乙基 3-氯-2-甲基-3-氧代丙酸乙酯

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

实验步骤: Methyl acetoacetate sodium salt (1.24 g; 9 mmole) prepared from methyl acetoacetate and sodium methoxide was suspended in dry toluene (10 ml), and a solution of ethyl 2-chloroformylpropanoate (1.12 g; 6.8 mmole) in dry toluene (5 ml) was dropwise added thereto at room temperature. The resultant mixture was stirred at the same temperature for 1 hour, and insoluble materials were removed by filtration. The filtrate was concentrated at 40° C. under reduced pressure, and the residue was purified by silica gel column chromatography to give ethyl 3,5-dioxo-4-methoxycarbonyl-2-methylhexanoate. at room temperature insoluble materials were removed by filtration The filtrate was concentrated at 40° C. under reduced pressure the residue was purified by silica gel column chromatography

反应条件: temp:56.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Under nitrogen atmosphere, a solution of KOtBu (11.5 g) in THF (203 mL) was cooled to 0° C., and thereto were added dropwise ethyl chloroacetate (12.5 g) and ethyl formate (7.60 g) in THF (40 mL). After the addition, the mixture was stirred at 0° C. for 3 hours, and further stirred at room temperature for 16 hours. Water and a 6N aqueous hydrochloric acid solution were added to the mixture, and the mixture was extracted with Et2O, and dried over MgSO4. The solvent was evaporated under reduced pressure to give ethyl 2-chloroformyl-propionate. Under nitrogen atmosphere, to a solution of ethyl 2-chloroformylpropionate in acetone (250 mL) was added thioacetamide (7.74 g), and the mixture was stirred at 56° C. for 6 hours, and stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (hexane/ethyl acetate=12.5/1→10/1) to give ethyl 2-methyl-1,3-thiazole-5-carboxylate (5.74 g, 32%). stirred at room temperature for 16 hours The solvent was evaporated under reduced pressure the residue was purified by silica gel column (hexane/ethyl acetate=12.5/1→10/1)

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Under nitrogen atmosphere, a solution of KOtBu (11.5 g) in THF (203 mL) was cooled to 0° C., and thereto were added dropwise ethyl chloroacetate (12.5 g) and ethyl formate (7.60 g) in THF (40 mL). After the addition, the mixture was stirred at 0° C. for 3 hours, and further stirred at room temperature for 16 hours. Water and a 6N aqueous hydrochloric acid solution were added to the mixture, and the mixture was extracted with Et2O, and dried over MgSO4. The solvent was evaporated under reduced pressure to give ethyl 2-chloroformyl-propionate. Under nitrogen atmosphere, to a solution of ethyl 2-chloroformylpropionate in acetone (250 mL) was added thioacetamide (7.74 g), and the mixture was stirred at 56° C. for 6 hours, and stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (hexane/ethyl acetate=12.5/1→10/1) to give ethyl 2-methyl-1,3-thiazole-5-carboxylate (5.74 g, 32%). After the addition further stirred at room temperature for 16 hours the mixture was extracted with Et2O dried over MgSO4 The solvent was evaporated under reduced pressure

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

实验步骤: To a stirred solution of [(R)-1-(N-Benzyl-carbamimidoyl)-2-methyl-propyl]-carbamic acid t-butyl ester (16.37 g, 53.6 mMol) in CH2Cl2 (150 mL) with cooling at 0° C. was added Et3N (9 mL, 64.3 mMol) followed by 2-chlorocarbonyl-propionic acid ethyl ester (10 g, 60.8 mMol) dropwise over 15 minutes. The reaction was allowed to warm to RT and stirred for 4 h, poured into a separatory funnel, washed with water, brine, dried (Na2SO4), and evaporated to dryness under vacuum. The unpurified acylamidine (˜90% pure by LCMS, MS (ES) m/e (M+H)+434.4) was taken up in DMF (150 mL) and heated to 100° C. with stirring for 18 h. The reaction was concentrated under vacuum and purified by flash chromatography (90:10:1, CH2Cl2:EtOAc:HOAc) then (30:70:1, EtOAc:hexane:HOAc) to give the title compound (8.42 g, 41%) as an off-white solid: MS (ES) m/e 388.2 (M+H)+. poured into a separatory funnel washed with water, brine dried (Na2SO4) evaporated to dryness under vacuum heated to 100° C. with stirring for 18 h The reaction was concentrated under vacuum purified by flash chromatography (90:10:1, CH2Cl2:EtOAc:HOAc)

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

实验步骤: To a stirred solution of [(R)-1-(N-Benzyl-carbamimidoyl)-2-methyl-propyl]-carbamic acid t-butyl ester (16.37 g, 53.6 mMol) in CH2Cl2 (150 mL) with cooling, at 0° C. was added Et3N (9 mL, 64.3 mMol) followed by 2-chlorocarbonyl-propionic acid ethyl ester (10 g, 60.8 mMol) dropwise over 15 minutes. The reaction was allowed to warm to RT and stirred for 4 h, poured into a separatory funnel, washed with water, brine, dried (Na2SO4), and evaporated to dryness under vacuum. The unpurified acylamidine (˜90% pure by LCMS, MS (ES) m/e (M+H)+ 434.4) was taken up in DMF (150 mL) and heated to 100° C. with stirring for 18 h. The reaction was concentrated under vacuum and purified by flash chromatography (90:10:1, CH2Cl2:EtOAc:HOAc) then (30:70:1, EtOAc:hexane:HOAc) to give the title compound (8.42 g, 41%) as an off-white solid: MS (ES) m/e 388.2 (M+H)+. poured into a separatory funnel washed with water, brine dried (Na2SO4) evaporated to dryness under vacuum heated to 100° C. with stirring for 18 h The reaction was concentrated under vacuum purified by flash chromatography (90:10:1, CH2Cl2:EtOAc:HOAc)

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

实验步骤: Methyl acetoacetate sodium salt (1.24 g; 9 mmole) prepared from methyl acetoacetate and sodium methoxide was suspended in dry toluene (10 ml), and a solution of ethyl 2-chloroformylpropanoate (1.12 g; 6.8 mmole) in dry toluene (5 ml) was dropwise added thereto at room temperature. The resultant mixture was stirred at the same temperature for 1 hour, and insoluble materials were removed by filtration. The filtrate was concentrated at 40° C. under reduced pressure, and the residue was purified by silica gel column chromatography to give ethyl 3,5-dioxo-4-methoxycarbonyl-2-methylhexanoate. at room temperature insoluble materials were removed by filtration The filtrate was concentrated at 40° C. under reduced pressure the residue was purified by silica gel column chromatography