2-(bromomethyl)-1,3-dichloro-5-methoxybenzene

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Dissolve commercially available 1-cyclohexyl-pyrrolidin-2-one (88.2 g, 527.9 mmol) in 2500 mL tetrahydrofuran and cool to −78° C. Add 176 mL 2 M LDA and stir for ˜5 min. Add 2-bromomethyl-1,3-dichloro-5-methoxy-benzene (95 g, 351.9 mmol) and allow the reaction to warm to room temperature. Pour the mixture into saturated ammonium chloride and extract twice with dichloromethane. Dry over sodium sulfate, filter and concentrate under vacuum to obtain a tan solid. Add hexanes and stir rapidly before filtering. Wash the filter cake several times with cold hexane to obtain 86 g (69%) of a light-tan solid: MS (m/z): 356 (M+). the reaction to warm to room temperature extract twice with dichloromethane Dry over sodium sulfate filter concentrate under vacuum to obtain a tan solid before filtering Wash the filter cake several times with cold hexane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Dissolve (2,6-dichloro-4-methoxy-phenyl)-methanol (113 g, 545.76 mmol) in 1200 mL dry THF and cool to 0 deg under nitrogen. Add PBr3 (59.1 g, 218.3 mmol) under nitrogen and stir at 0° C. for 30 minutes. Pour into saturated aqueous NaHCO3 and extract with EtOAc. Dry and concentrate under vacuum to obtain 129.4 g product as an off-white solid. NMR (CDCl3) δ 6.88 (s, 2H), 4.73 (s, 2H), 3.79 (s, 3H). cool to 0 deg under nitrogen extract with EtOAc Dry concentrate under vacuum

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Cool a solution of 1-(1,4-Dioxa-spiro[4.5]dec-8-yl)-pyrrolidin-2-one (5 g, 22.2 mmol) in tetrahydrofuran (100 mL) to −78° C. under nitrogen purge. Add LDA (2.0 M, 15 mL, 30 mmol) at a rate such that the internal reaction temperature did not reach above −67° C. Stir 30 min at −78° C., add a solution of 2-bromomethyl-1,3-dichloro-5-methoxy-benzene, 6.6 g, 24.4 mmol) in THF (20 mL) over a 1-2 minute period, remove the cold bath and allow reaction to warm over 3 hr. Quench the reaction with saturated aqueous ammonium chloride (100 mL), extract with ethyl acetate (3×100 mL), combine the extracts and dry over anhydrous sodium sulfate. Purify on silica column eluting with 8:2 hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate to afford the product as a ivory solid, 6.5 g, 71%. 1H NMR (CDCl3) δ 6.86 (s, 2H), 4.06-4.12 (m, 1H), 3.94 (s, 4H), 3.77 (s, 3H), 3.32-3.41 (m, 2H), 3.15-3.21 (m, 1H), 2.83-2.97 (m, 2H), 1.68-2.04 (m, 8H). LCMS m+1 414. purge did not reach above −67° C remove the cold bath reaction to warm over 3 hr Quench the reaction with saturated aqueous ammonium chloride (100 mL) extract with ethyl acetate (3×100 mL) dry over anhydrous sodium sulfate Purify on silica column eluting with 8:2 hexanes

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Cool a solution of 1-(1,4-Dioxa-spiro[4.5]dec-8-yl)-pyrrolidin-2-one (5 g, 22.2 mmol) in tetrahydrofuran (100 mL) to −78° C. under nitrogen purge. Add LDA (2.0 M, 15 mL, 30 mmol) at a rate such that the internal reaction temperature did not reach above −67° C. Stir 30 min at −78° C., add a solution of 2-bromomethyl-1,3-dichloro-5-methoxy-benzene, 6.6 g, 24.4 mmol) in THF (20 mL) over a 1-2 minute period, remove the cold bath and allow reaction to warm over 3 hr. Quench the reaction with saturated aqueous ammonium chloride (100 mL), extract with ethyl acetate (3×100 mL), combine the extracts and dry over anhydrous sodium sulfate. Purify on silica column eluting with 8:2 hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate to afford the product as a ivory solid, 6.5 g, 71%. 1H NMR (CDCl3) δ 6.86 (s, 2H), 4.06-4.12 (m, 1H), 3.94 (s, 4H), 3.77 (s, 3H), 3.32-3.41 (m, 2H), 3.15-3.21 (m, 1H), 2.83-2.97 (m, 2H), 1.68-2.04 (m, 8H). LCMS m+1 414. purge did not reach above −67° C remove the cold bath reaction to warm over 3 hr Quench the reaction with saturated aqueous ammonium chloride (100 mL) extract with ethyl acetate (3×100 mL) dry over anhydrous sodium sulfate Purify on silica column eluting with 8:2 hexanes

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Dissolve (2,6-dichloro-4-methoxy-phenyl)-methanol (113 g, 545.76 mmol) in 1200 mL dry tetrahydrofuran and cool to 0° C. under nitrogen. Add PBr3 (59.1 g, 218.3 mmol) under nitrogen and stir at 0° C. for 30 minutes. Pour into saturated aqueous sodium bicarbonate and extract with ethyl acetate. Dry and concentrate under vacuum to obtain 129.4 g product as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 6.88 (s, 2H), 4.73 (s, 2H), 3.79 (s, 3H). extract with ethyl acetate Dry concentrate under vacuum

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Dissolve (2,6-dichloro-4-methoxy-phenyl)-methanol (113 g, 545.76 mmol) in 1200 mL dry tetrahydrofuran and cool to 0° C. under nitrogen. Add PBr3 (59.1 g, 218.3 mmol) under nitrogen and stir at 0° C. for 30 minutes. Pour into saturated aqueous sodium bicarbonate and extract with ethyl acetate. Dry and concentrate under vacuum to obtain 129.4 g product as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 6.88 (s, 2H), 4.73 (s, 2H), 3.79 (s, 3H). extract with ethyl acetate Dry concentrate under vacuum