达格列净杂质10

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:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred solution of 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (intermediate B) (747 g, 2.31 mol) in dichloromethane was added slowly boron tribromide (1.15 kg, 4.62 mol) at −78° C. The reaction mixture was allowed to warm to room temperature. When the reaction was complete as measured by TLC, the reaction was quenched with water. The mixture was extracted with dichloromethane. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, then with water, and then with brine, and dried over Na2SO4. The residue was concentrated and then recrystallized in petroleum ether to obtain intermediate H as a white solid (460 g, yield 68%). 1H NMR (CDCl3, 400 MHz): δ 7.23˜7.29 (m, 3H), 7.08 (d, J=8.8 Hz, 2H), 6.79 (d, J=8.8 Hz, 2H), 5.01 (s, 1H), 4.00 (s, 2H). the reaction was quenched with water The mixture was extracted with dichloromethane The organic layer was washed with an aqueous solution of saturated sodium bicarbonate with water, and then with brine, and dried over Na2SO4 The residue was concentrated recrystallized in petroleum ether

反应条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred solution of Et3SiH (400 mL, 2.51 mol and 5-bromo-2-chloro-4′-ethoxybenzophenone (390 g, 1.15 mol) in 900 mL of a 1:2 mixture 1,2-dichloroethane/MeCN at 10° C. was added BF3.Et2O (150 mL, 1.58 mol) at such a rate that the temperature did not exceed 20°. Caution a moderate exotherm insues during the addition. After stirring overnight at 20° C., HPLC revealed the reaction to be 90% complete. After adding an additional 40 mL Et3SiH and 15 mL of BF3.Et2O, the reaction was heated to 50° for 3 hr. (Note elevated temperatures increase formation of the Ritter reaction product N-acetyl 5-bromo-2-chloro-4′-ethoxydiphenylmethylamine). Upon cooling, the reaction was quenched with 120 g of KOH in 300 mL of H2O. After stirring 2 hr, the layers were separated. The aqueous layer was extracted 2× with CH2Cl2; the combined organic layers were washed 1× with 300 mL portions of 2M KOH, 2× with H2O containing 10% brine to aid phase separation and with brine 2× prior to drying over Na2SO4. After removal of the volatiles, the residue was recrystallized from absolute EtOH to yield 230 g of 5-bromo-2-chloro-4′-ethoxydiphenylmethane as a white solid. did not exceed 20° Caution a moderate exotherm insues during the addition the reaction the reaction was heated to 50° for 3 hr increase Upon cooling the reaction was quenched with 120 g of KOH in 300 mL of H2O After stirring 2 hr the layers were separated The aqueous layer was extracted 2× with CH2Cl2 the combined organic layers were washed 1× with 300 mL portions of 2M KOH, 2× with H2O containing 10% brine phase separation with brine 2× prior to drying over Na2SO4 After removal of the volatiles the residue was recrystallized from absolute EtOH

反应条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred solution of Et3SiH (400 mL, 2.51 mol and 5-bromo-2-chloro-4′-ethoxybenzophenone (390 g, 1.15 mol) in 900 mL of a 1:2 mixture 1,2-dichloroethane/MeCN at 10° C. was added BF3.Et2O (150 mL, 1.58 mol) at such a rate that the temperature did not exceed 20°. Caution a moderate exotherm insues during the addition. After stirring overnight at 20° C., HPLC revealed the reaction to be 90% complete. After adding an additional 40 mL Et3SiH and 15 mL of BF3.Et2O, the reaction was heated to 50° for 3 hr. (Note elevated temperatures increase formation of the Ritter reaction product N-acetyl 5-bromo-2-chloro-4′-ethoxydiphenylmethylamine). Upon cooling, the reaction was quenched with 120 g of KOH in 300 mL of H2O. After stirring 2 hr, the layers were separated. The aqueous layer was extracted 2× with CH2Cl2; the combined organic layers were washed 1× with 300 mL portions of 2M KOH, 2× with H2O containing 10% brine to aid phase separation and with brine 2× prior to drying over Na2SO4. After removal of the volatiles, the residue was recrystallized from absolute EtOH to yield 230 g of 5-bromo-2-chloro-4′-ethoxydiphenylmethane as a white solid. did not exceed 20° Caution a moderate exotherm insues during the addition the reaction the reaction was heated to 50° for 3 hr increase Upon cooling the reaction was quenched with 120 g of KOH in 300 mL of H2O After stirring 2 hr the layers were separated The aqueous layer was extracted 2× with CH2Cl2 the combined organic layers were washed 1× with 300 mL portions of 2M KOH, 2× with H2O containing 10% brine phase separation with brine 2× prior to drying over Na2SO4 After removal of the volatiles the residue was recrystallized from absolute EtOH

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

实验步骤: To a solution of 4-bromo-1-chloro-2-[(4-ethoxyphenyl)methyl]benzene 17a (5.0 g, 15.35 mmol, purchased from Shanghai Caerulum Pharma Discovery Co., Ltd.) in dichloromethane (50 mL) was added a solution of boron tribromide (1.7 mL, 16.89 mmol) in dichloromethane (10 mL) dropwise. The mixture was stirred at room temperature for 30 min. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate till pH becomes 7 and extracted with dichloromethane (50 mL×2). The combined organic layers were washed with saturated aqueous sodium chloride (30 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 17b as a pale yellow solid (5.16 g, 100%). This material was not further purified. extracted with dichloromethane (50 mL×2) The combined organic layers were washed with saturated aqueous sodium chloride (30 mL×2) dried over anhydrous sodium sulfate filtered The filtrate was concentrated in vacuo

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 4-bromo-1-chloro-2-(4-ethoxyphenyl)methyl-benzene (30 g, 92.1 mmol, bought from Shanghai Kinsey pharmaceutical company) in anhydrous tetrahydrofuran (250 mL) was added n-butyllithium (40.3 mL, 96.7 mmol, 2.4 M in n-hexane) dropwise at −78° C. The mixture was stirred at −78° C. for 40 min and a solution of (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-(trimethylsilyloxymethyl) tetrahydropyran-2-one 1b (47.3 g, 101.3 mmol) in anhydrous tetrahydrofuran (50 mL) was added dropwise. After the addition, the mixture was further stirred at −78° C. for 5 hours and then quenched with 100 mL of saturated aqueous ammonium chloride. The mixture was allowed to warm up to room temperature and concentrated in vacuo. To the residue was added 150 mL of water. The resulting mixture was extracted with ethyl acetate (150 mL×3). The combined organic layers were washed with saturated aqueous sodium chloride (200 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound 1c as pale yellow oil (69.7 g, 100%). This crude product was used in next step without further purification. After the addition the mixture was further stirred at −78° C. for 5 hours quenched with 100 mL of saturated aqueous ammonium chloride to warm up to room temperature concentrated in vacuo To the residue was added 150 mL of water The resulting mixture was extracted with ethyl acetate (150 mL×3) The combined organic layers were washed with saturated aqueous sodium chloride (200 mL) dried over anhydrous sodium sulfate concentrated in vacuo

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 4-bromo-1-chloro-2-(4-ethoxyphenyl)methyl-benzene (30 g, 92.1 mmol, bought from Shanghai Kinsey pharmaceutical company) in anhydrous tetrahydrofuran (250 mL) was added n-butyllithium (40.3 mL, 96.7 mmol, 2.4 M in n-hexane) dropwise at −78° C. The mixture was stirred at −78° C. for 40 min and a solution of (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-(trimethylsilyloxymethyl) tetrahydropyran-2-one 1b (47.3 g, 101.3 mmol) in anhydrous tetrahydrofuran (50 mL) was added dropwise. After the addition, the mixture was further stirred at −78° C. for 5 hours and then quenched with 100 mL of saturated aqueous ammonium chloride. The mixture was allowed to warm up to room temperature and concentrated in vacuo. To the residue was added 150 mL of water. The resulting mixture was extracted with ethyl acetate (150 mL×3). The combined organic layers were washed with saturated aqueous sodium chloride (200 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound 1c as pale yellow oil (69.7 g, 100%). This crude product was used in next step without further purification. After the addition the mixture was further stirred at −78° C. for 5 hours quenched with 100 mL of saturated aqueous ammonium chloride to warm up to room temperature concentrated in vacuo To the residue was added 150 mL of water The resulting mixture was extracted with ethyl acetate (150 mL×3) The combined organic layers were washed with saturated aqueous sodium chloride (200 mL) dried over anhydrous sodium sulfate concentrated in vacuo

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 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (747 g, 2.31 mol) in dichloromethane was added boron tribromide (1.15 kg, 4.62 mol) slowly at −78° C. The reaction mixture was allowed to rise to room temperature. When the reaction was complete as measure by TLC, the reaction was quenched with water. The mixture was extracted with dichloromethane. The organic layer was washed with aqueous solution of saturated sodium bicarbonate, water, brine, dried over Na2SO4, and concentrated. The residue was recrystallized in petroleum ether to give the title compound as a white solid (460 g, yield 68%). 1H NMR (CDCl3, 400 MHz): δ 7.23˜7.29 (m, 3H), 7.08 (d, J=8.8 Hz, 2H), 6.79 (d, J=8.8 Hz, 2H), 5.01 (s, 1H), 4.00 (s, 2H). to rise to room temperature the reaction was quenched with water The mixture was extracted with dichloromethane The organic layer was washed with aqueous solution of saturated sodium bicarbonate, water, brine dried over Na2SO4 concentrated The residue was recrystallized in petroleum ether

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 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (747 g, 2.31 mol) in dichloromethane was added boron tribromide (1.15 kg, 4.62 mol) slowly at −78° C. The reaction mixture was allowed to rise to room temperature. When the reaction was complete as measure by TLC, the reaction was quenched with water. The mixture was extracted with dichloromethane. The organic layer was washed with aqueous solution of saturated sodium bicarbonate, water, brine, dried over Na2SO4, and concentrated. The residue was recrystallized in petroleum ether to give the title compound as a white solid (460 g, yield 68%). 1H NMR (CDCl3, 400 MHz): δ 7.23˜7.29 (m, 3H), 7.08 (d, J=8.8 Hz, 2H), 6.79 (d, J=8.8 Hz, 2H), 5.01 (s, 1H), 4.00 (s, 2H). to rise to room temperature the reaction was quenched with water The mixture was extracted with dichloromethane The organic layer was washed with aqueous solution of saturated sodium bicarbonate, water, brine dried over Na2SO4 concentrated The residue was recrystallized in petroleum ether

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: At −78° C., to a stirred solution of 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (8.47 g, 0.026 mol) (according to the synthesis procedure in the reference: Journal of Medicinal Chemistry, 2008, 51, 1145-1149) in dichloromethane (250 mL) was added slowly a solution of tribromoborane in dichloromethane (8 mL, 4 M) in drops, the mixture was stirred at −78° C. for further 30 minutes and then 1 hour at room temperature. Saturated aqueous sodium bicarbonate (200 mL) was added dropwise, the mixture was extracted for 3 times with ethyl acetate. The organic phases were combined and washed with saturated brine for one time, dried over anhydrous sodium sulfate. The solvent was evaporated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10:1) to afford the target compound. 1 hour at room temperature the mixture was extracted for 3 times with ethyl acetate washed with saturated brine for one time dried over anhydrous sodium sulfate The solvent was evaporated under vacuum The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10:1) to afford the target compound

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: At −78° C., to a stirred solution of 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (8.47 g, 0.026 mol) (according to the synthesis procedure in the reference: Journal of Medicinal Chemistry, 2008, 51, 1145-1149) in dichloromethane (250 mL) was added slowly a solution of tribromoborane in dichloromethane (8 mL, 4 M) in drops, the mixture was stirred at −78° C. for further 30 minutes and then 1 hour at room temperature. Saturated aqueous sodium bicarbonate (200 mL) was added dropwise, the mixture was extracted for 3 times with ethyl acetate. The organic phases were combined and washed with saturated brine for one time, dried over anhydrous sodium sulfate. The solvent was evaporated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10:1) to afford the target compound. 1 hour at room temperature the mixture was extracted for 3 times with ethyl acetate washed with saturated brine for one time dried over anhydrous sodium sulfate The solvent was evaporated under vacuum The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10:1) to afford the target compound