methyl 4-chloro-3-oxobutanoate

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of methyl 2-[(2,4-difluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.27 g, 1.0 mmol) which similarly prepared according to the procedure described in the Example 2, First step using methyl 4-chloroacetoacetate and 2,4-difluorophenyl isocyanate, and 7-azaindole-3-carboxaldehyde (0.15 g, 1.0 mmol) in 2-propanol (5.0 mL), L-proline (0.023 g, 0.20 mmol) was added at ambient temperature. The mixture was refluxed for 12 h. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound as solid (0.30 g, y. 75%). was added at ambient temperature The mixture was refluxed for 12 h the precipitate was collected by filtration washed with ethanol and diisopropyl ether then dried

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of methyl 2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.063 g, 0.25 mmol) which similarly prepared according to the procedure described in the Example 2, First step using methyl 4-chloroacetoacetate and 4-fluorophenyl isocyanate, 2-methoxyethanol (0.2 mL, 2.5 mmol) and zinc cluster catalyst (Zn4(OCOCF3)6O) (0.0048 g, 0.0050 mmol) in anhydrous dioxane (1.0 mL) was stirred with the microwave synthesizer (Biotage Initiator™) at 120° C. for 1 h. Cooled to ambient temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on silica gel(chloroform/ethyl acetate) to afford 2-methoxyethyl 2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (0.024 g, y. 33%). Cooled to ambient temperature the reaction mixture was concentrated under reduced pressure The residue was purified by chromatography on silica gel(chloroform/ethyl acetate)

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Under a nitrogen atmosphere, a solution of methyl 2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.13 g, 0.50 mmol) which similarly prepared according to the procedure described in the Example 2, First step using methyl 4-chloroacetoacetate and 4-fluorophenyl isocyanate, and zinc cluster catalyst (Zn4(OCOCF3)6O) (0.0062 g, 0.0065 mmol) in 1-butanol (2.0 mL) was stirred at 80° C. for 3 days then stirred at ambient temperature for further 3 days. The precipitate was collected by filtration, washed with 2-propanol and diisopropyl ether then dried to afford n-butyl 2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (0.078 g, y. 53%). then stirred at ambient temperature for further 3 days The precipitate was collected by filtration washed with 2-propanol and diisopropyl ether then dried

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of methyl 2-[(4-fluorophenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.25 g, 1.0 mmol) which similarly prepared according to the procedure described in the Example 2, First step using methyl 4-chloroacetoacetate and 4-fluorophenyl isocyanate, and 7-azaindole-3-carboxaldehyde (0.15 g, 1.0 mmol) in 2-propanol (5.0 mL), L-proline (0.023 g, 0.20 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound as solid (0.26 g, y. 68%). was added at ambient temperature The mixture was refluxed for 2 days the precipitate was collected by filtration washed with ethanol and diisopropyl ether then dried

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of methyl 4-oxo-2-(phenylamino)-4,5-dihydrofuran-3-carboxylate (0.047 g, 0.20 mmol) which similarly prepared according to the procedure described in the Example 2, First step using methyl 4-chloroacetoacetate and phenyl isocyanate, and 7-azaindole-3-carboxaldehyde (0.029 g, 0.20 mmol) in 2-propanol (1.0 mL), piperidine (0.022 mL, 0.22 mmol) was added at ambient temperature. The mixture was refluxed for 5 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound as solid (0.031 g, y. 43%). was added at ambient temperature The mixture was refluxed for 5 days the precipitate was collected by filtration washed with ethanol and diisopropyl ether then dried

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of methyl 4-oxo-2-(phenylamino)-4,5-dihydrofuran-3-carboxylate (0.047 g, 0.20 mmol) which similarly prepared according to the procedure described in the Example 2, First step using methyl 4-chloroacetoacetate and phenyl isocyanate, and 7-azaindole-3-carboxaldehyde (0.029 g, 0.20 mmol) in methanol (1.0 mL), piperidine (0.022 mL, 0.22 mmol) was added at ambient temperature. The mixture was refluxed for 5 days. Cooled to ambient temperature, the precipitate was collected by filtration, then purified by preparative HPLC, collected former fraction to afford the titled compound as solid (0.0075 g, y. 11%). was added at ambient temperature The mixture was refluxed for 5 days the precipitate was collected by filtration purified by preparative HPLC collected former fraction

反応条件: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Sodium hydride (17.32 g, 0.433 mol) was washed with hexane (100 ml×2) then was suspended in dimethylformamide (300 ml). To the mixture was dropwise added thiophenol (44.5 ml, 0.433 mol) in DMF (50 ml) under ice-methanol bath cooling with controlling the inner temperature of 5-10° C. under nitrogen atmosphere. After 1.5 h stirring at -5° C., methyl 4-chloroacetoacetate (50 ml, 0.433 mol) was dropwise added to the reaction mixture under ice-methanol bath cooling with controlling the inner temperature of 5-10° C. under nitrogen atmosphere and the reaction mixture was stirred at room temperature overnight. The mixture was acidified with 1N HCl to pH 2 under ice bath cooling then partitioned between EtOAc (500 ml) and H2O (100 ml). The aqueous phase was extracted with EtOAc (250 ml×2). The combined extracts were concentrated to about 500 ml and then washed with aq. NaHCO3 solution (150 ml) and brine (100 ml×3). The organic solution was dried over MgSO4 and concentrated to afford 100.88 g of methyl 4-phenylthioacetoacetate as an orange color oil. (104% yield).(contained 1/6 eq of DMF) 1H NMR (CDCl3) 7.42-7.18 (m, 5H), 3.80 (s 2H), 3.71 (s, 3H), 3.65 (s, 2H). cooling the inner temperature of 5-10° C. cooling the inner temperature of 5-10° C. the reaction mixture was stirred at room temperature overnight cooling then partitioned between EtOAc (500 ml) and H2O (100 ml) The aqueous phase was extracted with EtOAc (250 ml×2) The combined extracts were concentrated to about 500 ml washed with aq. NaHCO3 solution (150 ml) and brine (100 ml×3) The organic solution was dried over MgSO4 concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 127.2 g (1.2 mol) of sodium carbonate and 4.6 g (0.02 mol) of benzyltriethylammonium chloride are suspended in 800 ml of acetonitrile. While stirring there is added dropwise thereto within 8 hours a solution of 150.5 g (1 mol) of methyl 4-chloroacetoacetate and 138.8 g (1.5 mol) of chloroacetone in 200 ml of acetonitrile. The mixture is stirred at 20°-25° C. for a further 15 hours. The reaction mixture is poured into 750 ml of 2N HCl (pH value=1) and extracted three times with 300 ml of ether. The combined organic phases are dried over magnesium sulphate and concentrated on a rotary evaporator. The residue is treated with 200 ml of ether, the precipitated 2,5-bimethoxycarbonyl-1,4-cyclohexanedione is filtered off under suction and the filtrate is again concentrated. The crude product is column chromatographed on silica gel with ether/hexane 1:1 and gives 32.28 g (15.6%) of methyl 4-chloro-2-acetonylacetoacetate. is added dropwise The mixture is stirred at 20°-25° C. for a further 15 hours extracted three times with 300 ml of ether The combined organic phases are dried over magnesium sulphate concentrated on a rotary evaporator The residue is treated with 200 ml of ether the precipitated 2,5-bimethoxycarbonyl-1,4-cyclohexanedione is filtered off under suction the filtrate is again concentrated chromatographed on silica gel with ether/hexane 1:1

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 108 g (1.1 mol) of potassium acetate and 11.4 g (0.05 mol) of benzyltriethylammonium chloride are suspended in 900 ml of acetonitrile, treated with 50 ml of acetic acid and heated to reflux temperature. Within 31/2 hours there are added dropwise thereto 150.5 g (1 mol) of methyl 4-chloroacetoacetate in 100 ml of acetonitrile and the mixture is subsequently held at reflux temperature for 4 hours. The reaction mixture is washed 3 times with 200 ml of 5% NaH2PO4 solution each time and the aqueous phases are back-extracted with 200 ml of CH2Cl2. The combined organic phases are dried over magnesium sulphate and concentrated on a rotary evaporator. The crude product distils at 76°-85° C./0.6 mbar and gives 106.17 g (61%) of methyl 4-acetoxyacetoacetate. heated to reflux temperature Within 31/2 hours there are added dropwise at reflux temperature for 4 hours The reaction mixture is washed 3 times with 200 ml of 5% NaH2PO4 solution each time the aqueous phases are back-extracted with 200 ml of CH2Cl2 The combined organic phases are dried over magnesium sulphate concentrated on a rotary evaporator The crude product distils at 76°-85° C./0.6 mbar