3-乙酰氨基氮杂环丁烷

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

实验步骤: Starting materials: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and N-(azetidin-3-yl)acetamide

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

实验步骤: Starting materials: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and N-(azetidin-3-yl)acetamide

反应条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In 8 mL of N,N-dimethylformamide was dissolved 0.80 g of 5-[2-(3-chloropropoxy)ethyl]-1-benzothiophene, and 1.20 g of N-(3-azetidinyl)acetamide was added to the solution, after which the resulting mixture was stirred at 90° C. for 12 hours. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; chloroform:methanol=7:1) to obtain 0.39 g of N-(1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-azetidinyl)acetamide as a light-yellow oil. was added to the solution After the reaction mixture was cooled the organic layer was separated The organic layer was washed with water a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate distilled under reduced pressure to remove the solvent The residue was purified by a column chromatography (eluent; chloroform:methanol=7:1)

反应条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 0.80 g of 5-(2-(3-chloropropoxy)ethyl)-1-benzothiophene was dissolved in 8 ml of N,N-dimethylformamide. Thereafter, 1.20 g of N-(3-azetidinyl)acetamide was added to the obtained solution, and the obtained mixture was stirred at 90° C. for 12 hours. After cooling, water and ethyl acetate were added to the reaction mixture, and an organic layer was separated. The organic layer was successively washed with water and a saturated saline solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was distilled away under a reduced pressure. The residue was purified by column chromatography (eluent; chloroform:methanol=7:1), so as to obtain 0.39 g of a light yellow oil product, N-(1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-azetidinyl)acetamide. After cooling an organic layer was separated The organic layer was successively washed with water a saturated saline solution, and then dried over anhydrous magnesium sulfate Thereafter, the solvent was distilled away under a reduced pressure The residue was purified by column chromatography (eluent; chloroform:methanol=7:1)

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

实验步骤: To a suspension of N-azetidin-3-yl-acetamide (0.30 g crude, 1.99 mmol) and 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (0.43 g, 1.00 mmol) in anhydrous DMF (10 mL) was added triethylamine (3 mL). The reaction mixture was stirred at room temperature for 3 days under nitrogen. Solvent was evaporated under reduced pressure, water (50 mL) was added, and the precipitated solid was filtered. The aqueous phase was extracted with ethyl acetate (2×100 mL). The organic phase was dried over anhydrous Na2SO4. Solvent was evaporated, and crude compound was purified by the Simpliflash system (0-5% 7 N ammonia in methanol and CH2Cl2 as eluent) to give the title compound as a white solid. Yield: 0.30 g (63%). MP 111.8-113.6° C. 1H NMR (400 MHz, CDCl3): δ 9.60 (br s, 1H), 7.69 (s, 2H), 6.82 (d, J=2.34 Hz, 1H), 6.46 (d, J=2.34 Hz, 1H), 6.10 (d, J=7.81 Hz, 1H), 4.71-4.44 (m, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 3.85-3.67 (m, 4H), 3.26-3.13 (m, 2H), 2.90 (t, J=5.46 Hz, 2H), 2.36 (s, 6H), 2.01 (s, 3H). MS (ES+) m/z: 467.20 (M+1). Solvent was evaporated under reduced pressure, water (50 mL) was added the precipitated solid was filtered The aqueous phase was extracted with ethyl acetate (2×100 mL) The organic phase was dried over anhydrous Na2SO4 Solvent was evaporated crude compound was purified by the Simpliflash system (0-5% 7 N ammonia in methanol and CH2Cl2 as eluent)

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

实验步骤: To a suspension of N-azetidin-3-yl-acetamide (17) (1.99 mmol) and 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (18) (1.00 mmol) in anhydrous DMF (10 mL) was added triethylamine (3 mL). The reaction mixture was stirred at room temperature for 3 days under nitrogen. The solvent was evaporated under reduced pressure, water (50 mL) was added, and the precipitated solid was filtered off. The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated. The crude compound was purified by the Simpliflash system (0-5% 7 N ammonia in methanol and CH2Cl2 as eluent) to give the title compound 19 as a white solid. The solvent was evaporated under reduced pressure, water (50 mL) was added the precipitated solid was filtered off The aqueous layer was extracted with ethyl acetate (2×100 mL) The organic phase was dried over anhydrous Na2SO4 concentrated The crude compound was purified by the Simpliflash system (0-5% 7 N ammonia in methanol and CH2Cl2 as eluent)

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

实验步骤: To a suspension of N-azetidin-3-yl-acetamide (17) (1.99 mmol) and 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (18) (1.00 mmol) in anhydrous DMF (10 mL) was added triethylamine (3 mL). The reaction mixture was stirred at room temperature for 3 days under nitrogen. The solvent was evaporated under reduced pressure, water (50 mL) was added, and the precipitated solid was filtered off. The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated. The crude compound was purified by the Simpliflash system (0-5% 7 N ammonia in methanol and CH2Cl2 as eluent) to give the title compound 19 as a white solid. The solvent was evaporated under reduced pressure, water (50 mL) was added the precipitated solid was filtered off The aqueous layer was extracted with ethyl acetate (2×100 mL) The organic phase was dried over anhydrous Na2SO4 concentrated The crude compound was purified by the Simpliflash system (0-5% 7 N ammonia in methanol and CH2Cl2 as eluent)

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

实验步骤: Starting materials: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and N-(azetidin-3-yl)acetamide

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

实验步骤: Starting materials: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and N-(azetidin-3-yl)acetamide

反应条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 0.80 g of 5-(2-(3-chloropropoxy)ethyl)-1-benzothiophene was dissolved in 8 ml of N,N-dimethylformamide. Thereafter, 1.20 g of N-(3-azetidinyl)acetamide was added to the obtained solution, and the obtained mixture was stirred at 90° C. for 12 hours. After cooling, water and ethyl acetate were added to the reaction mixture, and an organic layer was separated. The organic layer was successively washed with water and a saturated saline solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was distilled away under a reduced pressure. The residue was purified by column chromatography (eluent; chloroform:methanol=7:1), so as to obtain 0.39 g of a light yellow oil product, N-(1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-azetidinyl)acetamide. After cooling an organic layer was separated The organic layer was successively washed with water a saturated saline solution, and then dried over anhydrous magnesium sulfate Thereafter, the solvent was distilled away under a reduced pressure The residue was purified by column chromatography (eluent; chloroform:methanol=7:1)

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

实验步骤: Starting materials: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and N-(azetidin-3-yl)acetamide

反应条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In 8 mL of N,N-dimethylformamide was dissolved 0.80 g of 5-[2-(3-chloropropoxy)ethyl]-1-benzothiophene, and 1.20 g of N-(3-azetidinyl)acetamide was added to the solution, after which the resulting mixture was stirred at 90° C. for 12 hours. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; chloroform:methanol=7:1) to obtain 0.39 g of N-(1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-azetidinyl)acetamide as a light-yellow oil. was added to the solution After the reaction mixture was cooled the organic layer was separated The organic layer was washed with water a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate distilled under reduced pressure to remove the solvent The residue was purified by a column chromatography (eluent; chloroform:methanol=7:1)