2-(2-甲基-1-氧代丙烷)环己酮

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 6-bromo-3-iodo-N-(4-methoxybenzyl)quinolin-2-amine (0.30 g, 0.640 mmol, prepared as in Example 1, Step 1-2), 2-ethylmorpholine (1.105 g, 9.59 mmol), copper(I) iodide (6.09 mg, 0.032 mmol), cesium carbonate (0.417 g, 1.279 mmol), and 2-isobutyrylcyclohexanone (0.021 mL, 0.128 mmol) in DMF (3 mL) was heated at 125° C. for 10 min. Some product was observed but mostly starting material. The mixture was heated again at 125° C. for 10 min more. This process was repeated 3× until the starting material was completely consumed. The reaction was brought to RT, poured into water (20 mL) and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, concentrated, and chromatographed on silica gel using gradient 2:1 hexanes/EtOAc to afford a brown oil as 6-bromo-3-(2-ethylmorpholino)-N-(4-methoxybenzyl)quinolin-2-amine. The mixture was heated again at 125° C. for 10 min more was completely consumed was brought to RT poured into water (20 mL) extracted with EtOAc The combined organics were dried over Na2SO4 filtered concentrated chromatographed on silica gel using gradient 2:1 hexanes/EtOAc

反应条件: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 6-bromo-3-iodo-N-(4-methoxybenzyl)quinolin-2-amine (0.25 g, 0.533 mmol, prepared as in Example 1, Step 1-2), 2-isobutyrylcyclohexanone (0.018 g, 0.107 mmol), (R)-5-methylmorpholin-3-one (0.92 g, 7.99 mmol), copper(I) iodide (5.07 mg, 0.027 mmol), and cesium carbonate (0.35 g, 1.066 mmol) in DMF (5 mL) was heated at 125° C. for 10 min. Some product was observed but mostly starting material. The mixture was heated again at 125° C. for 10 min more. This process was repeated 7× until the starting material was completely consumed. The reaction was brought to RT, poured into water (20 mL) and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, concentrated, and chromatographed on silica gel using gradient 2:1 hexanes/EtOAc to afford a light yellow solid as (R)-4-(6-bromo-2-(4-methoxybenzylamino)quinolin-3-yl)-5-methylmorpholin-3-one. The mixture was heated again at 125° C. for 10 min more was completely consumed was brought to RT poured into water (20 mL) extracted with EtOAc The combined organics were dried over Na2SO4 filtered concentrated chromatographed on silica gel using gradient 2:1 hexanes/EtOAc

反应条件: temp:125.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 6-bromo-3-iodo-N-(4-methoxybenzyl)quinolin-2-amine (710 mg, 1.5 mmol), morpholine (1.9 mL, 22.7 mmol), Cu(I)(14.4 mg, 0.08 mmol), cesium carbonate (986 mg, 3.0 mmol), 2-isobutyrylcyclohexanone (50.9 mg, 0.30 mmol) and DMF (10 mL) was heated to 125° C. in a microwave unit for 20 min. The mixture was concentrated in vacuo then partioned the crude product between EtOAc and water. The organic layer was washed with water and brine 3× each, dried over MgSO4 and concentrated in vacuo to give an orange colored oil. This material was purified by silica flash chromatography (0-5% MeOH/DCM) to give 6-bromo-N-(4-methoxybenzyl)-3-morpholinoquinolin-2-amine as a yellow colored oil. The mixture was concentrated in vacuo The organic layer was washed with water and brine 3× each, dried over MgSO4 concentrated in vacuo to give an orange colored oil This material was purified by silica flash chromatography (0-5% MeOH/DCM)

反应条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A screw-capped tube is charged with 2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole (example 41, 200 mg), copper(I) iodide (7 mg), 2-isobutyrylcyclohexanone (25 mg), cesium carbonate (280 mg), 3-(Boc-amino)pyrrolidine (160 mg) and anhydrous N,N-dimethylformamide (1 mL). The tube is evacuated, filled with argon and sealed. After stirring at 55° C. for 4 days, the mixture is diluted with ethyl acetate, water and ammonia. After decantation, the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 98/2/0.5 to 95/5/0.5). to afford (1-{3-[benzothiazol-2-yl-(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-yl)carbamic acid tert-butyl ester. The tube is evacuated filled with argon sealed the mixture is diluted with ethyl acetate, water and ammonia After decantation, the aqueous phase is extracted with ethyl acetate The pooled organic extracts are dried over magnesium sulfate concentrated under reduced pressure The residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 98/2/0.5 to 95/5/0.5)

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A screw-capped tube is charged with 2-[(3-iodophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole (example 41, 200 mg), copper(I) iodide (7 mg), 2-isobutyrylcyclohexanone (25 mg), cesium carbonate (280 mg), 3-(Boc-amino)pyrrolidine (160 mg) and anhydrous N,N-dimethylformamide (1 mL). The tube is evacuated, filled with argon and sealed. After stirring at 55° C. for 4 days, the mixture is diluted with ethyl acetate, water and ammonia. After decantation, the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 98/2/0.5 to 95/5/0.5), to afford (1-{3-[benzothiazol-2-yl-(1-methylpiperidin-4-yloxy)methyl]phenyl}pyrrolidin-3-yl)carbamic acid tert-butyl ester. The tube is evacuated filled with argon sealed the mixture is diluted with ethyl acetate, water and ammonia After decantation, the aqueous phase is extracted with ethyl acetate The pooled organic extracts are dried over magnesium sulfate concentrated under reduced pressure The residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 98/2/0.5 to 95/5/0.5)

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Copper iodide (1.0 equiv) and cesium carbonate (2.0 equiv) were added to a microwave vial and the vial was evacuated and filled with argon three times. Benzyl 3-iodobenzoate (4) in dry dimethylformamide (2 M), isopropylamine (2.0 equiv) and 2-isobutyrylcyclohexanone (0.2 equiv) were then added to the vial, the vial was sealed and the resulting mixture is heated to 100° C. under microwave irradiation for 2 hours. At that time, the vial was cooled to room temperature and the reaction mixture was diluted with ethyl acetate and filtered through a pad of Celite with aid of ethyl acetate. The filtrate was washed with brine (3×), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (ethyl acetate/hexanes as elutant) to provide benzyl 3-(isopropylamino)benzoate (5). the vial was evacuated filled with argon three times was sealed At that time, the vial was cooled to room temperature filtered through a pad of Celite with aid of ethyl acetate The filtrate was washed with brine (3×) dried over MgSO4 filtered concentrated in vacuo The residue was purified by flash chromatography on silica gel (ethyl acetate/hexanes as elutant)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A suspension of CuI (0.006 g, 0.030 mmol), benzyl N-[(1S,3R)-3-aminocyclo-hexyl]carbamate, 18e, (0.075 g, 0.302 mmol) and cesium carbonate (0.197 g, 0.604 mmol) in DMF was evacuated and refilled with nitrogen multiple times. 2-iodopyrazine (0.036 mL, 0.362 mmol) and 2-(2-methylpropanoyl)cyclohexanone (0.020 mL g, 0.121 mmol) were then added and the reaction was stirred at room temperature overnight. The reaction was diluted into ethyl acetate and aqueous saturated sodium bicarbonate. The organic phase was separated, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0-10% MeOH/CH2Cl2) to afford 40 mg of the desired product as yellow solid. was evacuated refilled with nitrogen multiple times The organic phase was separated dried (MgSO4) filtered concentrated in vacuo The crude residue was purified by silica gel chromatography (0-10% MeOH/CH2Cl2)

反应条件: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 3-bromo-5-iodopyridine (500 mg, 1.761 mmol, Aldrich), tert-butyl 3-aminopiperidine-1-carboxylate (388 mg, 1.937 mmol, Combi-blocks), Cut (33.5 mg, 0.176 mmol, Aldrich) and cesium carbonate (1148 mg, 3.52 mmol, Fluka) was capped, degassed and backfilled with argon (3×). Dioxane (2 mL) and 2-isobutyrylcyclohexanone (0.118 mL, 0.704 mmol) were added, and the reaction was heated to 55° C. After 16 h, the temperature was raised to 70° C. After 60 h at 70° C., the reaction mixture was cooled to 23° C., diluted with EtOAc (75 mL) and washed with brine (50 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluent: 25-60% EtOAc/hexane), affording tert-butyl 3-(5-bromopyridin-3-ylamino)piperidine-1-carboxylate (375 mg, 60%). MS (ESI, pos. ion) m/z: 356.1 (M+1), 358.1 (M+3). was capped degassed the temperature was raised to 70° C After 60 h at 70° C. the reaction mixture was cooled to 23° C. washed with brine (50 mL) dried over MgSO4 concentrated in vacuo purified by silica gel chromatography (eluent: 25-60% EtOAc/hexane)

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 3-bromo-5-iodopyridine (600 mg, 2.113 mmol, Aldrich), 4-(n-boc-amino)-piperidine (466 mg, 2.325 mmol, Aldrich), Cut (40.3 mg, 0.211 mmol, Aldrich) and cesium carbonate (1377 mg, 4.23 mmol, Strem) was capped, degassed and backfilled with argon (3×). Dioxane (2 mL) and 2-isobutyrylcyclohexanone (0.141 mL, 0.845 mmol, Aldrich) were added, and the reaction was stirred at 70° C. After 43 h, the reaction mixture was cooled to 23° C., diluted with EtOAc (50 mL) and washed with brine (50 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluent: 15-40% EtOAc/hexane), affording tert-butyl 1-(5-bromopyridin-3-yl)piperidin-4-ylcarbamate (198 mg, 26%). MS (ESI, pos. ion) m/z: 356.0 (M+1), 358.0 (M+3). was capped degassed the reaction mixture was cooled to 23° C. washed with brine (50 mL) dried over MgSO4 concentrated in vacuo purified by silica gel chromatography (eluent: 15-40% EtOAc/hexane)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A dried round bottom flask was charged with copper(I) iodide (0.10 g, 0.53 mmol), cesium carbonate (3.58 g, 11 mmol). The flask was evacuated and backfilled with nitrogen. Under the flow of nitrogen, (S)-pyrrolidin-3-yl-methanol (0.80 g, 7.9 mmol), 3-iodothiophene (0.54 ml, 5.3 mmol), 2-(2-methyl-1-oxopropyl)cyclohexanone (0.35 ml, 2.1 mmol), and N,N-dimethylformamide (5 ml) were added. The mixture was allowed to stir under nitrogen at ambient temperature for 12 hours. The mixture was diluted with ethyl acetate, passed through a glass filter to remove the inorganic salts and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=9/1 to 1/1) to afford (S)-[1-(thiophen-3-yl)pyrrolidin-3-yl]methanol (0.41 g, 2.2 mmol, 42%) as a brown oil. In the manner as above (2)-(6), with the use of methyl (3R)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate instead of methyl (3S)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate, (R)-[1-(thiophen-3-yl)pyrrolidin-3-yl]methanol was obtained (0.19 g, 1.0 mmol). The flask was evacuated filter to remove the inorganic salts the solvent was removed under reduced pressure The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=9/1 to 1/1)