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With borane-THF In tetrahydrofuran at 80℃; Inert atmosphere;
4.4 Step 4: Intermediate 2-(5-fluorobenzo[b]thiophen-3-yl)ethan-1-amine (3d)
General procedure: A 500 mL dry three-necked flask was taken and compound 3e (7.2 g, 34.45 mmol) was added.Dissolved in 150 mL of anhydrous tetrahydrofuran and heated to 80 °C under nitrogen.1 M borane / tetrahydrofuran (86.1 ml, 86.1 mmol) was added dropwise with heating.And stirred under reflux overnight, then cooled to room temperature.The reaction was quenched by dropwise addition of 6N hydrochloric acid (60 mL) at 0 °C.It was then stirred at room temperature for 3 hours, and a large amount of tetrahydrofuran was evaporated under reduced pressure.Then basified with 2M sodium hydroxide solution,It was extracted with diethyl ether (300 mL×3).Dry over anhydrous sodium sulfate and concentrate in vacuo.The product 3d (5.83 g, 86.7%) was obtained.It was used in the next step without further purification.
Rk. mit Essigsaeureanhydrid;
3
[ 274918-15-9 ]
N-2-(5-chlorobenzo[b]thiophen-3-yl)ethylamine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride In diethyl ether
Preparation of2-(5-chloro-l-benzothien-3-yl)ethanamine; A stirred solution of tert-butyl [2-(5-chloro-l-benzothien-3-yl)ethyl]carbamate (7.8 g, 25.1 mmol) in dichloromethane (100 mL) was treated with trifluoroacetic acid (28.5 g, 250 mmol) and the reaction mixture was stirred at RT for 16 h. An aqueous solution of sodium hydroxide (200 mL, IN) was carefully added and the temperature was maintained below 20 °C. The reaction mixture was stirred for 30 min and the EPO organic layer was dried (MgSO4), filtered and concentrated in vacuo to afford 4.9 g of the desired amine (92%).IHNMR (250MHz , CDCl3): δ 7.82 - 7.70 (2H, m); 7.4 - 7.1 (2H, m); 3.16 - 2.90 (4H, m); 1.6 - 1.4 (NH2, b).The hydrochloride salt was obtained by addition of ethereal hydrochloric acid and filtration of the colorless precipitate.
With triethylamine In tetrahydrofuran for 2h; Heating / reflux;
Synthesis of N-[2-(5-chloro-l-benzothien-3-yl)ethyll-2-(trifluoromethyl) benzamide (Compound B-4); A mixture of 2-(5-chloro-l-benzothien-3-yl)ethanamine (90.0 mg, 42.5 mmol) and triethylamine (43.5 mg, 42.5 mmol) in THF (5 mL) was treated with2-trifluoromethylbenzoyl chloride (89.0 mg, 42.5 mmol) and the mixture was heated at reflux for 2 h. After cooling to RT, the mixture was concentrated in vacuo and the residue taken up in ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash chromatography using a 4: 1 mixture of Heptane: Ethyl acetate afforded 160 mg (94%) ofiV-[2-(5-chloro-l-benzothien-3-yl)ethyl]-2- (trifluoromethyl) benzamide (Compound B-4).Mass Spectrum : [M+ 1] =384. EPO
Stage #1: tert-butyl [2-(5-chloro-1-benzothien-3-yl)ethyl]carbamate With trifluoroacetic acid In dichloromethane at 20℃; for 16h;
Stage #2: With sodium hydroxide In water at 20℃; for 0.5h;
Preparation of2-(5-chloro-l-benzothien-3-yl)ethanamine; A stirred solution of tert-butyl [2-(5-chloro-l-benzothien-3-yl)ethyl]carbamate (7.8 g, 25.1 mmol) in dichloromethane (100 mL) was treated with trifluoroacetic acid (28.5 g, 250 mmol) and the reaction mixture was stirred at RT for 16 h. An aqueous solution of sodium hydroxide (200 mL, IN) was carefully added and the temperature was maintained below 20 °C. The reaction mixture was stirred for 30 min and the EPO organic layer was dried (MgSO4), filtered and concentrated in vacuo to afford 4.9 g of the desired amine (92%).IHNMR (250MHz , CDCl3): δ 7.82 - 7.70 (2H, m); 7.4 - 7.1 (2H, m); 3.16 - 2.90 (4H, m); 1.6 - 1.4 (NH2, b).The hydrochloride salt was obtained by addition of ethereal hydrochloric acid and filtration of the colorless precipitate.
With diborane In tetrahydrofuran for 12h; Inert atmosphere; Reflux;
4.1.1.44. Ethyl (2-(5-fluorobenzo[b]thiophen-3-yl)ethyl)carbamate (18b).
Compound 16b (7.2 g, 34.5 mmol) was dissolved in THF(150 mL) and heated to 80 °C under N2 protection. After 1M borane in THF (86.1 mL, 86.1 mmol) was added dropwise, the reaction mixture was stirred overnight under reflux, then cool down and quenched by dropwised addition of 6 N HCl (60 mL). The reaction was continuously stirred for 3 h at rt. The THF was evaporated from the mixture in vacuum, and then basified with 2 N NaOH and extracted with ether (300 mL 3). The combined ethereal layerswere washed with water (50 mL x 2), dried over anhydrous sodium sulfate and concentrated under vacuum to give product 17b (5.8 g, 86.7%) which was used directly for the next step without further purification. To a solution of 17b (6.7 g, 29.8 mmol) and Et3N(12.5 mL, 89.58 mmol) in DCM (200 mL) was added ethyl carbonochloridate (4.26 mL, 44.79 mmol) dropwise at 0 °C, and then thereaction was stirred at room temperature for 2 h. After quenched with cold water, washed with NH4Cl solution, brine, dried (Na2SO4),the organic solvent was removed under vacuum and the residue was purified by column chromatography eluting with 0-10% ofethyl acetate/hexanes to give ethyl (2-(5-fluorobenzo[b]thiophen-3-yl)ethyl)carbamate 18b (7.1 g, 88.9%) as a pale yellow oil.
ethyl (2-(5-chlorobenzo[b]thiophen-3-yl)ethyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.38 g
With triethylamine In dichloromethane at 0 - 20℃; for 2h;
4.1.1.44. Ethyl (2-(5-fluorobenzo[b]thiophen-3-yl)ethyl)carbamate (18b).
General procedure: Compound 16b (7.2 g, 34.5 mmol) was dissolved in THF(150 mL) and heated to 80 °C under N2 protection. After 1M borane in THF (86.1 mL, 86.1 mmol) was added dropwise, the reaction mixture was stirred overnight under reflux, then cool down and quenched by dropwised addition of 6 N HCl (60 mL). The reaction was continuously stirred for 3 h at rt. The THF was evaporated from the mixture in vacuum, and then basified with 2 N NaOH and extracted with ether (300 mL 3). The combined ethereal layerswere washed with water (50 mL x 2), dried over anhydrous sodium sulfate and concentrated under vacuum to give product 17b (5.8 g, 86.7%) which was used directly for the next step without further purification. To a solution of 17b (6.7 g, 29.8 mmol) and Et3N(12.5 mL, 89.58 mmol) in DCM (200 mL) was added ethyl carbonochloridate (4.26 mL, 44.79 mmol) dropwise at 0 °C, and then thereaction was stirred at room temperature for 2 h. After quenched with cold water, washed with NH4Cl solution, brine, dried (Na2SO4),the organic solvent was removed under vacuum and the residue was purified by column chromatography eluting with 0-10% ofethyl acetate/hexanes to give ethyl (2-(5-fluorobenzo[b]thiophen-3-yl)ethyl)carbamate 18b (7.1 g, 88.9%) as a pale yellow oil.
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