3,4-dihydro-1H-quinolin-2-one (13.6 g, 60.3 mmol, 89%) as colorless needles. |
89% | With N-Bromosuccinimide In N,N-dimethyl-formamide at 0℃; Inert atmosphere; | 1 To a solution of 3,4-dihydro-1 H-quinolin-2-one (10.0 g, 67.9 mmol) in 100 ml dry DMF was added dropwise a solution of λ/-bromosuccinimide (12.7 g, 71.3 mmol) in 150 ml dry DMF at 0 °C. The mixture was stirred at 0 0C for 2 h, then 400 ml water was added and the solution was extracted with ethyl acetate (3 x 150 ml). The organic phase was washed with water (2 x 200 ml), then dried over MgSO4 and evaporated, affording a yellow solid which was purified by washing with cold ether providing pure 6-bromo-3,4-dihydro-1 H-quinolin-2-one (13.6 g, 60.3 mmol, 89 %) as colorless needles. |
87% | With N-Bromosuccinimide In N,N-dimethyl-formamide at 0℃; for 2h; | |
71% | With bis-[(trifluoroacetoxy)iodo]benzene; sodium bromide In ethanol at 25℃; for 0.166667h; Green chemistry; regioselective reaction; | |
69% | With N-Bromosuccinimide In N,N-dimethyl-formamide at 100℃; for 0.25h; | |
62% | With N-Bromosuccinimide In DMF (N,N-dimethyl-formamide) at 20℃; | 5 Preparation 5; Preparation of 6-Bromo-3,4-dihydro-1H-quinolin-2-one. Preparation 5 Preparation of 6-Bromo-3,4-dihydro-1H-quinolin-2-one. To a stirred solution of 3,4-dihydro-1H-quinolin-2-one (0.735 g, 5.0 mmol) in dry DMF (20.0 ML) under N2 at ambient temperature was added N-bromosuccimide (0.93 g, 5.2 mmol) portionwise.The solution was stirred under N2 overnight then the orange mixture was poured into H2O (200 ML) and the precipitated solid was extracted into ether(100 ML).The ether was separated extracted with of H2O, (4*150 ML) washed with brine and dried(MgSO4).Filtration and evaporation in vacuo gave the title compound (0.70 g, 62%) as a light tan powder. 1H NMR(CDCl3) δ 2.60 (2H, m), 2.90 (2H, m), 6.65 (1H, d), 7.2-7.3 (2H, m), 8.9(1H, br s). |
With bromine; acetic acid Edukt 2: 1 Mol.; | ||
With N-Bromosuccinimide In N,N-dimethyl-formamide | 56.a a) a) 6-Bromo-3,4-dihydro-2(1H)-quinolinone To a solution of 3,4-dihydro-2(1H)-quinolinone (30 g, 204 mmol) in dried DMF (250 mL) at 0° C. was slowly added N-bromosuccinimide (38 g, 1.05 eq) via a dropping funnel. The reaction mixture was stirred at room temperature overnight, then poured into cold water (3.5L) and the precipitate formed filtered off and dried in vacuo at 45° C. to give the title compound as a white solid. | |
With N-Bromosuccinimide In N,N-dimethyl-formamide at 0℃; | ||
With N-Bromosuccinimide In N,N-dimethyl-formamide at 0 - 20℃; for 12h; | 74.C To a stirred solution of 3,4-dihydroquinolin-2(l H)-one (74-2; 15.0 g, 0.11 mol) in N,N-dimethylformamide (150 mL) was added N-bromosuccinimide (18.4 g, 0.11 mol) portion wise at 0 °C. Reaction mass was allowed to stir at room temperature for 12 h. The reaction mixture was concentrated and diluted with ice cold water (300 mL) with constant stirring and the solid residue was filtered and dried to obtain the title compound (1-3). 1H MR (400 MHz, DMSO- | |
With N-Bromosuccinimide In N,N-dimethyl-formamide at 0℃; for 1h; | 3.1 Preparation of 6-bromo-3 ,4-dihydroquinolin-2( 1 H)-one, 13 3,4-Dihydroquinolin-2(1H)-one, 12 (25.0 g, 170 mmol) in DMF (50 mL) was added to a stirred solution of NBS (33.2 g, 186 mmol) in DMF (250 mL) at 0 °C and the mixture was stirred for 1 h. The progress of the reaction was monitored by TLC (TLC system: 50 % EtOAc/Pet ether, Rf value: 0.35). After completion of the reaction, the reaction mixture was quenched with water and then solid formed. The solid was filtered and dried under vacuum to afford the crude product. The crude product was purified over silica gel (100-200 mesh) column chromatography eluting with 3 % EtOAc/Pet ether to give 6-bromo-3,4-dihydroquinolin-2(1H)-one, 13 as a white solid. 1H NMR (400 MHz, CDC13) ö: 8.73 (s, 1 H), 7.28 (dd, 2 H, Jj = 10.8, J2 = 2.4 Hz), 6.69 (d, 1 H, J= 8.0 Hz), 2.95 (t, 2 H, J= 7.2 Hz), 2.65-2.61 (m, 2 H); LC-MS: 96.7 % at 215 nm (mlz 418 [M+H]). | |
With N-Bromosuccinimide In N,N-dimethyl-formamide at 0℃; for 1h; | 5.1 Example 5. Preparation of l-(4-(l,l,l,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)-2-oxo- l,2,3,4-tetrahydroquinoline-6-carboxamide [00101] Reaction step 1. Preparation of 6-bromo-3,4-dihydroquinolin-2(lH)-one, 13 [00101] Reaction step 1. Preparation of 6-bromo-3,4-dihydroquinolin-2(lH)-one, 13 [00102] 3,4-Dihydroquinolin-2(lH)-one, 12 (25.0 g, 169 mmol) in DMF (50 mL) was added to a stirred solution of NBS (33.2 g, 186 mmol) in DMF (250 mL) at 0 °C and the mixture was stirred for 1 h. The progress of the reaction was monitored by TLC (TLC system: 50 % EtO Ac/Pet ether, Rf value: 0.35). [00103] After completion of the reaction, the reaction mixture was quenched with water and then a solid formed. The solid was filtered and dried under vacuum to afford the crude product. The crude product was purified over silica gel (100-200 mesh) column chromatography eluting with 3 % EtOAc/Pet ether to give 6-bromo-3,4-dihydroquinolin-2(lH)-one, 13 as a white solid. LC/MS: calc M+H 227, obs 227; lH NMR (400 MHz, CDC13) δ: 8.73 (s, 1 H), 7.28 (dd, 2 H, J, = 10.8, J2 = 2.4 Hz), 6.69 (d, 1 H, J= 8.0 Hz), 2.95 (t, 2 H, J= 7.2 Hz), 2.65-2.61 (m, 2 H). | |
385.5 mg | With N-Bromosuccinimide In N,N-dimethyl-formamide at 0 - 20℃; for 9h; | 4.2.7.1 6-Bromo-3,4-dihydroquinolin-2(1H)-one (89) To a solution of 3,4-dihydro-2(1H)-quinolinone (454.8mg, 3.090mmol) in DMF (5mL) was added N-bromosuccinimide (587.1mg, 3.299mmol) in DMF (5mL) at 0°C. The mixture was then allowed to warm to ambient temperature, stirred for 9h, and diluted with ethyl acetate. The organic layer was washed with water and brine, dried, and concentrated. The residue was recrystallized from ethanol/water to yield the title compound (385.5mg, 1.705mmol) as an off-white solid. 1H NMR (CDCl3) δ: 8.56 (1H, br s), 7.30-7.26 (2H, m), 6.68 (1H, d, J=8.0Hz), 2.96 (2H, t, J=7.5Hz), 2.63 (2H, t, J=8.0Hz). 13C NMR (CDCl3) δ: 171.37, 136.34, 130.85, 130.39, 125.71, 116.84, 115.45, 30.32, 25.14. |
With N-Bromosuccinimide In acetonitrile at 0℃; for 2h; | Step A: 6-bromo-3.4-dihydroiuinolin-2(1H)-one Step A: 6-bromo-3.4-dihydroiuinolin-2(1H)-oneTo a solution of 3,4-dihydro-1H-quinolin-2-one (5.00 g, 31.0 mmol) in 40 mL of CH3CN was added NBS (6.80 g, 38.0 mmol) in portions at 0 °C. The mixture was stirred at 0 °C for 2 h, then 30 mL of water was added and the solution was extracted with ethyl acetate three times. The combined organic phase was dried over Na2504, filtered and then concentrated to afford the title compound. LC/MS[M+1] = 226. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With sulfuric acid; nitric acid In water at 0 - 20℃; for 2h; | 77.a; 12.d a) 6-Bromo-8-nitro-3,4-dihydro-2(1 H)-quinolinoneTo a stirred solution of 6-bromo-3,4-dihydro-2(1 H)-quinolinone (5.83 g, 25.8 mmol) in concentrated sulfuric acid (40 ml_) at 0 0C was added dropwise 90% aq nitric acid (1.3 ml_ 27.7 mmoL). The reaction was allowed to warm to room temperature and stirred for 2 h. The reaction was poured into ice water (300 mL), filtered, rinsed with water, and dried under vacuum. Purification by flash chromatography on silica gel (10% ethyl acetate/chloroform) gave the title compound (5.23 g, 75%) as a yellow solid: MS (ES) m/e 270.8 (M + H)+. |
With sulfuric acid; water; nitric acid | ||
With sulfuric acid; nitric acid at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | With copper(l) iodide; potassium carbonate In N,N-dimethyl-formamide at 90℃; for 48h; | |
With copper(I) iodide; potassium carbonate In methanol; dichloromethane; N,N-dimethyl-formamide | 13 Preparation of 6-(imidazol-1-yl)-3,4-dihydrocarbostyril, the compound of Formula IS EXAMPLE 13 Preparation of 6-(imidazol-1-yl)-3,4-dihydrocarbostyril, the compound of Formula IS A mixture of 1.0 g of 6-bromo-3,4-dihydrocarbostyril, 300 mg of imidazole, 40 mg of cuprous iodide and 600 mg of potassium carbonate in 4 ml of N,N-dimethylformamide was heated at 90° C. for 48 hours. The reaction mixture was poured into water and extracted with a mixture of 10% methanol in methylene chloride. The organic layer was dried over anhydrous sodium sulfate, the solvent removed under reduced pressure and the residue chromatographed on silica gel, eluding with 3% methanol in methylene chloride, giving 6-(imidazol-1-yl)-3,4-dihydrocarbostyril, m.p. 205°-208° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With potassium hydroxide; tetrakis(triphenylphosphine) palladium(0); tetrabutylammomium bromide In tetrahydrofuran for 48h; Heating; | |
With potassium hydroxide; tetrabutylammomium bromide In tetrahydrofuran; methanol; dichloromethane | 14 Preparation of 6-(3-pyridyl)-3,4-dihydrocarbostyril, the compound of Formula IR EXAMPLE 14 Preparation of 6-(3-pyridyl)-3,4-dihydrocarbostyril, the compound of Formula IR To a solution of 1.0 g of 6-bromo-3,4-dihydrocarbostyril, 520 mg of 3-pyridyldiethylborane and 205 mg. of tetrakis(triphenylphosphine)palladium in 20 ml of tetrahydrofuran was added 600 mg of powdered potassium hydroxide and 114 mg of tetrabutylammonium bromide. The mixture was refluxed for 48 hours under an inert atmosphere and the solvent then removed under reduced pressure. The residue was extracted with a mixture of 10% of methanol in methylene chloride and the organic solution washed with water and dried over anhydrous sodium sulfate. The solvent was removed from the dried solution under reduced pressure, and the residue chromatographed on silica gel, eluding with 5% methanol in methylene chloride to give 6-(3-pyridyl)-3,4-dihydrocarbostyril, m.p. 180°-182° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide In pyridine; triethylamine at 90℃; for 72h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide In pyridine; triethylamine at 90℃; for 72h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With titanium(III) chloride In tetrahydrofuran for 1h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With potassium iodide In acetonitrile Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium iodide In acetonitrile Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With Lawessons reagent In toluene for 2h; Reflux; Inert atmosphere; | 1.7 Step 7) 6 - bromo - 3, 4 - dihydroquinoline -2 (1H) - thione synthesis The 6 - bromo - 3, 4 - dihydroquinoline -2 (1H) - one (2.50g, 11 . 06mmol) and Lawson reagent (6.71g, 16 . 60mmol) is added to the toluene (20 ml) in, heating the reaction to reflux 2 hours after cooling to room temperature, and decompression turns on lathe does title compound is to be red solid (2.52g, 94.0%). |
79% | With Lawessons reagent In toluene for 0.75h; Heating; | |
75% | With Lawessons reagent In toluene at 120℃; for 3h; | 1.2 Step 2: 6-Bromo-3,4-dihydroquinolin-2(1H)-thione The compound 6-bromo-3,4-dihydroquinolin-2 (1H) -one (10.0 g, 44.23 mmol) was dissolved in toluene (100 mL)Lawesson reagent (8.95g, 22.12mmol),The suspension was heated to 120 ° C,Reaction for 3 hours.The system was then cooled to 10 ° C and solid precipitated. The solid was collected by filtration through a Buchner funnel and washed with a small amount of dichloromethane and dried to give 6-Bromo-3,4-dihydroquinolin-2(1H)-thione (8 g) in 75% yield. |
With Lawessons reagent In toluene at 100℃; for 3h; | 74.D To a stirred solution of 6-bromo-3,4-dihydroquinolin-2(l H)-one (74-3; 15.0 g, 0.066 mol) in toluene (150 mL) was added Lawesson's reagent (13.4 g, 0.033 mol). Reaction mass was refluxed at 100 °C for 3 h. The reaction mixture was concentrated and directly purified by silica gel column chromatography to obtain title compound. MS (M+2): 243.9. | |
With Lawessons reagent In toluene at 110℃; | 22.A 6-bromo-3,4-dihydroquinolin-2-(lH)-one (1.00 g, 4.42 mmol) and 2,4-bis(4- methoxyphenyl)-l,3,2,4-dithiadiphosphetane2,4-disulfide (0.895 g, 2.21 mmol) were suspended in toluene (110 mL) and then heated to 110 °C overnight. The reaction was then cooled to room temperature and concentrated under reduced pressure.Dichloromethane was added, giving a mixture that was filtered to provide the title compound: LCMS m/z 243.95 [M + 2 + H]+; 1H NMR (500 MHz, DMSO) δ 7.44 (s, 1 H), 7.39 (d, J = 8.4 Hz, 1 H), 7.01 (d, J = 8.4 Hz, 1 H), 2.92 - 2.89 (m, 2 H), 2.81 - 2.78 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: 79 percent / Lawesson's reagent / toluene / 0.75 h / Heating 2.1: 22 percent / K2CO3; 18-crown-6 / tetrahydrofuran / 3 h / 20 °C 3.1: toluene / 0.25 h / Heating 3.2: 42 percent / DBU / toluene / 0.33 h / Heating 4.1: 43 percent / Pd(OAc)2; PPh3; Et3N / 24 h / 95 °C 5.1: 75 percent / H2 / (PPh3)3RhCl / benzene / 6 h / 40 °C / 5171.48 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 120℃; Inert atmosphere; | S-16.1 Step 1 : Synthesis of 6-(4,4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-3,4- dihydroquinolin-2(lH)-one. To a solution of 6-bromo-3,4-dihydroquinolin-2(lH)-one (500 mg, 2.21 mmol, 1.0 equiv) in Dioxane (10 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2- dioxaborolane) (561 mg, 2.21 mmol, 1.0 equiv), KOAc (650 mg, 6.63 mmol, 3.0 equiv) and the mixture purged with N2 gas for 10 min, followed by the addition of PdCk(dppf).DCM (90 mg, 0.1 1 mmol . 0.05 equiv). The resulting reaction mixture was heated at 120° C for overnight. After the completion of reaction (monitored by TLC & LCMS), the mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 c 100 mL). Combined organic extracts were washed with water (50 mL * 2), dried over anhydrous NaiSOr and concentrated to obtain 6- (4,4,5,5-tetramethyi-L3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(lH)-one (300 mg, 50 % Yield) as an off white solid. LCMS 274.0 M 1 f j NMR (400 MHz, DMSG-ae) d 10.23 (s, 1H), 7.39 - 7.52 (m, 2H), 6.83 (d, J= 7.89 Hz 1H), 2.87 (t, J= 7.67 Hz, 2H), 2.39 - 2 47 (m, 2H), 1 .16 - 1.35 (m, 12H). |
With triethylamine In acetonitrile for 4h; Heating / reflux; | 6 Preparation 6; Preparation of 6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)3,4-dihydro-1H-quinolin-2-one. Preparation 6 Preparation of 6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)3,4-dihydro-1H-quinolin-2-one. 6-Bromo-3,4-dihydro-1H-quinolin-2-one (0.35 g, 1.35 mmol) was combined with pinacol borane (0.30 g, 2.33 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.04 g, 0.05 mmol) and triethylamine (0.65 ML, 4.65 mmol) in dry acetonitrile (7 ML) and heated at reflux under N2 for 4 hours then cooled to ambient temperature.The reaction mixture was dumped into diethyl ether and washed with water and saturated NaCl, dried (MgSO4), filtered, and concentrated to give the title compound (0.44 g) as a light yellow oil which was used without purification. | |
With tris-(dibenzylideneacetone)dipalladium(0); potassium acetate; catacxium A In Isopropyl acetate at 83℃; for 1h; Inert atmosphere; Microwave irradiation; | 33 6-Bromo-3,4-dihydro-lH-quinolin-2-one (45 mg, 0.2 mmol), bis(pinacolato)diboron (51 mg, 0.204 mmol), tris(dibenzylideneacetone)dipalladium (5.5 mg, 0.006 mmol), butyldi-1- adamantylphosphine (6.5 mg, 0.018 mmol), potassium acetate (59 mg, 0.6 mmol) were added into a 10 mL microwave vial containing a magnetic stirrer bar, followed by isopropyl acetate (0.45 mL). The vessel was sealed with a cap under an argon atmosphere, and then the resulting mixture was heated to 83 °C for 1 hour. After the reaction was completed as monitored by TLC and LC-MS, 2-(5-bromo-pyridin-3-ylamino)-2-phenyl-acetamide (61 mg, 0.2 mmol), potassium carbonate (81 mg, 0.6 mmol), isopropyl acetate (0.55 mL) and H20 (0.2 mL) were added into the above mixture successively. The vessel was sealed with a cap under an argon atmosphere, then the reaction mixture was heated to 90 °C for 40 mins under microwave. The mixture was cooled to room temperature and diluted with water (5 mL), extracted with ethyl acetate (10 mL x 3), and then the combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, concentrated in vacuo to give crude 2-[5-(2-oxo-l,2,3,4-tetrahydro-quinolin-6-yl)- pyridin-3-ylamino]-2-phenyl-acetamide. The crude compound was purified by C-18 reversed phase HPLC column to give 2-[5-(2-oxo-l,2,3,4-tetrahydro-quinolin-6-yl)-pyridin-3-ylamino]-2- phenyl-acetamide (19 mg) as a white solid. |
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; triethylamine at 87℃; for 24h; | 34 6-(4,4,5)5-Tetramethyl-l,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(lH)-one To a solution of 6-bromo-3)4-dihydroquinoIin-2(lH)-one (200 mg, 0.89 mmol) in 5 n L of acetonitrile was added pinacoldiboron (300 mg, 1.2 mmol), Pd(dppf)2Cl (30 mg, 0.09mmol), KOAc (250 mg, 2.1 mmol) and triethyl amine (ImL). The reaction was heated to 87 °C for 24 h, then cooled to T, The solids were filtered away, and the solvent was removed in vacuo, then extracted with EtOAc, water, brine and dried over Na2S04, The solvent was removed in vacuo to provide an off-white solid which was used without further purification |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium azide; sulfuric acid In benzene at 20 - 65℃; for 0.333333h; | 23.A Example 23; 2'-(6-Carbamimidoyl-3,4-dihydro-2H-quinolin-1-ylmethyl)-biphenyl-2-carboxylic acid; Part A: To a solution of 5-bromo-1-indanone (5.22 g of 90% pure, 22.3 mmol) in 70 mL of benzene was added concentrated H2SO4 (12.6 mL) dropwise at rt. The mixture was heated to 65° C. and sodium azide (3.26 g, 44.5 mmol) was then added portionwise in 20 min. The mixture was cooled to rt, and water and EtOAc were added. The two layers were separated and the aqueous layer was extracted with EtOAc. The combined organic solution was washed with brine, dried over MgSO4, and concentrated to give a brown solid. This material was purified by flash chromatography with 30-50% EtOAc in hexane to give 2.50 g of the desired amide. MS (ES+) 226.2, 228.2 (M+1)+. 1H NMR (CDCl3, 300 MHz) δ(ppm): 8.08 (s, 1H), 7.30 (s, 1H), 7.26 (d, 1H), 6.62 (d, 1H), 2.92 (t, 2H), 2.60 (t, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With borane; In tetrahydrofuran; at 20℃; for 7h;Reflux; Inert atmosphere; | The new N-sulfonamide tetrahydroquinoline derivatives were synthesized by following the synthetic approach (Scheme 1). 6-Bromo-3,4-dihydroquinolin-2(1H)-one was reduced to generate 6-bromo-1,2,3,4-tetrahydroquinoline. 6-bromo-1,2,3,4-tetrahydroquinoline was reacted with benzenesulfonyl chloride/benzylsulfonyl chloride and triethylamine in dichloromethane (DCM) at room temperature. Then, we coupled the bromo-substituent sulfamide intermediates to 1-(piperazin-1-yl)ethan-1-one by a Buchwald-Hartwig coupling reaction in the presence of Palladium(II) acetate,2-dicyclohexylphosphino-2',6'-di-i-porpoxy-1, and 1'-biphenyl and Cs2CO3. In this way, we obtained sulfonamide derivatives 1 and 2, which have only a carbon change in structure. Data of structural identification is presented in the Supporting Information |
The product from Part A was dissolved in 60 mL of THF. It was then added dropwise to a suspension of LiAlH4 (4.0 g) in 100 mL of THF at rt. The reaction mixture was heated to reflux after the addition for 1 h. It was cooled to rt, quenched with 4.5 mL of H2O, 4.5 mL of 1N NaOH, and 13 mL of H2O with cooling (ice-bath). It was then filtered through Celite and washed with THF. The filtrate was dried, concentrated and purified by flash column chromatography 30%-50% EtOAc/hexane) to give 1.5 g of the desired amine. 1HNMR (CDCl3, 300 MHz) 6 (ppm): 7.08 (s, 1H), 7.02 (d, 1H), 6.40 (d, 1H), 3.30 (t, 2H), 2.76 (t, 2H), 1.95 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: 5-Bromo-1-indanone With sodium azide; methanesulfonic acid In dichloromethane at 0 - 20℃; Stage #2: With sodium hydroxide In dichloromethane; water at 0℃; | 1 6-Bromo-3,4-dihvdroisoquinolin-l(2H)-one (1A):NaN3 (6.2 g, 94.78 mmol) was added to a solution of 5-bromo-l-indanone (10 g, 47.39 mmol) in 40 mL mixture of methane sulphonic acid and dichloromethane (1 : 1) in portion wise at 0 °C-5 °C. The resulting mixture was stirred for 8 h at room temperature. The reaction mixture was cooled to 0 °C in ice bath, neutralized with 5 % aq. NaOH solution, and the aqueous layer with extracted with ethyl acetate (2x100 mL). The combined organic layer was washed with water and brine solution, dried over sodium sulphate, filtered and concentrated under vacuum. The residue was purified by silica gel flash column chromatography by eluting with 30 % ethyl acetate in hexane to afford title compound (6.4 g, 60%) as solid. 1H NMR (400 MHz, CDC13): δ 7.95 (d, J = 8.4 Hz, 1H), 7.5 (d, J = 8.4 Hz, 1H), 7.4 (s, 1H), 6.1 (bs, 1H), 3.6 (t, J = 6.8 Hz, 2H), 3.0 (t, J = 6.4 Hz, 2H). |
60% | With sodium azide; methanesulfonic acid In dichloromethane at 0 - 20℃; for 8h; | 1 2-(i -Oxo-6-(4-(3-(3-(trilluoromethyl)phenyl)ureido) phenyl)-3,4-dihydroisoquinolin-2(i H)-yl)acetic acid6-Hromo-3,4-dihydroisoquinolin-i (2H)-one (iA)Procedures:10443] NaN3 (6.2 g, 94.78 mmol) was added to a solution of5-bromo-i-indanone(iO g, 47.39 mmol) in 40 mL of mixture of methane sulphonic acid and dichloromethane (i : i) in portion wise at 00 C.-5° C. The resulting mixture was stirred for 8 h at room temperature. The reaction mixture was cooled to0°C. in ice bath, neutralized with 5% aq. NaOH, and aqueous layer was extracted with ethyl acetate (2x1 00 mE). The combined organic layer was washed with water and brine solution, dried over Na2SO4 and filtered. The filtrate was concentrated under vacuum and purified by silica gel flash column chromatography using 30% ethyl acetate in hexane to afford title compound (6.4 g, 60%) as solid. ö ‘H NMR (400 MHz, CDC13): ö 7.95 (d, J=8.4 Hz, 1H), 7.5 (d, J=8.4 Hz, 1H), 7.4 (s, 1H), 6.1 (bs, 1H), 3.6 (t, J=6.8 Hz, 2 |
1: 25% 2: 46% | With sodium azide; methanesulfonic acid In chloroform at 0 - 10℃; for 2.5h; Heating / reflux; | 6; 7 5-Bromoindan-1-one (44 g, 209 mmol) was dissolved in CHCl3 (750 mL) with vigorous stirring and cooled to 0° C. Methanesulfonic acid (135 mL, 2090 mmol) was added dropwise. Sodium azide (40.7 g, 625 mmol) was added in portions over 30 min such that the internal temperature did not exceed 10° C. The reaction mixture was heated to reflux temperature and stirred for 2 h. The reaction mixture was cooled to room temperature and poured onto ice (1 kg) with manual stirring. The mixture was neutralized with NH4OH. The layers were separated. The organic solution was dried over MgSO4, filtered and concentrated in vacuo. Column chromatography (EtOAc) provided, after removal of solvent in vacuo: (1) 6-bromo-2H-1,2,3,4-quinol-1-one (10.7 g, 25% yield): 1H NMR (CDCl3, 300 MHz): 8.11 (br s, 1H), 7.32 (d, 1H, J=1), 7.29 (dd, 1H, J=8, 1), 6.23 (br s, 1H), 6.25 (br s, 1H), 2.98 (t, 2H, J=7), 2.65 (t, 2H, J=7); MS (APCI+): 267, 269 (C11H12BrN2O, M++H+CH3CN) and (2) 6-bromo-1H-1,2,3,4-tetrahydroisoquinolone (21.5 g, 46% yield): 1H NMR (CDCl3, 300 MHz): 7.95 (d, 1H, J=8), 7.51 (dd, 1H, J=8, 1), 7.21 (t, 1H, J=1), 6.25 (br s, 1H), 3.59 (t, 2H, J=7), 3.01 (t, 2H, J=7); MS (APCI+): 267, 269 (C11H12BrN2O, M++H+CH3CN). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium acetate In methanol for 24h; Heating / reflux; | 78.A Example 78 4-Aminomethyl-cyclohexanecarboxylic acid {1-[3-(2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-phenyll-2-phenyl-ethyl}-amide 78A. 6-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-3,4-dihydro-1H-quinolin-2-one: To 6-bromo-1,2,3,4-tetrahydro-2-quinolinone (3 g, 13.0 mmol) in MeOH (65 mL) degassed with Argon was added bis(neopentylglycoloto)boron (3.29 g, 14.5 mmol), KOAc (3.25 g, 33.0 mmol) and PdCl2(dppf).CH2Cl2 (0.32 g, 0.39 mmol) and the reaction was heated to reflux 24 h. The reaction was concentrated, quenched with water and extracted with EtOAc (2×25 mL), washed with brine and dried (MgSO4). Purification on silica gel (hexane/EtOAc then CH2Cl2/EtOAc) afforded 0.45 g of the boronate as a white solid. LC/MS m/z (M+H-C5H8)+=192. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium carbonate In 1,4-dioxane; water at 100℃; | 116.a a) 6-(4-Aminophenyl)-3,4-dihydro-2(1 H)-quinolinone A mixture of 6-bromo-3,4-dihydro-2(1 H)-quinolinone (2.64 g, 11.68 mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline (2.81 g, 12.80 mmol), sodium carbonate (3.7 g, 34.9 mmol) and tetrakis(triphenylphosphine)palladium (0) (250 mg, 0.22 mmol) in water (20 mL) and dioxane (50 mL) was sealed in pressure bottle under argon and heated at 1000C overnight. The mixture was cooled and diluted with water and extracted twice with ethyl acetate, the combined extracts washed with water and brine, dried and evaporated. The residue was slurried in ether to give the title compound as a pale yellow solid (2.5 g, 90%). 1 H NMR (400MHz, D6-DMSO) δ10.07 (s, 1 H), 7.34 (s, 1 H), 7.28-7.31 (m, 4H), 6.84 (d, J = 8.2 Hz, 1 H), 6.60 (dd, J = 6.7 and 1.8 Hz, 2H), 5.16 (br s, 2H), 2.90 (t, J = 7.1 Hz, 2H), 2.45 (t, J = 7.2 Hz, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium carbonate In 1,4-dioxane; water at 90℃; for 20h; | 12 6-(4-TrifluoromethylphenylV3.4-dihvdro-1 H-αuinolin-2-one A mixture of 6-bromo-3,4-dihydro-1 H-quinolin-2-one (0.226 g, 1.00 mmol), 4-(trifluoromethyl)phenylboronic acid (0.380 g, 2.0 mmol), tetrakis(triphenylphosphine)palladium (0) (0.065 g, 0.056 mmol), 2M aqueous EPO potassium carbonate (5 mL, 10 mmol) and dioxane (5 ml_) was stirred under argon at 90 0C for 20 h, then cooled, poured into 0.4M aqueous HCI (50 mL) and extracted with ethyl acetate. The extracts were washed with water, brine and dried (MgSO4), then the solvent removed under reduced pressure and the residue chromatographed (silica gel, 20-80% ethyl acetate/ hexane) to give the title compound (0.249 g, 85%) as a cream solid. 1H NMR (400MHz, D6-DMSO) δ 10.23 (s, 1 H), 7.86 (d, J = 8.2 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.60 (s, 1 H), 7.55 (dd, J = 8.2, 2.1 Hz, 1 H), 6.98 (d, J = 8.2 Hz, 1 H), 2.97 (t, J = 7.5 Hz, 2H), 2.51 (partially obscured by D5-DMSO, 2H). |
75% | Stage #1: 6-bromo-3,4-dihydro-1H-quinolin-2-one; 4-trifluoromethylphenylboronic acid With sodium hydrogencarbonate In water; N,N-dimethyl-formamide for 0.0833333h; Inert atmosphere; Stage #2: In water; N,N-dimethyl-formamide at 70℃; | 2.A A. Synthesis of a Compound of Formula (I) in which R1, R2, R3, R5, and R6 are Hydrogen, R4 is 6-(4-Trifluoromethyl)phenyl), R7 is Hydrogen, and X1 and X2 are both -CH= To a solution of 6-bromo-3,4-dihydroquinolin-2(1H)-one (2.260 g, 10.00 mmol) and 4-(trifluoromethyl)phenyl boronic acid (2.850 g, 15.00 mmol) in N,N-dimethylformamide (50 mL) was added sodium bicarbonate (3.360 g, 40.00 mmol) and water (5 mL). The reaction mixture was stirred for 5 minutes under an atmosphere of dry N2, then Pd(PPh3)4 (579 mg, 0.50 mmol) was added, and the resulting mixture was heated at 70° C. until the starting material (6-bromo-3,4-dihydroquinolin-2(1H)-one) was no longer seen by TLC. The mixture was cooled, diluted with ethyl acetate (50 mL), filtered through a layer of celite, which was washed with 10% N,N-dimethylfonnamide in ethyl acetate (100 mL), and the filtrate transferred to a separation funnel. The organic phase was washed with 1N sodium carbonate (100 mL), 30% ammonium chloride (100 mL), and brine (100 mL). Solvent was removed under reduced pressure to provide a yellow solid. Methanol (5.0 mL) was added, and the mixture sonicated, filtered, washed with methanol (5.0 mL), and dried under reduced pressure to afford 6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one (2.184 g, 7.5 mmol, 75%). LCMS mz 292.0 (M+H), anal HPLC ca 94% in purity, 1H NMR (400 MHz; CDCl3) δ 7.98 (s, 1H); 7.66 (m, 4H); 7.40-7.50 (m, 2H); 6.86 (d, J=9.0 Hz, 1H); 3.06 (t, J=7.6 Hz, 2H); 2.70 (t, J=7.6 Hz, 2H). |
With caesium carbonate In water; N,N-dimethyl-formamide at 90℃; for 2h; Inert atmosphere; | 1 462 mg 4-(Trifluormethyl)phenyl-ylboronic acid, 500 mg 6-B romo-3,4-di hydro- 1H- quinolin-2-one and 2.16 g cesium carbonate were dissolved in a mixture of 2 ml water and 8 ml dimethylformamide. The reaction mixture was degassed with argon and then 128 mg tetrakis(triphenylphosphine)palladium(0) were added and the mixture heated to 900C for two hours. The cooled reaction mixture was diluted with 100 ml ethyl acetate and washed with 50 ml water and brine. The organic layer was dried over MgSO4 and the solvent removed in vacuo. The resulting crude material was purified by purified by chromatography on silica gel to obtain 637 mg 6-(4-Trifluoromethyl-phenyl)- 3,4-dihydro-1 H-quinolin-2-one. C16H12F3NO (291.28), MS(ESI+): 333.21 (M+MeCN+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dichloromethane; water; N,N-dimethyl-formamide; at 120℃; for 0.166667h;Microwave irradiation; | 6-(4-Fluoro-3-methylphenyl)-3,4-dihvdro-1 H-quinolin-2-oneA solution of 6-bromo-1 ,2,3,4-tetrahydro-2-quinolinone (0.149 g, 0.66 mmol), 4-fluoro-3-methylphenylboronic acid (0.123 g, 0.80 mmol), [1 ,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium (II) dichloromethane adduct (0.016 g, 0.02 mmol) and 2M aqueous sodium carbonate solution (1 mL, 2.00 mmol) in N,N-dimethylformamide (2.0 mL) was subjected to microwave irradiation at 120 2C for 10 minutes. The reaction was filtered through a 0.45mum nylon syringe filter and purified directly by preparative HPLC. The product was allowed to precipitate from the HPLC fractions overnight then was filtered, rinsed with water and vacuum dried to give the product as a white solid. MS (ES) m/e 256 (M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dichloromethane; water; N,N-dimethyl-formamide; at 110℃; for 0.166667h;Microwave irradiation; | 6-(4-|"(1-Methylethyl)thio1phenyl>-3,4-dihyro-2(1 H)-quinolinone6-Bromo-3,4-dihydro-1 H-quinolin-2-one (0.500 g, 2.0 mmol), and 4-isopropyl thiophenyl boronic acid (0.470 g, 2.4 mmol) were dissolved in DMF (6 mL). To this solution was added 2M aq. sodium carbonate (3 mL, 6.0 mmol) followed by [1 ,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) dichloromethane complex (0.015 g, 0.02mmol). The reaction was heated in the Emrys Optimizer microwave reactor at 1 10 0C for 10 min. The reaction was filtered through Celite and purified by reverse phase HPLC (20-95% CH3CN : H2O, 0.1% TFA) to give the desired material (170 mg, 29%) as the trifluoroacetate salt. MS (ES) m/e 297 (M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
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38% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 90℃; | 6-r3-Chloro-4-(trifluoromethyl)phenyl1-3.4-dihvdro-2(1 H)-quinolinoneTo a solution of [3-chloro-4-(trif luoromethyl)phenyl]boronic acid (100 mg, 0.45 mmol) in dioxane (5 mL) and aqueous potassium carbonate (2 M, 5 mL) were added tetrakis(triphenylphosphine)palladium (0) (26 mg, 0.022 mmol) and 6-bromo-3,4- dihydro-2(1 H)-quinolinone (100 mg, 0.45 mmol). The mixture was heated at 90 0C overnight, cooled, poured into water and extracted with ethyl acetate (3 x 30 mL).The combined extracts were dried over MgStheta4, concentrated in vacuo and purified by flash chromatography (0-100% ethyl acetate in hexanes) to give the title compound (55 mg, 38%) as a white solid. 1 H NMR (400MHz, CDCI3) delta 8.58 (br s, 1 H), 7.86 (d, J = 2.3 Hz, 1 H), 7.66 (dd, J = 2.1 , 8.4 Hz, 1 H), 7.57 (d, J= 8.3 Hz, 1 H), 7.42 (m, 2H), 6.92 (d, J = 8.6 Hz, 1 H), 3.09 (t, J = 7.5 Hz, 2H), 2.73 (t, J = 7.6 Hz,2H). MS(ES+) m/e 326 [M+HJ+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate In dichloromethane; water; N,N-dimethyl-formamide at 110℃; for 0.166667h; Microwave irradiation; | 46 6-(2,2-Difluorobenzo[1 ,3ldioxol-5-yl)-3,4-dihvdro-1H-quinolin-2-oneA solution of 5-bromo-2,2-difluoro-1 ,3-benzodioxole (0.256 g, 1.Oδmmol), bis(pinacolato)diboron (0.302 g, 1.19mmol), [1 ,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (II) dichloromethane adduct (0.024 g, 0.03mmol), and potassium acetate (0.318 g, 3.24mmol) in N, N- dimethylformamide (2.0 ml_) was subjected to microwave irradiation at 100 9C for 6.5 minutes. To this was added more [1 ,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (II) dichloromethane adduct (0.024 g, 0.03mmol), 6-bromo-1 ,2,3,4-tetrahydro-2-quinolinone (0.233 g, 1 ,03mmol) in N.N-dimethylformamide (1.0 ml_), and 2M aqueous sodium carbonate solution (1.62 mL, 3.24 mmol). The reaction was again subjected to microwave irradiation at 110 9C for 10 minutes then filtered through a 0.45μm nylon syringe filter and purified directly by preparative HPLC. The product was allowed to precipitate from the HPLC fractions overnight then was filtered, rinsed with water and vacuum dried to give the product as a white solid. MS (ES) m/e 304 (M + H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5% | With potassium acetate; potassium carbonate; bis(pinacol)diborane In dichloromethane; water; N,N-dimethyl-formamide at 100℃; for 0.111111h; Microwave irradiation; | 102 6-f4-(1 ,1-Dimethylpropyl)-1 -cvclohexen-1 -vn-3,4-dihydro-2(1H)-αuinolinone To a microwave tube was added 6-bromo-3,4-dihydro-2(1 H)-quinolinone (100 mg, 0.444 mmol), 4-(1 ,1-dimethylpropyl)-1 -cyclohexen-1-yl trifluoromethanesulfonate (126 mg, 0.422 mmol), bis(pinacolato)diboron (124 mg, 0.488 mmol), [1 ,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium (II) dichloromethane adduct (22 mg, 0.026 mmol), potassium acetate (131 mg, 1.30 mmol), 2M aqueous potassium carbonate (650 μl_, 1.30 mmol), and DMF (3 mL). The tube was heated in the microwave at 100 0C for 400 s. The reaction mixture was diluted with ethyl acetate (20 mL) and filtered. The filtrate was washed with water (20 mL) and brine (20 mL). The organic layer was dried over MgSO4, filtered and solvent removed under reduced pressure. The crude residue was purified by rp-HPLC to give the title compound as a light brown powder (6.5 mg, 5%). 1 H NMR (400MHz, CDCI3) δ ppm 7.90 (s, 1 H) 7.19 (d, J=3.79 Hz, 2 H) 6.63 - 6.71 (m, 1 H) 6.04 - 6.10 (m, 1 H) 2.96 (t, EPO J=7.45 Hz1 2 H) 2.58 - 2.67 (m, 2 H) 2.44 - 2.47 (m, 1 H) 2.39 (ddd, J=9.41 , 4.74, 2.53 Hz, 1 H) 2.13 - 2.23 (m, 1 H) 1.90 - 2.02 (m, 2 H) 1.38 - 1.49 (m, 1 H) 1.25 - 1.36 (m, 4 H) 0.79 - 0.89 (m, 9 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; | 59.a; 12.a.1 a) (2-Oxo-i ,2,3,4-tetrahydro-6-quinolinyl)boronic acidTo a solution of 6-bromo-3,4-dihydro-2(1 /-/)-quinolinone (1 g, 4.4 mmol) in dry tetrahydrofuran (15 ml_) at 0 0C was added sodium hydride (212 mg, 60% dispersion, 5.23 mmol). After the mixture was stirred for half an hour at 0 0C, it was cooled to - 78 0C and n-butylithium (1.6 M in hexane, 3.1 ml_, 4.96 mmol) was added. The mixture was kept stirring for another half hour, then trimethyl borate (1.5 mL, 13.2 mmol) was added. The reaction was warmed to the room temperature, quenched with ice water and extracted with ethyl acetate (3 x 30 mL). The combined extracts was dried over MgSO4, filtered and concentrated in vacuo. The residue was used in the next step without purification. |
Yield | Reaction Conditions | Operation in experiment |
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With pyridine; copper(I) iodide; triethylamine In methanol; dichloromethane | 9.a Preparation of 6-[3-(imidazol-1-yl)prop-1-yn-1-yl]-3,4-dihydrocarbostyril, the compound of Formula IM (a) A mixture of 11.6 mg of cuprous iodide, 86 mg of bis (triphenylphosphine) palladium (II) dichloride, 1.5 g of 6-bromo-3,4-dihydrocarbostyril and 774 mg of N-propargylimidazole was stirred in a mixture of 10 ml of pyridine and 2 ml of triethylamine at 100° C. for 48 hours under nitrogen. The reaction was then treated with 10 ml of saturated aqueous potassium carbonate and extracted with a solution of 10% methanol in methylene chloride. The extract was dried over anhydrous sodium sulfate, the solvent removed under reduced pressure and the residue chromatographed on silica gel eluding with 4% methanol in methylene chloride, yielding 6-[3-(imidazol-1-yl)-prop-1-yn-1-yl]-3,4-dihydrocarbostyril, m.p. 164°-168° C. |
Yield | Reaction Conditions | Operation in experiment |
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With copper(I) iodide; potassium carbonate; triethylamine In pyridine; methanol; dichloromethane | 2 Preparation of 6-ethynyl-3,4-dihydrocarbostyril PREPARATION 2 Preparation of 6-ethynyl-3,4-dihydrocarbostyril A mixture of 8.0 g of 6-bromo-3,4-dihydrocarbostyril, 6.95 g of trimethylsilylacetylene, 460 mg of bis(triphenylphosphine)palladium dichloride and 62 mg of cuprous iodide in 53 ml of pyridine and 11 ml of triethylamine was refluxed for 3 days. The solvent was removed under reduced pressure, 50 ml of methanol added along with 300 mg of potassium carbonate, and the mixture stirred under nitrogen for 18 hours. The solvent was removed under reduced pressure and the residue chromatographed on silica gel, eluding with 3% methanol in methylene chloride, giving a product of 6-ethynyl-3,4-dihydrocarbostyril, m.p. 182°-184° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; ammonium chloride; In tetrahydrofuran; | b) 2-Oxo-1,2,3,4-tetrahydro-6-quinolinecarboxylic acid To dried THF (200 mL) under nitrogen was added 6-bromo-3,4-dihydro-2(1H)-quinolinone (5 g, 22.1 mmol). The solution was cooled to -78 C. and n-butyllithium (2.5M in THF) (29 mL, 3.3 eq) added, then stirred at -78 C. for 30 minutes. Nitrogen gas was passed through dry ice and into the reaction vessel for 10 minutes and then the reaction was allowed to warm to room temperature over 1 h. The mixture was quenched with saturated ammonium chloride solution and all non-acidic material was extracted into ethyl acetate (2*). The aqueous layer was acidified with 2M HCl, and the resultant precipitate filtered, washed and dried in vacuo at 45 C. to give the title compound as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate In water; N,N-dimethyl-formamide at 150℃; for 0.25h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | Stage #1: 6-bromo-3,4-dihydro-1H-quinolin-2-one With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: ethyl bromide In N,N-dimethyl-formamide for 12h; | |
59% | Stage #1: 6-bromo-3,4-dihydro-1H-quinolin-2-one With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: ethyl bromide In N,N-dimethyl-formamide | 3 To a solution of 6-bromo-3,4-dihydro-1H-quinolin-2-one (750 mg, 3.32 mmol) in 20 ml dry DMF was added potassium tert-butylate (804 mg, 6.64 mmol). After the mixture was stirred for 30 min at room temperature, a solution of ethyl bromide (724 mg, 6.64 mmol) in 10 ml dry DMF was added. Following overnight stirring, the mixture was diluted with 150 ml 1 N HCl. Extraction with ethyl acetate (2×100 mL) followed by washing of the organic extracts with water and brine, drying over MgSO4 and removal of the solvent in vacuo gave a light yellow solid. Purification by flash chromatography (hexanes/ethyl acetate, 1/1, Rf=0.52) gave 6-bromo-1-ethyl-3,4-dihydro-1H-quinolin-2-one (583 mg, 2.29 mmol, 59%) as a colorless solid. |
59% | Stage #1: 6-bromo-3,4-dihydro-1H-quinolin-2-one With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: ethyl bromide In N,N-dimethyl-formamide | 3 To a solution of 6-bromo-3,4-dihydro-1 H-quinolin-2-one (750 mg, 3.32 mmol) in 20 ml dry DMF was added potassium te/f-butylate (804 mg, 6.64 mmol). After the mixture was stirred for 30 min at room temperature, a solution of ethyl bromide (724 mg, 6.64 mmol) in 10 ml dry DMF was added. Following overnight stirring, the mixture was diluted with 150 ml 1 N HCI. Extraction with ethyl acetate (2 x 100 mL) followed by washing of the organic extracts with water and brine, drying over MgSO4 and removal of the solvent in vacuo gave a light yellow solid. Purification by flash chromatography (hexanes/ethyl acetate, 1/1 , Rf = 0.52) gave 6- bromo-1-ethyl-3,4-dihydro-1 H-quinolin-2-one (583 mg, 2.29 mmol, 59 %) as a colorless solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; water; toluene Inert atmosphere; Reflux; | |
96% | With sodium carbonate In ethanol; water; toluene Inert atmosphere; Reflux; | 1 The title compound was obtained via Suzuki coupling according to genera/procedure B from 6-bromo-3,4-dihydro-1H-quinolin-2-one (2.71 g, 12.0 mmol) and 3-pyridineboronic acid (1.23 g, 10.0 mmol) after crystallization from acetone/diethylether as colorless needles (2.15 g, 9.59 mmol, 96%), mp (acetone/diethylether) 189° C. 1H-NMR (500 MHz, DMSO-d6): δ=2.49 (t, 3J=7.3 Hz, 2H), 2.95 (t, 3J=7.3 Hz, 2H), 6.95 (d, 3J=8.2 Hz, 1H), 7.43 (ddd, 3J=7.9 Hz, 3J=4.7 Hz, 5J=0.6 Hz, 1H), 7.51 (dd, 3J=8.2 Hz, 4J=2.2 Hz, 1H), 7.56 (d, 4J=2.1 Hz, 1H), 8.00 (ddd, a 3J=7.9 Hz, 4J=2.2 Hz, 4J=1.6 Hz, 1H), 8.50 (dd, 3J=4.7 Hz, 4J=1.5 Hz, 1H), 8.84 (d, 4J=2.2 Hz, 1H), 10.19 (s, 1H). 13C-NMR (125 MHz, DMSO-d6): δ=24.8, 30.3, 115.6, 123.8, 124.3, 125.6, 126.2, 130.6, 133.4, 135.2, 138.4, 147.2, 147.8, 170.2. MS m/z 225.25 (MH+). General procedure B: Suzuki coupling with conventional heating. Pyridine boronic acid (1 equivalent), aryl bromide (1.3-1.5 equivalents), and tetrakis(triphenyl-phosphane)palladium(0) (5 mol %) were suspended in toluene/ethanol 4/1 to give a 0.07-0.1 M solution of boronic acid under an atmosphere of nitrogen. To this was added a 1 N aqueous solution of Na2CO3 (6 equivalents). The mixture was then refluxed for 12-18 h, cooled to room temperature, diluted with water and extracted several times with ethyl acetate. The combined extracts were dried over MgSO4, concentrated and purified by flash chromatography on silica gel and/or crystallization. If an oil was obtained, it was transferred into the hydrochloride salt by addition of 1N HCl solution in diethylether and/or THF. |
96% | With sodium carbonate In ethanol; water; toluene Inert atmosphere; Reflux; | 1 The title compound was obtained via Suzuki coupling according to general procedure B from 6-bromo-3,4-dihydro-1H-quinolin-2-one (2.71 g, 12.0 mmol) and 3-pyridineboronic acid (1.23 g, 10.0 mmol) after crystallization from acetone/diethylether as colorless needles (2.15 g, 9.59 mmol, 96 %), mp (acetone/diethylether) 189 0C. 1H-NMR (500 MHz, DMSO-Cf6): δ = 2.49 (t, 3J = 7.3 Hz, 2H), 2.95 (t, 3J = 7.3 Hz, 2H)1 6.95 (d, 3J = 8.2 Hz, 1 H), 7.43 (ddd, 3J = 7.9 Hz, 3J = 4.7 Hz, 5J = 0.6 Hz, 1 H)1 7.51 (dd, 3J = 8.2 Hz, 4J = 2.2 Hz, 1 H), 7.56 (d, 4J = 2.1 Hz, 1 H), 8.00 (ddd, 3J = 7.9 Hz, 4J = 2.2 Hz, 4J = 1.6 Hz, 1 H), 8.50 (dd, 3J = 4.7 Hz, 4J = 1.5 Hz, 1 H), 8.84 (d, 4J = 2.2 Hz, 1 H), 10.19 (s, 1 H). 13C-NMR (125 MHz, DMSOd6): δ = 24.8, 30.3, 115.6, 123.8, 124.3, 125.6, 126.2, 130.6, 133.4, 135.2, 138.4, 147.2, 147.8, 170.2. MS m/z 225.25 (MH+). General procedure B: Suzuki coupling with conventional heating. Pyridine boronic acid (1 equivalent), aryl bromide (1.3-1.5 equivalents), and tetrakis(triphenyl- phosphane)palladium(O) (5 mol %) were suspended in toluene/ethanol 4/1 to give a 0.07-0.1 M solution of boronic acid under an atmosphere of nitrogen. To this was added a 1 N aqueous solution of Na2CO3 (6 equivalents). The mixture was then refluxed for 12-18 h, cooled to room temperature, diluted with water and extracted several times with ethyl acetate. The combined extracts were dried over MgSO4, concentrated and purified by flash chromatography on silica gel and/or crystallization. If an oil was obtained, it was transferred into the hydrochloride salt by addition of 1 N HCI solution in diethylether and/or THF. |
With potassium carbonate In water; <i>tert</i>-butyl alcohol at 100℃; Inert atmosphere; Sealed tube; | 1.A A sealable tube containing 6-bromo-3,4-dihydroquinolin-2(lH)-one (0.10 g, 0.44 mmol), 3-pyridylboronic acid (0.56 g, 4.6 mmol), bis(di-tert-butyl(4-dimethylamino phenyl)phosphine)dichloropalladium(II) (6.3 mg, 8.9 μιηο), and potassium carbonate (0.18 g, 1.3 mmol) was flushed with nitrogen before tert-butanol (4.9 mL) and water (0.6 mL) were added. The tube was flushed again with nitrogen, sealed tightly and heated to 100 °C overnight. The reaction was then cooled to room temperature, poured into saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic extracts were combined, washed with water, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (0 - 15% methanol in ethyl acetate) provided the title compound: LCMS m/z 225.27 [M + H]+; 1H NMR (500 MHz, CD3OD) 6 8.77 (s, 1 H), 8.47 (d, J = 4.8 Hz, 1 H), 8.06 (ddd, J = 1.7, 2.0, 8.1 Hz, 1 H), 7.52 (s, 1 H), 7.50 - 7.47 (m, 2 H), 6.99 (d, J = 8.1 Hz, 1 H), 3.05 (t, J = 7.5, 7.7 Hz, 2 H), 2.61 (t, J = 7.5, 7.7 Hz, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | To a solution of 6-bromo-3,4-dihydro-1H-quinolin-2-one (750 mg, 3.32 mmol) in 20 ml dry DMF was added potassium tert-butylate (804 mg, 6.64 mmol). After the mixture was stirred for 30 min at room temperature, a solution of isopropyl bromide (814 mg, 6.64 mmol) in 10 ml dry DMF was added and the mixture heated to 80 C. After stirring for additional 48 h, the mixture was cooled to room temperature and diluted with 150 ml 1 N HCl. Extraction with ethyl acetate (2×100 mL) followed by washing of the organic extracts with water and brine, drying over MgSO4 and removal of the solvent in vacuo gave a light yellow solid. Purification by flash chromatography (hexanes/ethyl acetate, 4/1, Rf=0.21) gave 6-bromo-1-isopropyl-3,4-dihydro-1H-quinolin-2-one (347 mg, 1.29 mmol, 33%) as pale yellow solid. | |
33% | To a solution of 6-bromo-3,4-dihydro-1 H-quinolin-2-one (750 mg, 3.32 mmol) in 20 ml dry DMF was added potassium tert-butylate (804 mg, 6.64 mmol). After the mixture was stirred for 30 min at room temperature, a solution of isopropyl bromide (814 mg, 6.64 mmol) in 10 ml dry DMF was added and the mixture heated to 80 0C. After stirring for additional 48 h, the mixture was cooled to room temperature and diluted with 150 ml 1 N HCI. Extraction with ethyl acetate (2 x 100 mL) followed by washing of the organic extracts with water and brine, drying over MgSO4 and removal of the solvent in vacuo gave a light yellow solid. Purification by flash chromatography (hexanes/ethyl acetate, 4/1 , Rf = 0.21 ) gave 6-bromo-1-isopropyl- 3, 4-dihydro-1 H-quinolin-2-one (347 mg, 1.29 mmol, 33 %) as pale yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With tetrakis(triphenylphosphine) palladium(0); sodium hydrogencarbonate In water; N,N-dimethyl-formamide at 150℃; for 0.25h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | To a solution of 6-bromo-3,4-dihydroquinolin-2(1H)-one (5 g, 22.1 mmol) in DMF (100 mL) cooled to 0 C. was added potassium tert-butoxide (4.96 g, 44.2 mmol) portionwise and the reaction mixture was stirred at 0 C. for 15 min. Then, methyl iodide (4.08 g, 28.8 mmol) was added and the reaction mixture allowed to warm up to room temperature and stirring was continued over night. More MeI (1.25 g, 8.86 mmol) was added and the reaction mixture was heated to 40 C. until completion of the reaction. The mixture was diluted with EtOAc, poured into 100 mL of 1M HCl and the aqueous phase was extracted with EtOAc (2×200 mL). Combined organics were washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 30% EtOAc-heptane gradient to give the title compound (4.23 g, 80%) as an off white solid. MS: 240.0, 242.1 (M+H+) | |
80% | Intermediate A-l l-Methyl-6-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-3,4-dihydro-lH-quinolin-2- one[A] 6-Bromo- 1 -methyl-3 ,4-dihydro- lH-quinolin-2-oneTo a solution of 6-bromo-3,4-dihydroquinolin-2(lH)-one (5 g, 22.1 mmol) in DMF (100 mL) cooled to 0C was added potassium tert-butoxide (4.96 g, 44.2 mmol) portionwise and the reaction mixture was stirred at 0 C for 15 min. Then, methyl iodide (4.08 g, 28.8 mmol) was added and the reaction mixture allowed to warm up to room temperature and stirring was continued over night. More Mel (1.25 g, 8.86 mmol) was added and the reaction mixture was heated to 40 C until completion of the reaction. The mixture was diluted with EtOAc, poured into 100 mL of 1M HCl and the aqueous phase was extracted with EtOAc (2 x 200 mL). Combined organics were washed with brine, dried over Na2S04, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 30% EtO Ac-heptane gradient to give the title compound (4.23 g, 80 %) as an off white solid. MS: 240.0, 242.1 (M+H+). | |
80% | [A] 6-Bromo- 1 -methyl-3 ,4-dihydro- lH-quinolin-2-oneTo a solution of 6-bromo-3,4-dihydroquinolin-2(lH)-one (5 g, 22.1 mmol) in DMF (100 mL) cooled to 0C was added potassium tert-butoxide (4.96 g, 44.2 mmol) portionwise and the reaction mixture was stirred at 0 C for 15 min. Then, methyl iodide (4.08 g, 28.8 mmol) was added and the reaction mixture allowed to warm up to room temperature and stirring was continued over night. More Mel (1.25 g, 8.86 mmol) was added and the reaction mixture was heated to 40 C until completion of the reaction. The mixture was diluted with EtOAc, poured into 100 mL of 1M HCl and the aqueous phase was extracted with EtOAc (2 x 200 mL). Combined organics were washed with brine, dried over Na2S04, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 30% EtO Ac-heptane gradient to give the title compound (4.23 g, 80 %) as an off white solid. MS: 240.0, 242.1 (M+H+). |
80% | To a solution of 6-bromo-3,4-dihydroquinolin-2(lH)-one (5 g, 22.1 mmol) in DMF (100 mL) cooled to 0 C was added potassium ie/t-butoxide (4.96 g, 44.2 mmol) portionwise and the reaction mixture was stirred at 0 C for 15 min. Then, methyl iodide (4.08 g, 28.8 mmol) was added and the reaction mixture allowed to warm up to room temperature and stirring was continued over night. More Mel (1.25 g, 8.86 mmol) was added and the reaction mixture was heated to 40 C until completion of the reaction. The mixture was diluted with EtOAc, poured into 100 mL of 1M HC1 and the aqueous phase was extracted with EtOAc (2 x 200 mL). Combined organics were washed with brine, dried over Na2S04, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 30% EtO Ac-heptane gradient to give the title compound (4.23 g, 80 %) as an off white solid. MS: 240.0, 242.1 (M+H+). | |
80% | ΓΑ1 6-Bromo-l-methyl-3,4-dihvdroquinolin-2-one To a solution of 6-bromo-3,4-dihydro-lH-quinolin-2-one (5 g, 22.1 mmol) in DMF (100 mL) cooled to 0 C was added potassium ie/t-butoxide (4.96 g, 44.2 mmol) portion wise and the reaction mixture was stirred at 0 C for 15 min. Then, methyl iodide (4.08 g, 28.8 mmol) was added and the reaction mixture allowed to warm up to room temperature and stirring was continued overnight. More methyl iodide (1.25 g, 8.86 mmol) was added and the reaction mixture was heated to 40 C until completion of the reaction. The mixture was diluted with EtOAc, poured into 100 mL of IN HCl and the aqueous phase was extracted with EtOAc (2 x 200 mL). The combined organics were washed with brine, dried over anhy. Na2S04, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 30% EtO Ac-heptane gradient to give the title compound (4.23 g, 80 %) as an off white solid. MS: 240.0, 242.1 (M+H+). | |
80% | To a solution of 6-bromo-3,4-dihydro-lH-quinolin-2-one (5 g, 22.1 mmol) in DMF (100 mL) cooled to 0 C was added potassium ie/t-butoxide (4.96 g, 44.2 mmol) portion wise and the reaction mixture was stirred at 0 C for 15 min. Then, methyl iodide (4.08 g, 28.8 mmol) was added and the reaction mixture allowed to warm up to room temperature and stirring was continued overnight. More methyl iodide (1.25 g, 8.86 mmol) was added and the reaction mixture was heated to 40 C until completion of the reaction. The mixture was diluted with EtOAc, poured into 100 mL of IN HCl and the aqueous phase was extracted with EtOAc (2 x 200 mL). The combined organics were washed with brine, dried over anhy. Na2S04, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 30% EtO Ac-heptane gradient to give the title compound (4.23 g, 80 %) as an off white solid. MS: 240.0, 242.1 (M+H+). | |
78% | To a solution of 6-bromo-3,4-dihydro-1H-quinolin-2-one (339 mg, 1.50 mmol) in 15 ml dry DMF was added potassium tert-butylate (336 mg, 3.0 mmol). After the mixture was stirred for 30 min at room temperature, a solution of methyl iodide (426 mg, 3.0 mmol) in 5 ml dry DMF was added. Following overnight stirring, the mixture was diluted with 100 ml 1 N HCl. Extraction with ethyl acetate (2×100 mL) followed by washing of the organic extracts with water and brine, drying over MgSO4 and removal of the solvent in vacuo gave a light yellow solid. Purification by flash chromatography (hexanes/ethyl acetate, 7/3, Rf=0.21) gave 6-bromo-1-methyl-3,4-dihydro-1H-quinolin-2-one (281 mg, 1.17 mmol, 78%) as colorless needles. | |
78% | To a solution of 6-bromo-3,4-dihydro-1 H-quinolin-2-one (339 mg, 1.50 mmol) in 15 ml dry DMF was added potassium tert-butylate (336 mg, 3.0 mmol). After the mixture was stirred for 30 min at room temperature, a solution of methyl iodide (426 mg, 3.0 mmol) in 5 ml dry DMF was added. Following overnight stirring, the mixture was diluted with 100 ml 1 N HCI.Extraction with ethyl acetate (2 x 100 ml_) followed by washing of the organic extracts with water and brine, drying over MgSO4 and removal of the solvent in vacuo gave a light yellow solid. Purification by flash chromatography (hexanes/ethyl acetate, 7/3, R, = 0.21) gave 6- bromo-1-methyl-3,4-dihydro-1H-quinolin-2-one (281 mg, 1.17 mmol, 78 %) as colorless needles. | |
56% | To a stirred solution of 6-bromo-3,4-dihydroquinolin-2(lH)-one (0.250 g, 1.106 mmol, 1.0 equiv) in DMF (2.5 ml) was cooled at 0 UC. Sodium hyride (0.050 g, 2.22 mmol, 2.0 equiv) was added slowly in the above reaction mixture and stirred for 20 min. Mel (0.298 g, 2.22 mmol, 2.0 equiv) was added at 0 C. The resulting reaction mixture was stirred at RT for lh. Product formation was confirmed by TLC. After the completion of reaction, the reaction mixture was diluted with cold water (50 mL) and extracted with ethyl acetate (50 mL c 3). Combined organic extracts were washed with water (50 ml, c 2) & brine (50 mL), dried over anhydrous NaiSCfi and concentrated . The crude product was purified by flash chromatography (0-30% ethyl acetate in hexane as an eluent) to obtain 6-bromo-l-methyl-3,4-dihydroquinolin-2(lH)-one (0.15 g, 56 % Yield) as a brown solid. Tf NMR (400 MHz, DMSQ-rie) d 7.37 - 7 47 (m, 2 H) 7.03 (d, .7=9.21 Hz, 1 H) 3.22 (s, 3 H) 2.87 (t, 7=7.45 Hz, 2 H) 2.54 (d, =7.89 Hz, 2 H). | |
With potassium carbonate; In acetone; at 80℃; | To a mixture of 6-bromo-3,4-dihydroquinolin-2(1H)-one (0.4 g, 2 mmol) [Matrix Scientific, cat3279-90-1] and potassium carbonate (240 mg, 1.8 mmol) in acetone (8 mL) was added methyl iodide (0.44 mL, 7.1 mmol). The reaction mixture was stirred at 80 C. overnight then cooled to room temperature and concentrated. The residue was dissolved in EtOAc then washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was used in the next step without further purification. LC-MS calculated for C10H11BrNO (M+H)+: m/z=240.0. found 240.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 6-bromo-3,4-dihydro-1H-quinolin-2-one; 3-fluorophenylboronic acid With potassium carbonate In water; N,N-dimethyl-formamide for 0.0833333h; Inert atmosphere; Stage #2: In water; N,N-dimethyl-formamide at 86℃; for 5h; | 1.A A. Synthesis of a Compound of Formula (I) in which R1, R2, R3, R5, and R6 are Hydrogen, R4 is 6-(3-Fluorophenyl), R7 is Hydrogen, and X1 and X2 are both -CH= To a solution of 6-bromo-3,4-dihydroquinolin-2(1H)-one (1a) (226 mg, 1.00 mmol) and 3-fluorophenylboronic acid (210 mg, 1.50 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (415 mg, 3.00 mmol) and water (2.0 mL). The reaction mixture was stirred for 5 minutes under an atmosphere of dry N2, and PdCl2(PPh3)2 (35 mg, 0.05 mmol) was added. The resulting mixture was heated at 86° C. for 5 hours, cooled, diluted with ethyl acetate (20 mL), filtered through a layer of celite which was washed with ethyl acetate (60 mL), the filtrate transferred to a separation funnel, and washed with 2 N potassium carbonate (20 mL), followed by 30% ammonium chloride (40 mL), then brine (50 mL). The solvent was removed from the organic layer under resuced pressure, to provide a pale yellow solid. To this crude product was added methanol (2 mL), the mixture sonicated, filtered, washed with cold methanol (3.0 mL), and dried under reduced pressure, to afford 6-(3-fluorophenyl)-3,4-dihydroquinolin-2(1H)-one, the compound of Formula (1) in which R1 is hydrogen, as a white solid; MS mz 242.1 (M+H), anal HPLC>97% in purity. 1H NMR (400 MHz; dmso-D6) δ10.21 (s, 1H); 7.58 (d, J=2.1 Hz, 1H); 7.42-7.55 (m, 4H); 7.15 (m, 1H); 6.96 (d, J=8.2 Hz, 1H); 3.42 (t, J=7.6 Hz, 2H); 2.97 (t, J=7.6 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | A. Synthesis of tert-butyl 2-(6-bromo-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate To a mixture of 95% dry sodium hydride (834 mg, 33.0 mmol) in anhydrous N,N-dimethylformamide (30 mL) at room temperature was added a solution of 6-bromo-3,4-dihydroquinolin-2(1H)-one (6.780 g, 30.00 mmol) in anhydrous N,N-dimethylformamide (10 mL). The reaction mixture was stirred for 30 minutes under an atmosphere of dry N2, followed by addition of a solution of tert-butyl 2-bromoacetate (7.5 mL, 49.7 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at room temperature until the majority of the starting material was converted (confirmed by LCMS). The reaction mixture was quenched with methanol (40 mL), the mixture concentrated under reduced pressure, then diluted with ethyl acetate (150 mL). The organic phase was washed with water (100 mL), 30% ammonium chloride (100 mL) and brine (100 mL), dried, and concentrated under reduced pressure. Ethyl ether (20 mL) was added, and the mixture sonicated, filtered, washed with ether (20 mL), and dried to afford tert-butyl 2-(6-bromo-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate (7.348 g, 21.6 mmol, 72%). LCMS mz 285.9 (M-56+H), 363.9 (M+Na), anal HPLC>97% in purity. 1H NMR (400 MHz; CDCl3) delta 7.30-7.40 (m, 2H); 7.50-6.70 (m, 1H); 4.54 (s, 2H); 2.92 (m, 2H); 2.69 (m, 2H), 1.44 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Sodium hydride (60% in oil) (0.49 g) was added at 00C to a DMF solution (20 ml) of 6-bromo-3,4-dihydro-lH-quinolin-2- one (2.54 g) , followed by stirring for 30 minutes. 4-Bromomethylbiphenyl (3.05 g) was added, and the resulting mixture was stirred at room temperature overnight. Water was added to the reaction mixture, extraction with ethyl acetate was performed, and the extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane =.1:6 ? 1:2). The purified product was recrystallized from a chloroform- diisopropyl ether mixed solvent to thereby obtain 4.06 g (yield: 92%) of l-(4-biphenylmethyl)-6-bromo-3,4-dihydro-lH-quinolin-2- one as a white powder. 1H-NMR(DMSO-d6) dppm:2.65-2.78 (2H,m), 2.89-3.03 (2H,m), 5.17(2H,s), 6.90 (lH,d,J=8.7 Hz), 7.23-7.39 (4H,m), 7.39-7.50 (3H,m), 7.50-7.71 (4H,m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium methylate In methanol for 1h; Reflux; | 25.1 To a solution of 6-bromo-3,4-dihydroquinolin-2(1H)-one (3.39 g) in methanol (85 ml), sodium methoxide (2.43 g), 2-(1-cyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (3.39 g) and dichloro(bistriphenylphosphine)palladium (526 mg) were added and the mixture was heated under reflux for an hour. To the reaction system, water and ethyl acetate were added and after filtering the insolubles through Celite, the organic layer was recovered from the filtrate. After drying the resulting organic layer over anhydrous sodium sulfate, the desiccant was filtered off and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 4:1 to 2:1) to give the titled compound (2.90 g) as a colorless powder. MS(ESI/APCI Dual): 228(M+H) 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.60 - 1.71 (m, 2 H), 1.72 - 1.82 (m, 2 H), 2.15 - 2.24 (m, 2 H), 2.33 - 2.41 (m, 2 H), 2.59 - 2.67 (m, 2 H), 2.92 - 3.00 (m, 2 H), 6.03 - 6.09 (m, 1 H), 6.65 - 6.71 (m, 1 H), 7.16 - 7.22 (m, 2 H), 7.77 (br. s., 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With chlorosulfonic acid at 65℃; for 2h; Inert atmosphere; | 6-bromo-N-(3,4-dimethylphenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-7-sulfonamide General procedure: Method D: To an ice-cooled flask containing chlorosulfonic acid (0.741 mL, 11.06 mmol) was added 6-bromo-3,4-dihydroquinolin-2(1H)-one (0.50 g, 2.212 mmol) in three portions over 10 minutes. The flask was sealed and mixture was heated to 65 °C for 2 h. The reaction was cooled and poured over ice (10 g) to give a cloudy suspension that was extracted twice with EtOAc (20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting residue was dried under high vacuum for 1h and was then taken up in THF (14.75 mL). To the solution was added Et3N (0.617 mL, 4.42 mmol) and 3,4-dimethylaniline (0.536 g, 4.42 mmol), sequentially. The reaction was allowed to stir overnight. After concentration, the resulting residue was taken up in EtOAc (25 mL) and washed with NaHCO3 (2 x 100 mL), H2O (2 x 100 mL) and brine (1 x 100 mL). The organic layer was separated and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Residue was purified via flash chromatography (Acetone/Hexanes (gradient, 1:19 to 3:1)) to deliver product (486 mg, 42%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
486 mg | Stage #1: 6-bromo-3,4-dihydro-1H-quinolin-2-one With chlorosulfonic acid at 65℃; for 2h; Inert atmosphere; Stage #2: 4-amino-o-xylene With triethylamine Inert atmosphere; | 6-bromo-N-(3,4-dimethylphenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-7-sulfonamide General procedure: Method D: To an ice-cooled flask containing chlorosulfonic acid (0.741 mL, 11.06 mmol) was added 6-bromo-3,4-dihydroquinolin-2(1H)-one (0.50 g, 2.212 mmol) in three portions over 10 minutes. The flask was sealed and mixture was heated to 65 °C for 2 h. The reaction was cooled and poured over ice (10 g) to give a cloudy suspension that was extracted twice with EtOAc (20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting residue was dried under high vacuum for 1h and was then taken up in THF (14.75 mL). To the solution was added Et3N (0.617 mL, 4.42 mmol) and 3,4-dimethylaniline (0.536 g, 4.42 mmol), sequentially. The reaction was allowed to stir overnight. After concentration, the resulting residue was taken up in EtOAc (25 mL) and washed with NaHCO3 (2 x 100 mL), H2O (2 x 100 mL) and brine (1 x 100 mL). The organic layer was separated and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Residue was purified via flash chromatography (Acetone/Hexanes (gradient, 1:19 to 3:1)) to deliver product (486 mg, 42%) as a white solid.1H NMR (400 MHz, DMSO-d6) ppm 10.32 (1 H, s), 10.28 (1 H, s), 7.60 (2 H, s), 6.96 (1 H, d, J=8.2 Hz), 6.89 (1 H, d, J=1.8 Hz), 6.81 (1 H, dd, J=8.1, 1.9 Hz), 2.90 (2 H, t, J=7.5 Hz), 2.44 (2 H, t, J=7.6 Hz), 2.10 (3 H, s), 2.08 (3 H, s); Method 1, retention time: 5.167 min; HRMS: m/z (M+H)+ = 409.0221 (Calculated for C17H18BrN2O3S = 409.0216). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 6-bromo-3,4-dihydro-1H-quinolin-2-one With chlorosulfonic acid at 65℃; for 2h; Inert atmosphere; Stage #2: 3-chloro-p-toluidine With triethylamine Inert atmosphere; | 6-bromo-N-(3,4-dimethylphenyl)-2-oxo-1,2,3,4-tetrahydroquinoline-7-sulfonamide General procedure: Method D: To an ice-cooled flask containing chlorosulfonic acid (0.741 mL, 11.06 mmol) was added 6-bromo-3,4-dihydroquinolin-2(1H)-one (0.50 g, 2.212 mmol) in three portions over 10 minutes. The flask was sealed and mixture was heated to 65 °C for 2 h. The reaction was cooled and poured over ice (10 g) to give a cloudy suspension that was extracted twice with EtOAc (20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting residue was dried under high vacuum for 1h and was then taken up in THF (14.75 mL). To the solution was added Et3N (0.617 mL, 4.42 mmol) and 3,4-dimethylaniline (0.536 g, 4.42 mmol), sequentially. The reaction was allowed to stir overnight. After concentration, the resulting residue was taken up in EtOAc (25 mL) and washed with NaHCO3 (2 x 100 mL), H2O (2 x 100 mL) and brine (1 x 100 mL). The organic layer was separated and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Residue was purified via flash chromatography (Acetone/Hexanes (gradient, 1:19 to 3:1)) to deliver product (486 mg, 42%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-chloro-succinimide In N,N-dimethyl-formamide at 80℃; for 2h; | 80.A To a stirred solution of 6-bromo-3, 4-dihydroquinolin-2(l H)-one (74-3; 20 g, 0.088 mol) in N,N-dimethylformamide (200 mL) was added N-chlorosuccinimide portion wise (17.7 g, 0.132 mol) at 80 °C. Reaction mass was allowed to stir at 80 °C for 2 h. The reaction mixture was cooled and diluted with ice cold water. The precipitated solid filtered and dried to obtain title compound. 1H NMR (400 MHz, OMSO-d6) δ: 9.61 (bs, 1 H), 7.52-7.51 (d, J = 1.6 Hz, 1 H), 7.41 (s, 1 H), 2.93-2.90 (t, J = 8 Hz, 2 H). MS (M+l): 261.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: 6-bromo-3,4-dihydro-1H-quinolin-2-one With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 0℃; for 0.25h; Stage #2: methyl iodide In N,N-dimethyl-formamide at 0 - 40℃; | A-1; A [A] 6-Bromo-1-methyl-3,4-dihydro-1H-quinolin-2-one [A] 6-Bromo-1-methyl-3,4-dihydro-1H-quinolin-2-one[0340]6-bromo-3,4-dihydroquinolin-2(1H)-one (5 g, 22.1 mmol) in DMF (100 mL) cooled to 0° C. was added potassium tert-butoxide (4.96 g, 44.2 mmol) portionwise and the reaction mixture was stirred at 0° C. for 15 min. Then, methyl iodide (4.08 g, 28.8 mmol) was added and the reaction mixture allowed to warm up to room temperature and stirring was continued over night. More MeI (1.25 g, 8.86 mmol) was added and the reaction mixture was heated to 40° C. until completion of the reaction. The mixture was diluted with EtOAc, poured into 100 mL of 1M HCl and the aqueous phase was extracted with EtOAc (2×200 mL). Combined organics were washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 30% EtOAc-heptane gradient to give the title compound (4.23 g, 80%) as an off white solid. MS: 240.0, 242.1 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 6-bromo-3,4-dihydro-1H-quinolin-2-one With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol In tetrahydrofuran at 65℃; | 3.2 Preparation of 6-bromo-1-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)-3 ,4-dihydroquinolin-2( 1H)-one, 14 A solution of 6-bromo-3,4-dihydroquinolin-2(1H)-one, 13 (10.0 g, 44 mmol) in THF (25 mL) was added to stirred solution of 60% NaH (3.53 g, 88 mmol) in THF (100 mL) at 0°C and the mixture was stirred for 30 mm. A solution of 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (2) (18.4 g, 55.3 mmol) in THF (25 mL) was added and slowly heated to 65 °C overnight. The progress of the reaction was monitored by TLC (TLC system: 30 % EtOAc/Pet ether, Rf value: 0.45). After completion of the reaction, the reaction mixture was poured into ice cold water and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The crude product was washed with pet ether followed by dichloromethane to afford 6-bromo-1-(4- (1,1,1,3,3,3 -hexafluoro-2-hydroxypropan-2-yl)benzyl)-3 ,4-dihydroquinolin-2( 1 H)-one, 14. 1H NMR (400 MHz, DMSO-d6) δ: 8.65 (s, 1 H), 7.61 (d, 2 H, J 8.4 Hz), 7.47 (d, 1 H, J2.0 Hz), 7.35-7.30 (m, 3 H), 6.85 (d, 1 H, J= 8.4 Hz), 5.17 (s, 2 H), 2.98 (t, 2 H, J 6.8 Hz),2.71 (m, 2 H). | |
Stage #1: 6-bromo-3,4-dihydro-1H-quinolin-2-one With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol In tetrahydrofuran at 0 - 65℃; | 5.2 Reaction step 2, Preparation of 6-bromo-l-(4-(l, l,l,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)- 3,4-dihydroquinolin-2(lH)-one, 14 00104] A solution of 6-bromo-3,4-dihydroquinolin-2(lH)-one, 13 (10.0 g, 44.2 mmol) in THF (25 mL) was added to stirred solution of 60% NaH (3.53 g, 88.4 mmol) in THF (100 mL) at 0 °C and the mixture was stirred for 30 min. A solution of 2-(4-(bromomethyl)phenyl)-l,l, l,3,3,3- hexafluoropropan-2-ol, 2 (18.4 g, 55.3 mmol) in THF (25 mL) was added and the mixture was slowly heated to 65 °C overnight. The progress of the reaction was monitored by TLC (TLC system: 30 % EtO Ac/Pet ether, Rf value: 0.45). [00105] After completion of the reaction, the reaction mixture was poured into ice cold water and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to afford crude product. The crude product was washed with pet ether followed by dichloromethane to afford 6- bromo- l-(4-(l,l, l,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)-3,4-dihydroquinolin-2(lH)-one, 14. LC/MS calc M+H 482, obs 482; lH NMR (400 MHz, DMSO-d6) δ: 8.65 (s, 1 H), 7.61 (d, 2 H, J = 8.4 Hz), 7.47 (d, 1 H, J= 2.0 Hz), 7.35-7.30 (m, 3 H), 6.85 (d, 1 H, J= 8.4 Hz), 5.17 (s, 2 H), 2.98 (t, 2 H, J= 6.8 Hz), 2.71 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; XPhos In toluene at 100℃; for 9h; Inert atmosphere; | 6-(Phenylamino)-3,4-dihydroquinolin-2(1H)-one (11a). General procedure: Toluene (4.5mL) was added to a flask containing 6-bromo-3,4-dihydroquinolin-2(1H)-one (300mg, 1.33mmol), 3-(trifluoromethoxy)aniline (231μL, 1.73mmol), Pd2(dba)3 (15.2mg, 0.02mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (31.6mg, 0.07mmol) and NaOt-Bu (192mg, 2.00mmol) under an argon atmosphere. The mixture was stirred at 100°C for 9h. After cooling, the reaction mixture was diluted with EtOAc, and filtered through a pad of Celite. The filtrate was concentrated in vacuo. Crude material was purified by flash chromatography with n-hexane/EtOAc (2:3) to afford the desired diaryl amine 11i |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; XPhos In toluene at 100℃; for 9h; Inert atmosphere; | 6-[4-(Trifluoromethyl)phenyl]amino}-3,4-dihydroquinolin-2(1H)-one (5b). General procedure: Toluene (4.5 mL) was added to a flask containing 6-bromo-3,4-dihydroquinolin-2(1H)-one (300 mg, 1.33 mmol), 3-(trifluoromethoxy)aniline (231 μL, 1.73 mmol), Pd2(dba)3 (15.2 mg, 0.02 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (31.6 mg, 0.07 mmol) and NaOt-Bu (192 mg, 2.00 mmol) under an argon atmosphere. The mixture was stirred at 100 °C for 9 h. After cooling, the reaction mixture was diluted with EtOAc, and filtered through a pad of Celite. The filtrate was concentrated in vacuo. Crude material was purified by flash chromatography with n-hexane/EtOAc (2:3) to afford the desired diaryl amine 11i |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; XPhos In toluene at 100℃; for 9h; Inert atmosphere; | 6-[2-(Trifluoromethyl)phenyl]amino}-3,4-dihydroquinolin-2(1H)-one (5c). General procedure: Toluene (4.5 mL) was added to a flask containing 6-bromo-3,4-dihydroquinolin-2(1H)-one (300 mg, 1.33 mmol), 3-(trifluoromethoxy)aniline (231 μL, 1.73 mmol), Pd2(dba)3 (15.2 mg, 0.02 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (31.6 mg, 0.07 mmol) and NaOt-Bu (192 mg, 2.00 mmol) under an argon atmosphere. The mixture was stirred at 100 °C for 9 h. After cooling, the reaction mixture was diluted with EtOAc, and filtered through a pad of Celite. The filtrate was concentrated in vacuo. Crude material was purified by flash chromatography with n-hexane/EtOAc (2:3) to afford the desired diaryl amine 11i |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; XPhos In toluene at 100℃; for 9h; Inert atmosphere; | 6-[(3-Nitrophenyl)amino]-3,4-dihydroquinolin-2(1H)-one (11k). General procedure: Toluene (4.5mL) was added to a flask containing 6-bromo-3,4-dihydroquinolin-2(1H)-one (300mg, 1.33mmol), 3-(trifluoromethoxy)aniline (231μL, 1.73mmol), Pd2(dba)3 (15.2mg, 0.02mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (31.6mg, 0.07mmol) and NaOt-Bu (192mg, 2.00mmol) under an argon atmosphere. The mixture was stirred at 100°C for 9h. After cooling, the reaction mixture was diluted with EtOAc, and filtered through a pad of Celite. The filtrate was concentrated in vacuo. Crude material was purified by flash chromatography with n-hexane/EtOAc (2:3) to afford the desired diaryl amine 11i |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; XPhos In toluene at 100℃; for 9h; Inert atmosphere; | 6-[(3-Ethylphenyl)amino]-3,4-dihydroquinolin-2(1H)-one (11b). General procedure: Toluene (4.5mL) was added to a flask containing 6-bromo-3,4-dihydroquinolin-2(1H)-one (300mg, 1.33mmol), 3-(trifluoromethoxy)aniline (231μL, 1.73mmol), Pd2(dba)3 (15.2mg, 0.02mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (31.6mg, 0.07mmol) and NaOt-Bu (192mg, 2.00mmol) under an argon atmosphere. The mixture was stirred at 100°C for 9h. After cooling, the reaction mixture was diluted with EtOAc, and filtered through a pad of Celite. The filtrate was concentrated in vacuo. Crude material was purified by flash chromatography with n-hexane/EtOAc (2:3) to afford the desired diaryl amine 11i |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; XPhos In toluene at 100℃; for 9h; Inert atmosphere; | 6-[(3-Isopropylphenyl)amino]-3,4-dihydroquinolin-2(1H)-one (11c): General procedure: Toluene (4.5mL) was added to a flask containing 6-bromo-3,4-dihydroquinolin-2(1H)-one (300mg, 1.33mmol), 3-(trifluoromethoxy)aniline (231μL, 1.73mmol), Pd2(dba)3 (15.2mg, 0.02mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (31.6mg, 0.07mmol) and NaOt-Bu (192mg, 2.00mmol) under an argon atmosphere. The mixture was stirred at 100°C for 9h. After cooling, the reaction mixture was diluted with EtOAc, and filtered through a pad of Celite. The filtrate was concentrated in vacuo. Crude material was purified by flash chromatography with n-hexane/EtOAc (2:3) to afford the desired diaryl amine 11i |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; XPhos In toluene at 100℃; for 9h; Inert atmosphere; | 6-[3,5-Bis(trifluoromethyl)phenyl]amino}-3,4-dihydroquinolin-2(1H)-one (11e). General procedure: Toluene (4.5mL) was added to a flask containing 6-bromo-3,4-dihydroquinolin-2(1H)-one (300mg, 1.33mmol), 3-(trifluoromethoxy)aniline (231μL, 1.73mmol), Pd2(dba)3 (15.2mg, 0.02mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (31.6mg, 0.07mmol) and NaOt-Bu (192mg, 2.00mmol) under an argon atmosphere. The mixture was stirred at 100°C for 9h. After cooling, the reaction mixture was diluted with EtOAc, and filtered through a pad of Celite. The filtrate was concentrated in vacuo. Crude material was purified by flash chromatography with n-hexane/EtOAc (2:3) to afford the desired diaryl amine 11i |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; XPhos In toluene at 100℃; for 9h; Inert atmosphere; | 6-[(1,1'-Biphenyl)-3-ylamino]-3,4-dihydroquinolin-2(1H)-one (11f): General procedure: Toluene (4.5mL) was added to a flask containing 6-bromo-3,4-dihydroquinolin-2(1H)-one (300mg, 1.33mmol), 3-(trifluoromethoxy)aniline (231μL, 1.73mmol), Pd2(dba)3 (15.2mg, 0.02mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (31.6mg, 0.07mmol) and NaOt-Bu (192mg, 2.00mmol) under an argon atmosphere. The mixture was stirred at 100°C for 9h. After cooling, the reaction mixture was diluted with EtOAc, and filtered through a pad of Celite. The filtrate was concentrated in vacuo. Crude material was purified by flash chromatography with n-hexane/EtOAc (2:3) to afford the desired diaryl amine 11i |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; XPhos In toluene at 100℃; for 9h; Inert atmosphere; | 6-[(3-Phenoxyphenyl)amino]-3,4-dihydroquinolin-2(1H)-one (11g): General procedure: Toluene (4.5mL) was added to a flask containing 6-bromo-3,4-dihydroquinolin-2(1H)-one (300mg, 1.33mmol), 3-(trifluoromethoxy)aniline (231μL, 1.73mmol), Pd2(dba)3 (15.2mg, 0.02mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (31.6mg, 0.07mmol) and NaOt-Bu (192mg, 2.00mmol) under an argon atmosphere. The mixture was stirred at 100°C for 9h. After cooling, the reaction mixture was diluted with EtOAc, and filtered through a pad of Celite. The filtrate was concentrated in vacuo. Crude material was purified by flash chromatography with n-hexane/EtOAc (2:3) to afford the desired diaryl amine 11i |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; XPhos In toluene at 100℃; for 9h; Inert atmosphere; | 6-[(3-Methoxyphenyl)amino]-3,4-dihydroquinolin-2(1H)-one (11h): General procedure: Toluene (4.5mL) was added to a flask containing 6-bromo-3,4-dihydroquinolin-2(1H)-one (300mg, 1.33mmol), 3-(trifluoromethoxy)aniline (231μL, 1.73mmol), Pd2(dba)3 (15.2mg, 0.02mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (31.6mg, 0.07mmol) and NaOt-Bu (192mg, 2.00mmol) under an argon atmosphere. The mixture was stirred at 100°C for 9h. After cooling, the reaction mixture was diluted with EtOAc, and filtered through a pad of Celite. The filtrate was concentrated in vacuo. Crude material was purified by flash chromatography with n-hexane/EtOAc (2:3) to afford the desired diaryl amine 11i |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; XPhos In toluene at 100℃; for 9h; Inert atmosphere; | Methyl 3-[(2-Oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino]benzoate (11m). General procedure: Toluene (4.5mL) was added to a flask containing 6-bromo-3,4-dihydroquinolin-2(1H)-one (300mg, 1.33mmol), 3-(trifluoromethoxy)aniline (231μL, 1.73mmol), Pd2(dba)3 (15.2mg, 0.02mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (31.6mg, 0.07mmol) and NaOt-Bu (192mg, 2.00mmol) under an argon atmosphere. The mixture was stirred at 100°C for 9h. After cooling, the reaction mixture was diluted with EtOAc, and filtered through a pad of Celite. The filtrate was concentrated in vacuo. Crude material was purified by flash chromatography with n-hexane/EtOAc (2:3) to afford the desired diaryl amine 11i |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; XPhos In toluene at 100℃; for 9h; Inert atmosphere; | 2 4.1.2 General procedure of N-arylation for preparation of diaryl amine compounds: synthesis of 6-[3-(trifluoromethoxy)phenyl]amino}-3,4-dihydroquinolin-2(1H)-one (11i) Toluene (4.5 mL) was added to a flask containing 6-bromo-3,4-dihydroquinolin-2(1H)-one (300 mg, 1.33 mmol), 3-(trifluoromethoxy)aniline (231 μL, 1.73 mmol), Pd2(dba)3 (15.2 mg, 0.02 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (31.6 mg, 0.07 mmol) and NaOt-Bu (192 mg, 2.00 mmol) under an argon atmosphere. The mixture was stirred at 100 °C for 9 h. After cooling, the reaction mixture was diluted with EtOAc, and filtered through a pad of Celite. The filtrate was concentrated in vacuo. Crude material was purified by flash chromatography with n-hexane/EtOAc (2:3) to afford the desired diaryl amine 11i (292 mg, 68% yield): pale yellow solid; mp 160-162 °C; IR (neat) cm-1: 1667 (C=O), 3219 (NH), 3315 (NH); 1H NMR (500 MHz, DMSO-d6) δ 2.43 (t, J = 6.9 Hz, 2H; CH2), 2.85 (t, J = 6.9 Hz, 2H; CH2), 6.63 (d, J = 8.0 Hz, 1H; Ar), 6.79 (s, 1H; Ar), 6.81 (d, J = 8.0 Hz, 1H; Ar), 6.91-6.96 (m, 3H; Ar), 7.25 (t, J = 8.0 Hz, 1H; Ar), 8.25 (s, 1H; NH), 9.99 (s, 1H; NH); 13C NMR (125 MHz, DMSO-d6) δ 25.0, 30.4, 106.3, 109.6, 113.1, 115.8, 118.7, 119.5, 120.1 (q), 124.7, 130.7, 133.1, 136.1, 146.9, 149.4, 169.8; Anal. Calcd for C16H13F3N2O2: C, 59.63; H, 4.07; N, 8.69. Found: C, 59.51; H, 4.12; N, 8.59. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With tributyl-amine; palladium diacetate; tri tert-butylphosphoniumtetrafluoroborate; In 1-methyl-pyrrolidin-2-one; at 150℃; for 4h; | A de-aerated mixture of 89 (49.2mg, 0.218mmol), <strong>[1864-94-4]phenyl formate</strong> (51.3mg, 0.420mmol), tributylamine (95muL, 0.40mmol), Pd(OAc)2 (5.2mg, 0.023mmol) and P(tBu)3·HBF4 (26.6mg, 0.0917mmol) in NMP (600muL) was stirred at 150C for 4h, then cooled to ambient temperature and diluted with AcOEt. The organic layer was washed with water, 2N aqueous HCl and brine, then dried and concentrated. Column chromatography (n-hexane/AcOEt=94/6 to 52/48) of the residue gave the title compound (28.0mg, 0.105mmol, 48% yield) as a colorless solid. 1H NMR (CD3OD/CDCl3) delta: 8.01 (1H, d, J=1.7Hz), 7.99 (1H, dd, J=8.6, 1.7Hz), 7.43 (2H, dd, J=8.0, 7.5Hz), 7.27 (1H, t, J=7.5Hz), 7.19 (2H, d, J=8.0Hz), 6.99 (1H, d, J=8.6Hz), 3.05 (2H, t, J=6.9Hz), 2.63 (2H, t, J=6.9Hz). 13C NMR (CD3OD/CDCl3) delta: 173.79, 166.30, 152.46, 144.11, 130.97 (2C), 130.51 (2C), 126.91, 125.39, 124.88, 122.84 (2C), 116.43, 31.26, 25.96. FAB-MS m/z: 268 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10.8% | With dichlorobis(tri-O-tolylphosphine)palladium; potassium carbonate In N,N-dimethyl-formamide at 100℃; Inert atmosphere; | 1 (rac)-(E)-6-(3-(4-(4-chlorophenyl)piperazin-1-yl)-4-hydroxybut-1-en-1-yl)-3,4-dihydroquinolin-2(1H)-one General procedure: A mixture of bromo derivative 5 (1.6 mmol), potassium carbonate (4.9 mmol) and olefin intermediate 3 (1.6 mmol) in anhydrous DMF (50 mE) was degassed and filled with argon gas. Palladium catalyst (0.08 mmol) was added to the mixture and heated at 1000 C. for 16 h. The resulting pale brown mixture was cooled to room temperature, which was diluted with brine and ethyl acetate followed by filtration to eliminate the insoluble material. A second method to process the reaction mixture was to filter through a pad of celite, and later mix with ethyl acetate and brine for extraction of products. The extracted organic layer was washed with brine, dried over sodium sulfate and evaporated on a rotary evaporator. The residue was purified by flash column chromatography on silica gel (230-400 mesh; 40 g) using a gradient solvent mixture of dichloromethane:methanol (100:0 to 95:5). In case of more polar compounds about 0.05% ammonia solution was used as another co-solvent to accelerate the elution. The less polar keto compound 6 was eluted first (Yield=5-20%) followed by olefin product 7 (Yield=5-60%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; diphenylphosphoranyl azide; triphenylphosphine In tetrahydrofuran at 45℃; for 18h; | A Step A: 7-bromo-4,5 -dihydrotetrazolo [1,5-al guinoline To a solution of 6-bromo-3,4-dihydroquinolin-2(1I])-one (550 mg, 2.43 mmol) in THF (30 mL) was added triphenylphosphine (2.55 g, 9.73 mmol) and DPPA (2.41 g, 8.85 mmol), DIAD (1.78 g, 8.85 mmol). The mixture was stirred at 45 °C for 18 hr, and concentrated. The residue was purified by flash column chromatography (0-30% EtOAc in petroleum ether) to afford the title compound. ‘H-NMR (400 MHz, CDC13) ö ppm 7.89 (d, J 8.2 Hz, 1H), 7.65-7.51 (m, 2H), 3.44-3.30 (m, 2H), 3.23-3.10 (m, 2H). | |
With di-isopropyl azodicarboxylate; diphenyl phosphoryl azide; triphenylphosphine In tetrahydrofuran at 45℃; for 18h; | A Step A: 7-bromo-4,5 -dihydrotetrazolo [1,5-al ciuinoline To a solution of 6-bromo-3,4-dihydroquinolin-2(1H)-one (550 mg, 2.43 mmol) in THF (30 mL) was added triphenylphosphine (2.55 g, 9.73 mmol) and DPPA (2.41 g, 8.85 mmol), DIAD (1.78 g, 8.85 mmol). The mixture was stirred at 45 °C for 18 hr, and concentrated. The residue was purified by flash column chromatography (0-30% EtOAc in petroleum ether) to afford the title compound. ‘H-NMR (400 MHz, CDC13) ö ppm 7.89 (d, J 8.2 Hz, 1H), 7.65-7.51 (m, 2H), 3.44-3.30 (m, 2H), 3.23-3.10 (m, 2H). | |
With 2-(diphenylphosphino)pyridine; di-isopropyl azodicarboxylate; diphenyl phosphoryl azide In tetrahydrofuran at 45℃; for 24h; | Step B: 7-bromo-4, 5-dihydrotetrazolo[ 1 .5-aliuinoline Step B: 7-bromo-4, 5-dihydrotetrazolo[ 1 .5-aliuinolineA solution of 6-bromo-3,4-dihydroquinolin-2(1I])-one (1.00 g, 4.4 mmol) and diphenyl-2- pyridylphosphine (4.60 g, 17.6 mmol) in THF (15 mL) was added diisopropyl azadicarboxylate (3.60 g, 17.6 mmol), followed by addition of DPPA (4.80 g, 17.6 mmol). The mixture was stirred at 45 °C for 24 h, diluted with ethyl acetate and washed with saturated aqueous sodiumbicarbonate solution. The organic layer was dried over anhydrous Na2504 and concentrated.The residue was purified by flash chromatography on a silica gel column using petroleumether/EtOAc from 10:1 to 3:1 as eluting solvents to afford the title compound as a yellow solid.LC/MS [M+1]= 251. |
With di-isopropyl azodicarboxylate; diphenyl phosphoryl azide; triphenylphosphine In tetrahydrofuran at 45℃; for 18h; | Step A: 7-bromo-4,5-dihydrotetrazolo[1,5-a]quinoline To a solution of 6-bromo-3,4-dihydroquinolin-2(1H)-one (550 mg, 2.43 mmol) in THF (30 mL) was added triphenylphosphine (2.55 g, 9.73 mmol) and DPPA (2.41 g, 8.85 mmol), DIAD (1.78 g, 8.85 mmol). The mixture was stirred at 45° C. for 18 hr, and concentrated. The residue was purified by flash column chromatography (0-30% EtOAc in petroleum ether) to afford the title compound. 1H-NMR (400 MHz, CDCl3) δ ppm 7.89 (d, J=8.2 Hz, 1H), 7.65-7.51 (m, 2H), 3.44-3.30 (m, 2H), 3.23-3.10 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
140 mg | Stage #1: 6-bromo-3,4-dihydro-1H-quinolin-2-one With potassium <i>tert</i>-butylate In N,N-dimethyl acetamide for 0.166667h; Cooling with ice; Stage #2: benzyl bromide In N,N-dimethyl acetamide at 20℃; for 0.5h; Cooling with ice; | 6 [Reference Example 6] [Reference Example 6] (0442) (0443) To the solution of 120 mg of 6-bromo-3,4-dihydroquinolin-2(1H)-one in 3 mL of N,N-dimethylacetamide, 71.4 mg of potassium tert-butoxide was added under ice-cooling, and the resultant was stirred for 10 minutes. To the reaction mixture, 69 µL of benzyl bromide was added under ice-cooling, and the resultant was stirred at room temperature for 30 minutes. Ethyl acetate and water were added to the reaction mixture, and the resultant was adjusted to pH 2.0 with 2 mol/L hydrochloric acid. The organic layer was separated, sequentially washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate = 90:10-70:30) to give 140 mg of 1-benzyl-6-bromo-3,4-dihydroquinolin-2(1H)-one as a white solid. 1H-NMR (DMSO-d6) δ: 2.66-2.75 (2H, m), 2.91-3.00 (2H, m), 5.13 (2H, s), 6.84 (1H, d, J = 8.6 Hz), 7.16-7.25 (3H, m), 7.26-7.35 (3H, m), 7.45 (1H, d, J = 2.0 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With tris-(dibenzylideneacetone)dipalladium(0); lithium hexamethyldisilazane; DavePhos In tetrahydrofuran at 65℃; for 24h; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,2-dimethoxyethane; water; at 80℃; for 20.0h; | Pd(PPh3)4 (51 mg, 0.044 mmol) was added to a degassed solution of 6-bromo-3,4-dihydro-1 H- quinolin-2-one (50 mg, 0.221 mmol), 1 ,3-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridin-2-one (prepared using described procedure in US20130053362, 82 mg, 0.332 mmol), and Cs2C03 (144 mg, 0.442 mmol) in DME (3 mL) and water (0.3 mL). The resulting mixture was heated to 80 C for 20 h and then cooled to rt. The mixture was diluted with saturated NaHC03 (20 mL) and EtOAc (20 mL), and the aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over MgS04, filtered, and concentrated under reduced pressure. The material was purified by flash chromatography on silica using a mixture of EtOAc in hexane as eluent to provide Intermediate 2 (25 mg, 42%). 1H NMR (500 MHz, CDCI3) delta 8.03 (s, 1 H), 7.46 (dd, J = 2.6, 1.2 Hz, 1 H), 7.33 (d, J = 2.3 Hz, 1 H), 7.23 - 7.19 (m, 2H), 6.80 (d, J = 8.7 Hz, 1 H), 3.63 (s, 3H), 3.04 - 2.99 (m, 2H), 2.67 (dd, J = 8.3, 6.8 Hz, 2H), 2.23 (s, 3H). MS (ESI) [M+Hf 269.3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 100℃; for 0.833333h; Inert atmosphere; Microwave irradiation; | 9 (2S,4R)-l-(2-(3-Acetyl-lH-indazol-l-yl)acetyl)-4-fluoro-N-(2-fluoro-3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine-2-carboxamide (0.144 g), 6- bromobenzo[d]thiazol-2-amine (0.050 g), Pd(dppf)Cl2 (36 mg) and potassium carbonate (0.151 g) were taken up in a pressure tube under argon. To this mixture, 4 mL of dioxane and 1 mL of water were added. The mixture was bubbled with argon for 5 min and the vial stoppered and subjected to microwave irradiation at 100 °C for 45 min. The volatiles were removed under reduced pressure and the residue was purified by ISCO (0-3 % MeOH in CH2CI2) to afford compound 100. 1H MR (400 MHz, DMSO)(major rotamer) δ 2.14-2.31 (m, 1H), 2.54-2.64 (m, 1H), 2.62 (s, 3H), 3.95-4.08 (m, 1H) 4.25 (dd, J = 22.4, 12.8 Hz, 1H) 4.77 (t, J = 8.4 Hz, 1H), 5.57 (d, J = 52.8 Hz, 1), 5.59 (d, J = 17.2 Hz, 1H), 5.79 (d, J = 17.2 Hz, 1H), 7.14 - 7.41 (m, 5H), 7.47 (t, J = 7.6 Hz, 1H), 7.57 (s, 2H), 7.69 (d, J = 8.5 Hz, 1H), 7.78 - 7.83 (m, 2H), 8.19 (d, J = 8.1 Hz, 1H), 9.91 (s, 1H). 19F- MR (DMSO-de) (major rotamer): δ -130.5, -175.9 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid In toluene at 110℃; for 24h; | 7.1 Example 7 (1) 0.5mmol (119.0 mg) 1-p-chlorophenyl-3-(trimethylsilyl)prop-2-yn-1-ol and 0.25mmol (56.23 mg) 6-bromo-3,4-dihydro-2(1H)-quinolinone and 0.05mmol (8.6 mg) of PTSA were dissolved in 10 ml toluene. At 110 °C, reflux reaction for 24h. After the reaction, stop the reaction, to produce intermediate 3gg (R1=Cl, R2=Br). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid In toluene at 110℃; for 24h; | 6.1 Example 6 (1) 0.5mmol (119.0 mg) 1-o-chlorophenyl-3-(trimethylsilyl)prop-2-yn-1-ol, 0.25mmol (56.23 mg) 6-bromo-3,4-dihydro-2(1H)-quinolinone and 0.05mmol (8.6 mg) of PTSA were dissolved in 10 ml toluene. At 110 °C, reflux reaction for 24h. After the reaction, stop the reaction, to produce intermediate 3ff (R1=Cl, R2=Br). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With tris(dibenzylideneacetone)dipalladium(0) chloroform complex In toluene at 120℃; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With tert.-butyl lithium In tetrahydrofuran; pentane at -78℃; for 4h; Inert atmosphere; | 3.1 Step 1: 2-oxo-1,2,3,4-tetrahydroquinoline-6-carbaldehyde Under nitrogen protection,100mL three bottles,The compound 6-bromo-3,4-dihydroquinolin-2 (1H) -one (2.5 g, 11.06 mmol)And N, N-dimethylformamide (2.5 g, 11.06 mmol) were dissolved in dry tetrahydrofuran (50 mL) and cooled to -78 ° C.A solution of tert-butyllithium (24.1 mL, 38.7 mmol, 1.6 M in pentane) was slowly added dropwise,After completion of the dropwise addition, the reaction was continued at -78 ° C for 4 hours,Acetic acid (2.5 mL) was added and the temperature was slowly warmed to room temperature.The reaction solution was diluted with ethyl acetate (100 mL) and washed successively with saturated sodium bicarbonate solution and brine. The organic phase was dried, filtered and concentrated to give 2-oxo-1,2,3,4-tetrahydroquinoline-6-carbaldehyde (0.6 g) in 30% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With hydrogen; triethylamine In ethanol; water at 140℃; for 110h; Autoclave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With dmap; triethylamine In dichloromethane at 0 - 20℃; for 6h; Inert atmosphere; | |
83% | With dmap; triethylamine In dichloromethane at 20℃; for 16h; | 1a.1 Step 1 tert-butyl 6-bromo-3,4-dihydro-2-oxoquinoline-1(2H)-carboxylateStep 1: 6-bromo-1 ,2,3,4-tetra-hydro-2-quinolinone (5.0 g, 22.12 mmol) was dissolved in CH2CI2 (100 mL) and triethylamine (3.39 mL, 24.33 mmol) was added followed by 4-(dimethylamino)-pyridine (260 mg, 2.21 mmol) and the portionwise addition of di-tert-butyl dicarbonate(5.07 g, 23.23 mmol), upon which gas evolution was observed. The mixture was stirred at rt for 16 h. The reaction was quenched with water and the two phases were separated. The organiclayer was dried over Mg504, filtered and the solution was concentrated to dryness. The crude material was purified by silica gel column chromatography eluting with heptane and a gradient of heptane/EtOAc from [100:0] to [85:15]. The product fractions were combined and concentrated to dryness to afford tertbutyl 6-bromo-3,4-dihydro-2-oxoquinoline-1 (2H)-carboxylate (6.00 g, 83%) as off-white solid.1 H NMR (300 MHz, CDCI3, d in ppm): 1.53 (s, 9H), 2.56-2.61 (m, 2H), 2.84-2.89 (m, 2H), 6.79 (d, 1H, J=9.OHz), 7.25-7.27 (m, 2H). |
With dmap In dichloromethane at 20℃; Inert atmosphere; | 3. Experimental Procedure for the Preparation of N-Boc-1,4-dihydroquinolines General procedure: 3,4-dihydroquinolin-2(1H)-ones 5 (54.4 mmol, 1.0 equiv) and 160 mL CH2Cl2 were added to a flame dried and argon flushed 500 mL two-neck round-bottom flask. Then 7.5 mL Et3N (54.4 mmol, 1.0 equiv), 14.2 g (Boc)2O (65.3 mmol, 1.2 equiv) and 656 mg DMAP (4-dimethylaminopyridine) (5.4 mmol, 10 mol%) were added under the room temperature. The reaction was stirred until full conversion (monitored by TLC [petroleum ether (PE)/ethyl acetate (EA) = 5/1)]. The reaction mixture was concentrated, then transferred to funnel. 200 mL water was added and the phases were separated. The aqueous phase was extracted with Et2O three times. The combined organic phases were washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution. Then the combined organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuum. The resulting crude product was purified by flash column silica gel chromatography to yield the product 6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 100℃; for 0.333333h; Microwave irradiation; | 2 Protocol B General procedure: to a solution of the substituted amine (1 equiv) and substituted acid (1 equiv) in DMF (0.30 mmol/mL) were added triethylamine (3 equiv) and PyBOP(1 equiv). The reaction mixture was heated at 100°C for 20 mm underr microwave irradiation. After cooling to rt, the reaction mixture was quenched with sat. NH4CI. The solution was extracted with EtOAc. The combined organic layers were washed with sat. NH4CI, dried over MgSO4, filtered and the solution was concentrated under reduced pressure (Figure 3AB). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39.4% | With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; XPhos In toluene at 100℃; for 1h; Inert atmosphere; | 19 Example 19Methyl 4-((2-oxo- 1 ,2,3,4-tetrahydroquinolin-6-yl)amino)benzoate To a solution of 6-bromo-3,4-dihydroquinolin-2(1H)-one (50 mg) and methyl 4- aminobenzoate 58 (43.5 mg) in toluene (1 ml) were added sequentially under argontris(dibenzylidineacetone)dipalladium (3.04 mg), 2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl (5.27 mg) and sodium tert-butoxide (31.9 mg). The reaction mixture was stirred at 100 °C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel, eluent: 0 to 10% of methanol in dichloromethane) to afford methyl 4-((2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino)benzoate (25.8 mg, 39.4%) as a light yellow solid. MS (ISP):297.2 ([M+H]j. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)indolin-2-one (10 g, 38.6 mmol) was added in toluene (250 ml_). The mixture was cooled down to 0C and NaH 60% in mineral oil (2.315 g, 57.9 mmol) was added portionwise. The reaction mixture was allowed to warm up and stir at RT for 30 min. Dimethyl sulfate (5.53 ml_, 57.9 mmol) was added and the reaction mixture was heated up and stirred at 60C for 3 hr, cooled down to 5C and quenched with water (50 ml_). The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHC03 solution and brine. The organic layer was dried over MgS04, filtered and concentrated under reduced pressure to afford the title product (1 1.3 g, 36.0 mmol, 93% yield) as brown solid. Rt = 1.03 min (UPLC-MS); ESI-MS = 274.2 [M+1]+ (UPLC-MS); 1H NMR (400 MHz, DMSO-d6) d ppm 1.29 (s, 12 H) 3.13 (s, 3 H) 3.55 (s, 2 H) 6.99 (d, J= 7.82 Hz, 1 H) 7.53 (s, 1 H) 7.61 (d, J= 7.95 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With trans-bis(triphenylphosphine)palladium dichloride; sodium carbonate In 1,4-dioxane; water at 100℃; Inert atmosphere; | S-37.1 Step 1 : Synthesis of 6-vinyl-3,4-dihydroquinolin-2(lH)-one. To a solution of 6- bromo-3,4-dihydroquinolin~2(H)-one (0.290 g, 1.29 mmol, 0.8 equiv) and 4,4,5,5-tetramethyl- 2-vinyl-l ,3,2~dioxaborolane (0 250 g, 1 62 mmol, 1 .0 equiv), in dioxane (10 niL) and water (1 niL) was added NarCCb (0.343 g, 3.24 mmol, 2.0 equiv). The resulting reaction mixture was purged with N . gas for 10 min followed by the addition of Pd(PPh3)Ch (0.056 g, 0.081 mmol, 0.05 equiv). The resulting reaction mixture was heated at 100° C for overnight. Product formation was confirmed by LCMS and TLC. After the completion of reaction, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL c 2). Combined organic extracts were washed with water (50 mL >< 2), dried over anhydrous NarSCL and concentrated under reduced pressure. The crude product was purified by flash chromatography (0-30 % ethyl acetate in hexane as an eluent) to obtain 6-vinyl-3,4- dihydroquinolin-2(lH)-one (0.140 g, 60 % yield) as a yellow' semi solid. LCMS 173.9 [M+Hf |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | Stage #1: 6-bromo-3,4-dihydro-1H-quinolin-2-one With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.166667h; Inert atmosphere; Stage #2: 2,6-dimethyl-4-(triisopropyl-silanyloxy)-benzaldehyde In tetrahydrofuran; hexane at -78℃; for 16h; Inert atmosphere; | 1.1 Step 1) 6-[(2,6-Dimethyl-4-triisopropylsiloxy-phenyl)-hydroxy-methyl]-3,4-dihydro-1H-quinolin-2-one 1b Under nitrogen protection, add the n-butyl lithium n-hexane solution (0.45mL, 1.1mmol, 2.5mol/L) dropwise to 6-bromo-3,4-dihydro-1H-quinolin-2-one 1a at -78 (0.10g, 0.44mmol) in tetrahydrofuran (5mL), stir for 10 minutes, A solution of 2,6-dimethyl-4-triisopropylsiloxy-benzaldehyde (0.14 g, 0.46 mmol) in tetrahydrofuran (1 mL) was added dropwise, and the reaction solution was reacted at -78°C for 16 hours. Saturated ammonium chloride aqueous solution (10 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL), the organic phase was washed with saturated sodium chloride aqueous solution (10 mL), dried over anhydrous sodium sulfate, and concentrated by suction filtration. Preparation of TLC plate [petroleum ether/ethyl acetate (v/v)=2/1] purification to obtain the title compound 1b (61 mg, yield 30%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate In 1,4-dioxane at 95℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: 6-bromo-3,4-dihydro-1H-quinolin-2-one With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Sealed tube; Stage #2: 2-iodo-propane In N,N-dimethyl-formamide at 20℃; for 6h; | 1.9.1 Step 1. Synthesis of 1-isopropyl-6-bromo-3,4-dihydro-2(1H)-quinolinone (B-1-1): Dissolve 6-bromo-3,4-dihydro-2(1H)-quinolinone (2.26g, 10.0mmol) in 30mL at 0°C In N,N-dimethylformamide, slowly add sodium hydride (720mg, 30.0mmol) to the solution, seal the reaction with a balloon, stir for 30min, leave it at room temperature and add iodopropane (3.00mL, 30.0mmol) dropwise After reacting for 6 hours, the reaction mixture was first quenched with a small amount of water, then diluted with 300 mL of water, and extracted with 300 mL of dichloromethane three times. The organic layers were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure.The crude product was further purified by flash preparative liquid chromatography (petroleum ether: ethyl acetate = 4:1) to obtain B-1-1 (2.28 g, 8.5 mmol). White oily liquid with a yield of 85%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.52% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; water; toluene at 90℃; for 16h; Inert atmosphere; | 11.1; 85.1 To a mixture of 6-bromo-3,4-dihydro-1H-quinolin-2-one (2 g, 8.85 mmol, 1 eq) and pyridine;2, 4, 6-trivinyl-1,3,5,2,4,6-trioxatriborinane (2.55 g, 10.62 mmol, 1.2 eq) in toluene (40 mL), EtOH (8 mL) and H2O (2 mL) was added Pd(PPh3)4 (1.02 g, 884.68 umol, 0.1 eq) and Na2CO3 (2.81 g, 26.54 mmol, 3 eq) under N2. The mixture was heated to 90°C and stirred for 16 hours. The mixture was cooled to 20 °C and poured into ice-water (60 mL) and stirred for 15 min. The aqueous phase was extracted with ethyl acetate (80 mL*3). The combined organic phase was washed with brine (50 mL*2), dried with anhydrous NaiSCL, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether: Ethyl acetate=50:1-0:1). Compound 6-vinyl-3,4-dihydro-1H-quinolin-2-one (1.05 g, 6.06 mmol, 68.52% yield) was obtained as yellow solid. LCMS: (M+H)+ : 173.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With 1,10-Phenanthroline; carbon monoxide; water-d2; copper diacetate; triethylamine at 120℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With Ir(CF3ppy)<SUB>3</SUB> In acetonitrile at 25℃; for 12h; Inert atmosphere; Irradiation; Overall yield = 61 percent; Overall yield = 13.8 mg; |
Tags: 3279-90-1 synthesis path| 3279-90-1 SDS| 3279-90-1 COA| 3279-90-1 purity| 3279-90-1 application| 3279-90-1 NMR| 3279-90-1 COA| 3279-90-1 structure
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Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
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 |
Sorry,this product has been discontinued.
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