* 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.
Reference：
[1] Journal of the Chemical Society, 1947, p. 232,236
[2] Journal of the Chemical Society, 1947, p. 232,236
[3] Journal of the Chemical Society, 1947, p. 232,236
2
[ 23082-51-1 ]
[ 39061-72-8 ]
Yield
Reaction Conditions
Operation in experiment
89%
With iron; acetic acid In water for 16 h; Reflux
1-(2-Amino-4-chlorophenyl)ethanone A mixture of methyl 1-(4-chloro-2-nitrophenyl)ethanone (5.0 g, 25 mmol) and Fe (5.6 g, 100 mmol) in CH3COOH (50 mL) and H2O (50 mL) was stirred at reflux for 16 h. The mixture was allowed to cool to RT and quenched with saturated NaHCO3 aqueous solution. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3 aqueous solution and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether= 1:4) to afford the desired product (3.8 g, 89percent yield) as a yellow solid.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 24, p. 7381 - 7387
[2] Patent: WO2015/54572, 2015, A1, . Location in patent: Page/Page column 274
[3] Journal of the Chemical Society [Section] C: Organic, 1968, p. 2747 - 2751
[4] Patent: US4379929, 1983, A,
[5] Patent: US2008/287458, 2008, A1, . Location in patent: Page/Page column 39
3
[ 38487-86-4 ]
[ 676-58-4 ]
[ 39061-72-8 ]
Yield
Reaction Conditions
Operation in experiment
96%
Stage #1: at 0 - 25℃; for 3.33333 h; Inert atmosphere Stage #2: With hydrogenchloride In tetrahydrofuran; diethyl ether; water at -60 - 18℃; for 3 h; Stage #3: With potassium hydroxide In water
Example 5 rel-4-(7-Chloro-4-oxo-1-pyridin-2-yl-1,4-dihydro-quinolin-3-ylmethyl)-N-((1S,2S,3R,5S,7S)-5-hydroxy-adamantan-2-yl)-benzamide A 2 liter three neck flask equipped with an addition funnel, an argon inlet, and an overhead mechanical stirrer was charged with 2-amino-4-chlorobenzonitrile (15 g, 0.098 mol) and anhydrous diethyl ether (1.2 L). The reaction flask was back-filled with argon gas. The mixture was then cooled to 0° C. in an ice water bath. At this time, the reaction was treated with a solution of methyl magnesium chloride (3.0 M in tetrahydrofuran, 100 mL, 0.30 mol). The addition process occurred over 90 min. At this time, the reaction mixture was stirred at 0° C. for an additional 90 min. The reaction was then warmed to 25° C. and was stirred at 25° C. for 20 min. At this time, the reaction mixture was cooled to -60° C. using a dry ice/acetone bath and was then treated slowly dropwise with a 6N aqueous hydrochloric acid solution (100 mL). The reaction mixture was then allowed to warm to 18° C. with stirring over the course of 3 h. At this time, the reaction was treated with an additional amount of the 6N aqueous hydrochloric acid solution (100 mL). At this time, the reaction mixture was transferred to a separatory funnel. The organic layer was separated and set aside. The aqueous layer was brought to pH 9 by the slow addition of solid potassium hydroxide with stirring. The resulting mixture was then extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford 1-(2-amino-4-chlorophenyl)ethanone (16.1 g, 96percent) as a tan solid.
1-(2-Amino-4-chlorophenyl)ethanone A mixture of methyl <strong>[23082-51-1]1-(4-chloro-2-nitrophenyl)ethanone</strong> (5.0 g, 25 mmol) and Fe (5.6 g, 100 mmol) in CH3COOH (50 mL) and H2O (50 mL) was stirred at reflux for 16 h. The mixture was allowed to cool to RT and quenched with saturated NaHCO3 aqueous solution. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3 aqueous solution and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether= 1:4) to afford the desired product (3.8 g, 89% yield) as a yellow solid.
EXAMPLE 18 2-Amino-4-chloroacetophenone This compound is prepared from <strong>[23082-51-1]4-chloro-2-nitroacetophenone</strong> according to the teaching of Example 2.
Example 5 rel-4-(7-Chloro-4-oxo-1-pyridin-2-yl-1,4-dihydro-quinolin-3-ylmethyl)-N-((1S,2S,3R,5S,7S)-5-hydroxy-adamantan-2-yl)-benzamide A 2 liter three neck flask equipped with an addition funnel, an argon inlet, and an overhead mechanical stirrer was charged with 2-amino-4-chlorobenzonitrile (15 g, 0.098 mol) and anhydrous diethyl ether (1.2 L). The reaction flask was back-filled with argon gas. The mixture was then cooled to 0 C. in an ice water bath. At this time, the reaction was treated with a solution of methyl magnesium chloride (3.0 M in tetrahydrofuran, 100 mL, 0.30 mol). The addition process occurred over 90 min. At this time, the reaction mixture was stirred at 0 C. for an additional 90 min. The reaction was then warmed to 25 C. and was stirred at 25 C. for 20 min. At this time, the reaction mixture was cooled to -60 C. using a dry ice/acetone bath and was then treated slowly dropwise with a 6N aqueous hydrochloric acid solution (100 mL). The reaction mixture was then allowed to warm to 18 C. with stirring over the course of 3 h. At this time, the reaction was treated with an additional amount of the 6N aqueous hydrochloric acid solution (100 mL). At this time, the reaction mixture was transferred to a separatory funnel. The organic layer was separated and set aside. The aqueous layer was brought to pH 9 by the slow addition of solid potassium hydroxide with stirring. The resulting mixture was then extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford 1-(2-amino-4-chlorophenyl)ethanone (16.1 g, 96%) as a tan solid.
1- (2-amino-4-chlorophenyl)ethanone; [1319] To a vigourosly stirred, Et20 (100 mL) solution of 2-amino-4- chlorobenzonitrile (1.00 g, 6.55 mmol) cooled in an ice-H20 bath was added MeMgCI (3.0 M in THF, 6.5 mL, 19.7 mmol) dropwise over 5 min. During that time the reaction became a thick yellow suspension. Stirring was continued at the temperature for 1 h before the cooling bath was removed and the reaction stirred for 21 h at rt. The resultant light yellow suspension cooled to-60 C and treated with aq HCI (5 M, 8 mL, 40 mmol) dropwise over - 3 min. The mixture was allowed to warm slowly to rt within the cooling bath. Later more aq HCI ( 5 M, 6.5 mL, 33 mmol) was added. The Et20 layer was separated, the aq phase was basicified (pH 4-5) by addition of solid KOH and later extracted with EtOAc (3x). The Et20 and EtOAc layers were combined, dried (Na2S04) and concentrated under reduced pressure to afford the title material which was used without further purification; ¹H NMR (400 MHz, CDC13) No. 7.63 (d, J = 8.4 Hz, 1H), 6.65 (d, J = 2.0 Hz, 1H), 6.60 (dd, J = 2.0 Hz, 8.0 Hz, 1H), 6.40 (br, 2H), 2.55 (s, 3H) ; MS (ES+): m/z 170.07 (100) [MH+]; HPLC: tR = 3.12 min (OpenLynx, polar_5min).
With 1-butylimidazolium tetrafluoroborate; at 100℃; for 57h;
7-Chloro-4-methyl-2-phenylquinoline; [1318] Acetophenone (0.66 mL, 5.69 mmol) was added to 1-(2-amino-4- chlorophenyl) ethanone (0.868 g, 5.69 mmol) and [Hbim] BF4 (1.50 g, 7.08 mmol) under Ar. The reaction mixture was heated at 100 C for 57 h then cooled to rt and partitioned between EtOAc and H20. The aq layer was extracted with EtOAc. The combined organics were dried (Na2S04) and concentrated under reduced pressure. Purification by flash chromatography on SiOz (70 g, EtOAc in hexanes 0:100-> 1: 40 -> 1: 30) afforded a lightly colored oil. The material was dissolved in DCM (100 mL) and stirred with PS-Ts-NHNH2 (2.07 g, 2.87 mmol/g, 5.94 mmol) for 2.5 d at rt and then with MP-carbonate (-0.25 g, 2.74 mmol/g, 0.68 mmol) for 4 h. The resins were removed by filtration through Celite. The residue and Celite were rinsed with DCM multiple times. The filtrate was concentrated under reduced pressure to provide the title compound as a light yellow oil; 'H NMR (400 MHz, CDC13) No. 8.18-8.12 (m, 3H), 7.92 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 0.8 Hz, 1H), 7.54-7.46 (m, 4H), 2.75 (s, 3H) ; MS (ES+) : m/z 254.24 (35) [MH+]; HPLC: tR = 3.82 min (OpenLynx, nonpolar_5min).
8-chloro-11-methyl-2,3,4,5-tetrahydro-1<i>H</i>-azepino[4,5-<i>b</i>]quinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 134 8-Chloro-1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline, 8-chloro-2,3,4,5-tetrahydro-11-methyl-1H-azepino[4,3-b]quinoline and their dihydrochlorides were prepared from hexahydro-azepinone-(4) hydrochloride and 2-amino-4-chloro-acetophenone analogous to Example 127. Yield of the dihydrochloride of the [4,5-b]-isomer: 24% of theory; m.p. 287 C (decomp.). Yield of the dihydrochloride of the [4,3-b]-isomer: 16% of theory; m.p. 304 C.
a) A mixture of 6.5 g (0.038 mol) of <strong>[39061-72-8]1-(2-amino-4-chlorophenyl)-ethanone</strong> and 5.2 g (0.046 mol) of ethyl cyanoacetate was heated to 200 C. for 4 hrs., with a water/ethanol mixture formed being distilled off. The mixture was stirred at 210 C. for a further 2 hrs., left to cool to room temperature, the resulting brown mass was ground in a mortar, suspended in ethanol overnight, filtered off, washed with ethanol and dried in a vacuum. Yield: 7.28g (87%) of 7-chloro-2-hydroxy-4-methyl-quinoline-3-carbonitrile as pale brown crystals; m.p. >350 C. MS: me/e (% base peak)=218 (C11 H7 ClN2 O+, 100), 190 (53), 189 (35), 163 (7.5), 155(13), 140(4), 128(11), 101 (6), 77 (20).
A 3-necked round-bottomed flask equipped with a mechanic stirrer, a thermocouple probe, a reflux condenser and a nitrogen bubbler was charged with <strong>[39061-72-8]1-(2-amino-4-chlorophenyl)ethanone</strong> (81 g, 478 mmol) in di-n-butyl ether (1 L). The reaction was then treated with pulverized potassium carbonate (200 g, 1.45 mol) and copper powder (5 g, 78 mmol). The reaction mixture was refluxed at 140-145 C. for 3 h. At this time, additional potassium carbonate (100 g, 0.72 mol), iodobenzene (100 g, 0.49 mol) and copper powder (2 g, 31 mmol) was added. The resulting mixture was refluxed overnight. At this time, the reaction was cooled to 25 C., filtered and washed with methyl tert-butyl ether. The filtrate was concentrated in vacuo. Flash chromatography (4"*16" silica gel column; 0-2% ethyl acetate/hexanes) followed by concentration of the appropriate fractions, slurrying with hexanes, filtration and drying afforded 1-(4-chloro-2-phenylamino-phenyl)-ethanone (79.3 g, 67.6%) as a yellow solid.
With potassium carbonate; potassium iodide;copper; In dibutyl ether; at 160℃;Heating / reflux;
A mixture of <strong>[39061-72-8]1-(2-amino-4-chlorophenyl)-ethanone</strong> (1.85 g), copper powder (140 mg), KI (360 mg), K2CO3 (3.06 g) and iodobenzene (4.8 mL) in dibutyl ether (40 mL) was heated at 160 C. (oil bath temperature) overnight. More copper powder (140 mg), KI (360 mg), K2CO3 (3.06 g) and iodobenzene (4.8 mL) were added and the reaction mixture was heated at reflux overnight. The resulting mixture was then cooled and concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate, the organic layer was separated and the aqueous layer was extracted with ethyl acetate (2*50 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (EtOAc/hexane) to afford 2.2 g of 1-(4-chloro-2-phenylamino-phenyl)-ethanone.
D-1-(2-Amino-4-chlorophenyl)ethanone2.55 ml of trifluoroacetic acid are added dropwise to a solution of 0.9 g of the compound from the preceding stage in 17 ml of DCM and the mixture is left stirring at AT overnight. The reaction mixture is washed with a 10% NaOH solution and with a saturated NaCl solution and dried over MgSO4, and the solvent is evaporated. 0.5 g of the expected compound is obtained.
With trifluoroacetic acid; In dichloromethane; at 20℃;
D-1-(2-Amino-4-chlorophenyl)ethanone 2.55 ml of trifluoroacetic acid are added dropwise to a solution of 0.9 g of the compound from the preceding stage in 17 ml of DCM and the mixture is left stirring at AT overnight. The reaction mixture is washed with a 10% NaOH solution and with a saturated NaCl solution and dried over MgSO4, and the solvent is evaporated. 0.6 g of the expected compound is obtained.
(IX): R3=8-OMe A solution of 2 g of the compound from Preparation 1.2 in 8 ml of concentrated HCl is cooled to 0 C., a solution of 1.25 g of NaNO2 in 2.7 ml of water is added dropwise while maintaining the temperature of the reaction mixture below 10 C. and the mixture is left stirring at 0 C. for 2 hours and at AT overnight. The reaction mixture is concentrated under vacuum, 50 ml of an AcONa solution are added and the precipitate formed is filtered off and washed with 20 ml of water. 1.95 g of the expected compound are obtained.
1-[4-chloro-2-(pyridin-2-ylamino)-phenyl]-ethanone trifluoroacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
25.6%
A solution of <strong>[39061-72-8]1-(2-amino-4-chlorophenyl)ethanone</strong> (1000 mg, 5.9 mmol) in dioxane (14.7 mL) at 25 C. in a thick walled high pressure reaction flask was treated with sodium phenoxide (958 mg, 8.25 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (108 mg, 118 mumol), tris(dibenzylideneacetone)dipalladium(0) (75.1 mg, 130 mumol) and 2-chloropyridine (669 mg, 5.9 mmol). The reaction flask was tightly capped and then heated to 100 C. for 2 d. At this time, the reaction was cooled to 25 C., diluted with a 10% solution of methanol/methylene chloride (50 mL) and filtered through a pad of Celite rinsing with a 10% solution of methanol/methylene chloride (2*30 mL). The filtrate was concentrated in vacuo. The crude material was purified using reverse phase chromatography (ammonium acetate/acetonitrile with trifluoroacetic acid) to afford the trifluoroacetic acid salt of 1-[4-chloro-2-(pyridin-2-ylamino)-phenyl]-ethanone (544 mg, 25.6%) as an off-white solid. ES+-HRMS m/e calcd for C13H11ClN2O [M+H+] 247.0633 found 247.0628; 1H NMR (400 MHz, DMSO-d6) delta ppm 12.26 (br. s., 1H) 8.87 (s, 1H) 8.71 (d, J=6.4 Hz, 1H) 8.14 (t, J=7.8 Hz, 1H) 7.65 (d, J=8.5 Hz, 1H) 7.28-7.45 (m, 3H) 7.19 (br. s., 1H) 1.82 (br. s., 3H).
7-chloro-3-[4-((1S,2S,3R,5S,7S)-5-hydroxy-adamantan-2-ylcarbamoyl)-benzyl]-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester[ No CAS ]
3-[4-((1S,2S,3R,5S,7S)-5-acetoxy-adamantan-2-ylcarbamoyl)-benzyl]-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester[ No CAS ]
7-chloro-3-{4-[(1S,2S,3R,5S,7S)-5-(2-chloro-acetylamino)-adamantan-2-ylcarbamoyl]-benzyl}-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester[ No CAS ]
3-[4-((1S,2S,3R,5S,7S)-5-acetylamino-adamantan-2-ylcarbamoyl)-benzyl]-7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester[ No CAS ]
7-chloro-3-{4-[(1S,2S,3R,5S,7S)-5-(2,2-dimethyl-propionylamino)-adamantan-2-ylcarbamoyl]-benzyl}-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester[ No CAS ]
7-chloro-3-{4-[(1S,2S,3R,5S,7S)-5-(2-hydroxy-2-methyl-propionylamino)-adamantan-2-ylcarbamoyl]-benzyl}-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester[ No CAS ]
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