安赛蜜EP杂质A

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Polyphosphate ester (1.15 g, 3.89 mmol, 0.30 eq) was added to a sealed tube containing a solution of urea (1.17 g, 19.4 mmol), valeraldehyde (1.38 ml, 12.9 mmol) and acetoacetamide (1.31 g, 12.9 mmol) in THF (15 mL) under argon and heated at 75° C. for three hours. The reaction mixture was cooled to room temperature, polyphosphate ester (8.80 g, 29.8 mmol) was added and the reaction mixture was heated at 85° C. for four hours. The reaction mixture was cooled to room temperature and poured on ice. The aqueous solution was neutralized with 1N NaOH and extracted with chloroform (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated under vacuum to give the title compound (0.940 g, 97%): HRMS 192.1143 (M−H)−. The product was used in the next step without further purification. The reaction mixture was cooled to room temperature the reaction mixture was heated at 85° C. for four hours The reaction mixture was cooled to room temperature poured on ice extracted with chloroform (3×100 mL) The combined organic layers were dried (Na2SO4) filtered concentrated under vacuum

反应条件: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 3,5-bis(trifluoromethyl)benzaldehyde (2.42 g, 10.0 mmol), acetoacetamide (1.01 g, 10.0 mmol), urea (0.90 g, 15.0 mmol), copper chloride (0.1 g, 1.0 mmol), boron trifluoride etherate (0.09 mL), AcOH (0.04 mL), and THF (20 mL) was heated at 65° C. for 18 h and cooled to room temperature. The resulting precipitates were collected by vacuum filtration, washed with THF, and air dried to give the title compound as an off-white solid(1.33 g, 36%). cooled to room temperature The resulting precipitates were collected by vacuum filtration washed with THF, and air dried

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

实验步骤: Sodium acetate (30 g, 0.37 mol) is added to a stirred mixture of diethyl(ethoxymethylene)oxalacetate (87 g, 0.36 mol) and acetoacetamide (36 g, 0.36 mol) in absolute ethanol (300 mL). After stirring the reaction mixture for 30 minutes, the ethanol is distilled off under reduced pressure, the residue acidified to pH 2 with dilute aqueous hydrochloric acid and the resulting solid filtered off. Crystallization from an ethanol-water mixture affords diethyl 5-acetyl-1,6-dihydro-6-oxo-2,3-pyridinedicarboxylate as crystals mp 200°-209° C. the ethanol is distilled off under reduced pressure the resulting solid filtered off Crystallization from an ethanol-water mixture

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

实验步骤: N-[5-(4'-(1,1-dimethylethyl)phenyl)thien-2-yl]-amine, as prepared in Preparation 5, was dis tetrahydrofuran (50 mL). The solution was then treated with diketene (3.0 mL) at 50° C. for 90 minutes. Evaporation of the solvent and chromatography of the residue on silica gel (100 g, elute with ethyl acetate/hexane mixtures) yielded the acetoacetamide, a compound of formula (C). The acetoacetamide (1.14 g) was then dissolved in benzene (30 mL). The solution was treated with pyrrolidine (0.90 mL) and then refluxed for 2 hours with a Dean Stark trap. The reaction mixture was then cooled to room temperature and the product isolated by filtration to yield 1.130 g of N-5-(4'-(1,1-dimethylethyl)phenyl)thien-2-yl]-3-pyrrolidyl-2-butenamide, m.p. 205°-207° C. B. In a similar manner, but replacing N-[5-(4'-(1,1-dimethylethyl)phenyl)thien-2-yl]amine with other appropriately substituted amines, the following compounds are made: refluxed for 2 hours with a Dean Stark trap the product isolated by filtration

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

实验步骤: The prior art preparation of 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxamides (Ia) has been effected by two methods. The first method has included (1) converting acetoacetamide to alphachloroacetoacetamide, (2) reacting this with 2-mercaptoethanol in a mutual solvent in the presence of a base, (3) subjecting the resulting product to acidic conditions whereby it cyclizes with loss of water to form 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxamide (Ia) and (4) isolating said product from the reaction mixture. The second method of preparing same has used alkyl acetoacetate in place of acetoacetamide as a starting material. Thus, from the procedure analogous to the first method described above, the resulting 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboalkoxide (Ib) was converted to 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxamide (Ia).

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

实验步骤: The prior art preparation of 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxamides (Ia) has been effected by two methods. The first method has included (1) converting acetoacetamide to alphachloroacetoacetamide, (2) reacting this with 2-mercaptoethanol in a mutual solvent in the presence of a base, (3) subjecting the resulting product to acidic conditions whereby it cyclizes with loss of water to form 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxamide (Ia) and (4) isolating said product from the reaction mixture. The second method of preparing same has used alkyl acetoacetate in place of acetoacetamide as a starting material. Thus, from the procedure analogous to the first method described above, the resulting 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboalkoxide (Ib) was converted to 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxamide (Ia).

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

实验步骤: Sodium acetate (30 g, 0.37 mol) is added to a stirred mixture of diethyl(ethoxymethylene)oxalacetate (87 g, 0.36 mol) and acetoacetamide (36 g, 0.36 mol) in absolute ethanol (300 mL). After stirring the reaction mixture for 30 minutes, the ethanol is distilled off under reduced pressure, the residue acidified to pH 2 with dilute aqueous hydrochloric acid and the resulting solid filtered off. Crystallization from an ethanol-water mixture affords diethyl 5-acetyl-1,6-dihydro-6-oxo-2,3-pyridinedicarboxylate as crystals mp 200°-209° C. the ethanol is distilled off under reduced pressure the resulting solid filtered off Crystallization from an ethanol-water mixture

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

实验步骤: Sodium acetate (30 g, 0.37 mol) is added to a stirred mixture of diethyl(ethoxymethylene)oxalacetate (87 g, 0.36 mol) and acetoacetamide (36 g, 0.36 mol) in absolute ethanol (300 mL). After stirring the reaction mixture for 30 minutes, the ethanol is distilled off under reduced pressure, the residue acidified to pH 2 with dilute aqueous hydrochloric acid and the resulting solid filtered off. Crystallization from an ethanol-water mixture affords diethyl 5-acetyl-1,6-dihydro-6-oxo-2,3-pyridinedicarboxylate as crystals mp 200°-209° C. the ethanol is distilled off under reduced pressure the resulting solid filtered off Crystallization from an ethanol-water mixture

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

实验步骤: A solution of 4-ethoxy-1,1,1-trifluoro-3-buten-2-one (4.21 g, 22.5 mmol), ethanol (42 mL), acetoacetamide (2.28 g, 22.5 mmol), and sodium ethoxide (21 wt % in ethanol, 8.41 mL, 22.5 mmol) was heated to 75° C. After 12 hours, the mixture was cooled to room temperature over 30 minutes, stirred for 4 hours, then cooled to <5° C. After 10 minutes, the white slurry was filtered, washing with cold ethanol (5 mL). The white solid was dried in a vacuum oven at 60° C. to provide the title compound (4.39 g, 19.3 mmol, 86% yield). MS (DCI) m/z 206 (M+H)+. cooled to <5° C After 10 minutes the white slurry was filtered washing with cold ethanol (5 mL) The white solid was dried in a vacuum oven at 60° C.

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

实验步骤: To a 500 mL, 5-necked flask, equipped with a circulating jacket, a thermometer, a nitrogen blanket line atop a condenser, an addition funnel, a syringe pump, and a mechanical stirrer, were charged 101.1 g of acetoacetamide (1.00 mol), 100 mL of deionized water and 100 g of methanol. The mixture was stirred at ambient temperature until all solids were dissolved. A 45% aqueous potassium hydroxide solution (99.6 g, 0.80 mol) was then added to the above solution through the addition funnel over a period of 5 minutes. The resulting mixture was stirred for 30 minutes and then cooled to 15° C. Ethyl bromide (130.8 g, 1.20 mol) was added to the mixture through the syringe pump over a period of 30 minutes. The resulting mixture was stirred at 15° C. for 16 hours. All volatiles were then removed at 60° C./20 mmHg. The solid residue was dissolved in 300 mL of water and extracted with chloroform. A total of six chloroform extractions were performed (60 mL+5×200 mL). The first extraction contained a high level of 2,2-diethylacetoacetamide and was discarded. The remaining extraction solutions were combined. After chloroform was removed in vacuo, 67.7 g of 2-ethylacetoacetamide was obtained. Crude yield: 66% (based on KOH charge). To a 500 mL, 5-necked flask, equipped with a circulating jacket were dissolved The resulting mixture was stirred for 30 minutes cooled to 15° C The resulting mixture was stirred at 15° C. for 16 hours All volatiles were then removed at 60° C./20 mmHg The solid residue was dissolved in 300 mL of water extracted with chloroform A total of six chloroform extractions The first extraction The remaining extraction solutions After chloroform was removed in vacuo