泰地唑胺杂质68

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-Bromo-5-fluoro-aniline (5.00 g, 95 mass % article, 25.0 mmol), m-nitrobenzenesulfonic acid (2.65 g, 13.0 mmol), 20.0 mL of 85 wt % aqueous phosphoric acid solution and ferrous sulfate heptahydrate (65.5 mg, 0.250 mmol) were placed in a 100 mL three-neck flask equipped with a magnetic stirrer, a reflux condenser, a thermometer and a dropping funnel and the mixture was heated to 80° C. in an oil bath. Subsequently, trans-2-hexenal (6.51 g, 98 mass % article, 65.0 mmol) was added dropwise thereto through the dropping funnel for 1 hour. After completion of the dropwise addition, the mixture was heated and stirred at 100° C. for 2 hours. Then, the reaction mixture was poured into water and neutralized to pH 7 by ammonia water. The neutralized liquid was extracted with dichloromethane, and then dichloromethane was removed under reduced pressure. The resulting crude reaction product was purified by column chromatography (Hexane/AcOEt=100/0→1/10) using silica gel, followed by drying under reduced pressure to give 625 mg of 8-bromo-5-fluoro-2-propylquinoline as a yellowish white solid (yield: 9.33%). equipped with a magnetic stirrer, a reflux condenser After completion of the dropwise addition the mixture was heated The neutralized liquid was extracted with dichloromethane dichloromethane was removed under reduced pressure The resulting crude reaction product was purified by column chromatography (Hexane/AcOEt=100/0→1/10) by drying under reduced pressure

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-Bromo-5-fluoro-aniline (5.00 g, 95 mass % article, 25.0 mmol), m-nitrobenzenesulfonic acid (2.65 g, 13.0 mmol), 20.0 mL of 85 wt % aqueous phosphoric acid solution and ferrous sulfate heptahydrate (65.5 mg, 0.250 mmol) were placed in a 100 mL three-neck flask equipped with a magnetic stirrer, a reflux condenser, a thermometer and a dropping funnel and the mixture was heated to 80° C. in an oil bath. Subsequently, crotonaldehyde (4.64 g, 98 mass % article, 65.0 mmol) was added dropwise thereto through the dropping funnel for 1 hour. After completion of the dropwise addition, the mixture was heated and stirred at 100° C. for 2 hours. Then, the reaction mixture was poured into water and neutralized to pH 7 by ammonia water. The neutralized liquid was extracted with dichloromethane, and then dichloromethane was removed under reduced pressure. The resulting crude reaction product was purified by column chromatography (Hexane/AcOEt=100/0→1/1) using silica gel, followed by drying under reduced pressure to give 1.31 g of 8-bromo-5-fluoro-2-methyl-quinoline as a yellowish white solid (yield: 21.8%). equipped with a magnetic stirrer, a reflux condenser After completion of the dropwise addition the mixture was heated The neutralized liquid was extracted with dichloromethane dichloromethane was removed under reduced pressure The resulting crude reaction product was purified by column chromatography (Hexane/AcOEt=100/0→1/1) by drying under reduced pressure

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-Bromo-5-fluoro-aniline (2.50 g, 95 mass % article, 12.5 mmol), m-nitrobenzenesulfonic acid (1.33 g, 6.53 mmol), 10.0 mL of 85 wt % aqueous phosphoric acid solution and ferrous sulfate heptahydrate (34.8 mg, 0.125 mmol) were placed in a 100 mL three-neck flask equipped with a magnetic stirrer, a reflux condenser, a thermometer and a dropping funnel and the mixture was heated to 80° C. in an oil bath. Subsequently, 2.32 g of methacrolein (98 mass % article, 32.5 mmol) was added dropwise thereto through the dropping funnel for 1 hour. After completion of the dropwise addition, the mixture was heated and stirred at 100° C. for 2 hours. Then, the reaction mixture was poured into water and neutralized to pH 7 by ammonia water. The neutralized liquid was extracted with dichloromethane and then, dichloromethane was removed under reduced pressure. The resulting crude reaction product was purified by column chromatography (Hexane/AcOEt=100/0→1/1) using silica gel, followed by drying under reduced pressure to give 730 mg of 8-bromo-5-fluoro-3-methyl-quinoline as a yellow white solid (yield: 24.3%). equipped with a magnetic stirrer, a reflux condenser After completion of the dropwise addition the mixture was heated The neutralized liquid was extracted with dichloromethane dichloromethane was removed under reduced pressure The resulting crude reaction product was purified by column chromatography (Hexane/AcOEt=100/0→1/1) by drying under reduced pressure

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-Bromo-5-fluoro-aniline (5.00 g, 95 mass % article, 25.0 mmol), m-nitrobenzenesulfonic acid (2.65 g, 13.1 mmol), 20.0 mL of 85 wt % aqueous phosphoric acid solution and ferrous sulfate heptahydrate (69.5 mg, 0.250 mmol) were placed in a 100 mL three-neck flask equipped with a magnetic stirrer, a reflux condenser, a thermometer and a dropping funnel and the mixture was heated to 80° C. in an oil bath. Subsequently, 2-butylacrolein (7.44 g, 98 mass % article, 65.0 mmol) was added dropwise thereto through the dropping funnel for 1 hour. After completion of the dropwise addition, the mixture was heated and stirred at 100° C. for 2 hours. Then, the reaction mixture was poured into water and neutralized to pH 7 by ammonia water. The neutralized liquid was extracted with dichloromethane and then, dichloromethane was removed under reduced pressure. The resulting crude reaction product was purified by column chromatography (Hexane/AcOEt=100/0→1/1) using silica gel, followed by drying under reduced pressure to give 1.35 g of 8-bromo-3-butyl-5-fluoroquinoline as a brown solid (yield: 19.2%). equipped with a magnetic stirrer, a reflux condenser After completion of the dropwise addition the mixture was heated The neutralized liquid was extracted with dichloromethane dichloromethane was removed under reduced pressure The resulting crude reaction product was purified by column chromatography (Hexane/AcOEt=100/0→1/1) by drying under reduced pressure

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

实验步骤: To an ice-cold solution of 2-bromo-5-fluoroaniline (50.0 g, 263.14 mmol) in DCM (400 mL) was added triethyl amine (48.0 mL, 342.10 mmol). The resulting mixture was stirred at 0° C. for 10 min followed by addition of pivaloyl chloride (36.0 mL, 289.50 mmol) then stirred at rt for 3 h. After completion of reaction (by TLC), the reaction mixture was diluted with DCM and washed with saturated solution of NaHCO3. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified over 100-200 M silica-gel by using 1.0% EtOAc:hexane to obtain the product as an off white solid (66.0 g, 92% yield). then stirred at rt for 3 h After completion of reaction (by TLC) washed with saturated solution of NaHCO3 The organic layer was washed with brine dried over anhydrous Na2SO4 filtered evaporated under reduced pressure The crude residue was purified over 100-200 M silica-gel

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

实验步骤: To an ice-cold solution of 2-bromo-5-fluoroaniline (50.0 g, 263.14 mmol) in DCM (400 mL) was added triethyl amine (48.0 mL, 342.10 mmol). The resulting mixture was stirred at 0° C. for 10 min followed by addition of pivaloyl chloride (36.0 mL, 289.50 mmol) then stirred at rt for 3 h. After completion of reaction (by TLC), the reaction mixture was diluted with DCM and washed with saturated solution of NaHCO3. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified over 100-200 M silica-gel by using 1.0% EtOAc:hexane to obtain the product as an off white solid (66.0 g, 92% yield). then stirred at rt for 3 h After completion of reaction (by TLC) washed with saturated solution of NaHCO3 The organic layer was washed with brine dried over anhydrous Na2SO4 filtered evaporated under reduced pressure The crude residue was purified over 100-200 M silica-gel

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a mixture of 2-bromo-5-fluoroaniline (35.00 g, 184 mmol, Aldrich), palladium (II) acetate (2.06 g, 9.18 mmol, Strem) and tri(o-tolyl)phosphine (5.60 g, 18.40 mmol; Strem) in acetonitrile (350 ml) at RT was added methyl acrylate (33.00 ml, 365 mmol, Aldrich) and triethylamine (64.00 ml, 460 mmol, Aldrich). The reaction was heated at 80° C. for 24 h. The reaction mixture was diluted with EtOAc (500 mL) and the resulting colorless crystalline solid was filtered and washed with EtOAc. The organic solution was concentrated to dryness and the solids were slurried in 10% EtOAc/hexane at 60° C. for 1 h. The slurry was cooled to RT and filtered. The solid was washed with 10% EtOAc/hexane and sucked dry with air to give 18.30 g (51%) of a light-yellow crystalline solid. m/z=195.9 (M+1). the resulting colorless crystalline solid was filtered washed with EtOAc The organic solution was concentrated to dryness The slurry was cooled to RT filtered The solid was washed with 10% EtOAc/hexane sucked dry with air

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a mixture of 2-bromo-5-fluoroaniline (35.00 g, 184 mmol, Aldrich), palladium (II) acetate (2.06 g, 9.18 mmol, Strem) and tri(o-tolyl)phosphine (5.60 g, 18.40 mmol; Strem) in acetonitrile (350 ml) at RT was added methyl acrylate (33.00 ml, 365 mmol, Aldrich) and triethylamine (64.00 ml, 460 mmol, Aldrich). The reaction was heated at 80° C. for 24 h. The reaction mixture was diluted with EtOAc (500 mL) and the resulting colorless crystalline solid was filtered and washed with EtOAc. The organic solution was concentrated to dryness and the solids were slurried in 10% EtOAc/hexane at 60° C. for 1 h. The slurry was cooled to RT and filtered. The solid was washed with 10% EtOAc/hexane and sucked dry with air to give 18.30 g (51%) of a light-yellow crystalline solid. m/z=195.9 (M+1). the resulting colorless crystalline solid was filtered washed with EtOAc The organic solution was concentrated to dryness The slurry was cooled to RT filtered The solid was washed with 10% EtOAc/hexane sucked dry with air

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

实验步骤: A mixture of 2-bromo-5-fluoroaniline (5 g) in ethanol (17.5 ml) and 1.6M HCl (50 mL) at −5° C. was treated with 2.5M NaNO2 (10.5 ml). 4.5M potassium acetate (29.2 ml) was then added, followed by ethyl 2-oxocyclopentanecarboxylate (3.8 ml). The reaction mixture was stirred at 0° C. for 15 minutes, warmed to 20° C. over 1.5 hours, extracted with dichloromethane, concentrated and dried in vacuo. The residue was dissolved in 67 ml of (H2SO4/ethanol, 17:50), refluxed for 2 days, cooled to room temperature, quenched with water and extracted with dichloromethane. The combined extracts were washed with brine, dried (MgSO4), filtered and concentrated. The concentrate was purified by column chromatography on silica gel with 5-20% ethyl acetate in hexanes. The product was purified further by trituration with ethanol. warmed to 20° C. over 1.5 hours extracted with dichloromethane concentrated dried in vacuo The residue was dissolved in 67 ml of (H2SO4/ethanol, 17:50) refluxed for 2 days cooled to room temperature quenched with water extracted with dichloromethane The combined extracts were washed with brine dried (MgSO4) filtered concentrated The concentrate was purified by column chromatography on silica gel with 5-20% ethyl acetate in hexanes The product was purified further by trituration with ethanol

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

实验步骤: A mixture of 2-bromo-5-fluoroaniline (5 g) in ethanol (17.5 ml) and 1.6M HCl (50 mL) at −5° C. was treated with 2.5M NaNO2 (10.5 ml). 4.5M potassium acetate (29.2 ml) was then added, followed by ethyl 2-oxocyclopentanecarboxylate (3.8 ml). The reaction mixture was stirred at 0° C. for 15 minutes, warmed to 20° C. over 1.5 hours, extracted with dichloromethane, concentrated and dried in vacuo. The residue was dissolved in 67 ml of (H2SO4/ethanol, 17:50), refluxed for 2 days, cooled to room temperature, quenched with water and extracted with dichloromethane. The combined extracts were washed with brine, dried (MgSO4), filtered and concentrated. The concentrate was purified by column chromatography on silica gel with 5-20% ethyl acetate in hexanes. The product was purified further by trituration with ethanol. warmed to 20° C. over 1.5 hours extracted with dichloromethane concentrated dried in vacuo The residue was dissolved in 67 ml of (H2SO4/ethanol, 17:50) refluxed for 2 days cooled to room temperature quenched with water extracted with dichloromethane The combined extracts were washed with brine dried (MgSO4) filtered concentrated The concentrate was purified by column chromatography on silica gel with 5-20% ethyl acetate in hexanes The product was purified further by trituration with ethanol

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

实验步骤: Trimethylacetyl chloride (4.2 mL, 34.1 mL) was fast dropwise added to a solution of 2-bromo-5-fluorobenzenamine (4.31 g, 22.7 mmol) in CH2Cl2 (50 mL) at room temperature, followed by the addition of DIEA (7.9 mL, 45.4 mmol). The resulting mixture was stirred at room temperature for 2 hrs, and then partitioned between HCl (1N, 200 mL) and EtOAc(250 mL). After separation, the organic phase was washed with brine (50 mL), dried on MgSO4, concentrated on rotary vacuum, and purified on flash chromatography eluting with 20˜40% EtOAc/hexanes (1200 mL) to afford the expected product, as a colorless oil (6.07 g, 98% yield); 1H NMR (400 MHz, CDCl3) δ ppm 1.33 (s, 9 H), 6.69 (ddd, J=8.81, 7.55, 3.02 Hz, 1 H), 7.45 (dd, J=8.81, 5.79 Hz, 1 H), 8.04 (s, 1 H), 8.28 (dd, J=11.08, 3.02 Hz, 1 H); Mass spec. 274.04 (MH+), Calc. for C11H13BrFNO 273.02. partitioned between HCl (1N, 200 mL) and EtOAc(250 mL) After separation the organic phase was washed with brine (50 mL) dried on MgSO4 concentrated on rotary vacuum purified on flash chromatography eluting with 20˜40% EtOAc/hexanes (1200 mL)