叔丁基(环丙基甲基)氨基甲酸酯

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 NaH (11.96 g, 299 mmol) in 260 mL DMF at 0° C. was sequentially added 2-(chloromethyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one (20 g, 100 mmol) and tert-butyl cyclopropylmethylcarbamate (17.07 g, 100 mmol) in small portions in order to maintain the internal temperature at or below 5° C. The reaction mixture was allowed to warm to room temperature slowly with continued stirring over 12 h. The reaction was cooled to 0 C and water was added slowly (˜250 mL total). The reaction mixture was concentrated in vacuo, taken up in ethyl acetate, filtered and concentrated to a red oil. The material was purified on a pad of silica gel, loading with 20% ethyl acetate in heptanes and eluting with 100% ethyl acetate via a sharp gradient. The title compound was obtained as an off-white solid (20.79 g). at 0° C. to maintain the internal temperature at or below 5° C was added slowly (˜250 mL total) The reaction mixture was concentrated in vacuo filtered concentrated to a red oil The material was purified on a pad of silica gel, loading with 20% ethyl acetate in heptanes eluting with 100% ethyl acetate via a sharp gradient

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 NaH (11.96 g, 299 mmol) in 260 mL DMF at 0° C. was sequentially added 2-(chloromethyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one (20 g, 100 mmol) and tert-butyl cyclopropylmethylcarbamate (17.07 g, 100 mmol) in small portions in order to maintain the internal temperature at or below 5° C. The reaction mixture was allowed to warm to room temperature slowly with continued stirring over 12 h. The reaction was cooled to 0 C and water was added slowly (˜250 mL total). The reaction mixture was concentrated in vacuo, taken up in ethyl acetate, filtered and concentrated to a red oil. The material was purified on a pad of silica gel, loading with 20% ethyl acetate in heptanes and eluting with 100% ethyl acetate via a sharp gradient. The title compound was obtained as an off-white solid (20.79 g). at 0° C. to maintain the internal temperature at or below 5° C was added slowly (˜250 mL total) The reaction mixture was concentrated in vacuo filtered concentrated to a red oil The material was purified on a pad of silica gel, loading with 20% ethyl acetate in heptanes eluting with 100% ethyl acetate via a sharp gradient

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

实验步骤: Tert-butyl cyclopropylmethylcarbamate (11.2 g, 65.4 mmol) was dissolved into THF (60 mL) and set to stir at −78° C. BuLi (2.5M, 28.8 mL) was then added portionwise over 10 minutes. The reaction was allowed to stir while warming to −20° C. for 10 minutes, and continued stirring at that temperature for another 10 minutes. The reaction was then recooled to −78° C. at which point chloro(methoxy)methane (5.79 g, 72.0 mmol) was added via syringe. The reaction was then allowed to stir overnight with warming. The reaction was then quenched with 1 N HCl and the organic layer separated. The aqueous layer was then extracted with DCM (2×), and the combined organic portions were dried with MgSO4, filtered and concentrated. The crude material was purified by passing through a silica plug eluting 10:1 Hex/EtOAc to give tert-butyl cyclopropylmethyl(methoxymethyl)carbamate (12.8 g, 91%) as a clear liquid. to stir while warming to −20° C. for 10 minutes continued stirring at that temperature for another 10 minutes was added via syringe to stir overnight with warming The reaction was then quenched with 1 N HCl the organic layer separated The aqueous layer was then extracted with DCM (2×) the combined organic portions were dried with MgSO4 filtered concentrated The crude material was purified eluting 10:1 Hex/EtOAc

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

实验步骤: Tert-butyl cyclopropylmethylcarbamate (11.2 g, 65.4 mmol) was dissolved into THF (60 mL) and set to stir at −78° C. BuLi (2.5M, 28.8 mL) was then added portionwise over 10 minutes. The reaction was allowed to stir while warming to −20° C. for 10 minutes, and continued stirring at that temperature for another 10 minutes. The reaction was then recooled to −78° C. at which point chloro(methoxy)methane (5.79 g, 72.0 mmol) was added via syringe. The reaction was then allowed to stir overnight with warming. The reaction was then quenched with 1 N HCl and the organic layer separated. The aqueous layer was then extracted with DCM (2×), and the combined organic portions were dried with MgSO4, filtered and concentrated. The crude material was purified by passing through a silica plug eluting 10:1 Hex/EtOAc to give tert-butyl cyclopropylmethyl(methoxymethyl)carbamate (12.8 g, 91%) as a clear liquid. to stir while warming to −20° C. for 10 minutes continued stirring at that temperature for another 10 minutes was added via syringe to stir overnight with warming The reaction was then quenched with 1 N HCl the organic layer separated The aqueous layer was then extracted with DCM (2×) the combined organic portions were dried with MgSO4 filtered concentrated The crude material was purified eluting 10:1 Hex/EtOAc

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 NaH (11.96 g, 299 mmol) in 260 mL DMF at 0° C. was sequentially added 2-(chloromethyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one (20 g, 100 mmol) and tert-butyl cyclopropylmethylcarbamate (17.07 g, 100 mmol) in small portions in order to maintain the internal temperature at or below 5° C. The reaction mixture was allowed to warm to room temperature slowly with continued stirring over 12 h. The reaction was cooled to 0 C and water was added slowly (˜250 mL total). The reaction mixture was concentrated in vacuo, taken up in ethyl acetate, filtered and concentrated to a red oil. The material was purified on a pad of silica gel, loading with 20% ethyl acetate in heptanes and eluting with 100% ethyl acetate via a sharp gradient. The title compound was obtained as an off-white solid (20.79 g). at 0° C. to maintain the internal temperature at or below 5° C was added slowly (˜250 mL total) The reaction mixture was concentrated in vacuo filtered concentrated to a red oil The material was purified on a pad of silica gel, loading with 20% ethyl acetate in heptanes eluting with 100% ethyl acetate via a sharp gradient

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

实验步骤: Tert-butyl cyclopropylmethylcarbamate (11.2 g, 65.4 mmol) was dissolved into THF (60 mL) and set to stir at −78° C. BuLi (2.5M, 28.8 mL) was then added portionwise over 10 minutes. The reaction was allowed to stir while warming to −20° C. for 10 minutes, and continued stirring at that temperature for another 10 minutes. The reaction was then recooled to −78° C. at which point chloro(methoxy)methane (5.79 g, 72.0 mmol) was added via syringe. The reaction was then allowed to stir overnight with warming. The reaction was then quenched with 1 N HCl and the organic layer separated. The aqueous layer was then extracted with DCM (2×), and the combined organic portions were dried with MgSO4, filtered and concentrated. The crude material was purified by passing through a silica plug eluting 10:1 Hex/EtOAc to give tert-butyl cyclopropylmethyl(methoxymethyl)carbamate (12.8 g, 91%) as a clear liquid. to stir while warming to −20° C. for 10 minutes continued stirring at that temperature for another 10 minutes was added via syringe to stir overnight with warming The reaction was then quenched with 1 N HCl the organic layer separated The aqueous layer was then extracted with DCM (2×) the combined organic portions were dried with MgSO4 filtered concentrated The crude material was purified eluting 10:1 Hex/EtOAc

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

实验步骤: Tert-butyl cyclopropylmethylcarbamate (11.2 g, 65.4 mmol) was dissolved into THF (60 mL) and set to stir at −78° C. BuLi (2.5M, 28.8 mL) was then added portionwise over 10 minutes. The reaction was allowed to stir while warming to −20° C. for 10 minutes, and continued stirring at that temperature for another 10 minutes. The reaction was then recooled to −78° C. at which point chloro(methoxy)methane (5.79 g, 72.0 mmol) was added via syringe. The reaction was then allowed to stir overnight with warming. The reaction was then quenched with 1N HCl and the organic layer separated. The aquoues layer was then extracted with DCM (2×), and the combined organic portions were dried with MgSO4, filtered and concentrated. The crude material was purified by passing through a silica plug eluting 10:1 Hex/EtOAc to give tert-butyl cyclopropylmethyl(methoxymethyl)carbamate (12.8 g, 91%) as a clear liquid. to stir while warming to −20° C. for 10 minutes continued stirring at that temperature for another 10 minutes was added via syringe to stir overnight with warming The reaction was then quenched with 1N HCl the organic layer separated The aquoues layer was then extracted with DCM (2×) the combined organic portions were dried with MgSO4 filtered concentrated The crude material was purified eluting 10:1 Hex/EtOAc

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

实验步骤: A solution of tert-butyl(cyclopropylmethyl)carbamate (4 g, 23.4 mmol) in DMF (35 mL) was added to a suspension of NaH (60% suspension in mineral oil) (0.58 g, 25.7 mmol) in DMF (5 mL) at 0-5° C., to it was added Iodomethane (2.5 mL, 40 mmol) and stirring was continued at 25° C. for 16 h. Reaction mixture was quenched with cold water, extracted with ethyl acetate (3×50 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude, which was purified by flash chromatography (Biotage, Column: silica gel 12 g pack size, solid load, Mobile Phase: EtOAc in n-Hexane: 0 to 5% as eluent) to afford tert-butyl(cyclopropylmethyl)(methyl)carbamate (Int-37) as pale yellow oil. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.0-2.9 (2H, d), 2.85 (3H, s), 1.4 (9H, s), 0.9-0.7 (1H, bs), 0.5-0.3 (2H, m), 0.2-0.05 (2H, m). Reaction mixture was quenched with cold water extracted with ethyl acetate (3×50 mL) dried over anhydrous sodium sulphate concentrated under reduced pressure to afford the crude, which was purified by flash chromatography (Biotage, Column: silica gel 12 g pack size, solid load, Mobile Phase: EtOAc in n-Hexane: 0 to 5% as eluent)

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

实验步骤: A solution of tert-butyl(cyclopropylmethyl)carbamate (4 g, 23.4 mmol) in DMF (35 mL) was added to a suspension of NaH (60% suspension in mineral oil) (0.58 g, 25.7 mmol) in DMF (5 mL) at 0-5° C., to it was added Iodomethane (2.5 mL, 40 mmol) and stirring was continued at 25° C. for 16 h. Reaction mixture was quenched with cold water, extracted with ethyl acetate (3×50 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude, which was purified by flash chromatography (Biotage, Column: silica gel 12 g pack size, solid load, Mobile Phase: EtOAc in n-Hexane: 0 to 5% as eluent) to afford tert-butyl(cyclopropylmethyl)(methyl)carbamate (Int-37) as pale yellow oil. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.0-2.9 (2H, d), 2.85 (3H, s), 1.4 (9H, s), 0.9-0.7 (1H, bs), 0.5-0.3 (2H, m), 0.2-0.05 (2H, m). Reaction mixture was quenched with cold water extracted with ethyl acetate (3×50 mL) dried over anhydrous sodium sulphate concentrated under reduced pressure to afford the crude, which was purified by flash chromatography (Biotage, Column: silica gel 12 g pack size, solid load, Mobile Phase: EtOAc in n-Hexane: 0 to 5% as eluent)

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

实验步骤: Tert-butyl cyclopropylmethylcarbamate (11.2 g, 65.4 mmol) was dissolved into THF (60 mL) and set to stir at −78° C. BuLi (2.5M, 28.8 mL) was then added portionwise over 10 minutes. The reaction was allowed to stir while warming to −20° C. for 10 minutes, and continued stirring at that temperature for another 10 minutes. The reaction was then recooled to −78° C. at which point chloro(methoxy)methane (5.79 g, 72.0 mmol) was added via syringe. The reaction was then allowed to stir overnight with warming. The reaction was then quenched with 1 N HCl and the organic layer separated. The aqueous layer was then extracted with DCM (2×), and the combined organic portions were dried with MgSO4, filtered and concentrated. The crude material was purified by passing through a silica plug eluting 10:1 Hex/EtOAc to give tert-butyl cyclopropylmethyl(methoxymethyl)carbamate (12.8 g, 91%) as a clear liquid. to stir while warming to −20° C. for 10 minutes continued stirring at that temperature for another 10 minutes was added via syringe to stir overnight with warming The reaction was then quenched with 1 N HCl the organic layer separated The aqueous layer was then extracted with DCM (2×) the combined organic portions were dried with MgSO4 filtered concentrated The crude material was purified eluting 10:1 Hex/EtOAc