bromo(methoxy)methane

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: 77 g (0.6 moles) of bromomethylmethyl ether (a reagent available from Tokyo Chemical Industry Co., Ltd.) was added dropwise in 51 g (0.5 moles) of triethylamine (a reagent available from Tokyo Chemical Industry Co., Ltd.), and the mixture was allowed to react at 60 to 70° C. for 6 hours. After completion of the reaction, hexane was added for crystallization, thereby obtaining 96 g (percent yield: 85%) of a crystal of triethyl(methoxymethyl)ammonium bromide. 52 g (0.18 moles) of lithium bis(trifluoromethylsulfonyl)imide (a reagent available from Kanto Chemical Co., Inc.) was added to 34 g (0.15 moles) of this triethyl(methoxymethyl)ammonium bromide, and the mixture was allowed to react in an aqueous system. Subsequently, the reaction mixture was stirred for aging at room temperature for 3 hours. After completion of stirring, a lower layer (product) was separated. The separated product was washed with pure water four times and then washed with hexane four times. After completion of washing, the product was dried in vacuo at 100° C. and at a degree of vacuum of 0.5 kPa for 5 hours. Confirmation of the thus obtained product was carried out by means of 1H-NMR, 13C-NMR and 19F-NMR. A yield of the product (colorless transparent liquid) was 59 g (percent yield: 93%) to react at 60 to 70° C. for 6 hours was added for crystallization

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

Procedure: 62 g (0.5 moles) of bromomethylmethyl ether (a reagent available from Tokyo Chemical Industry Co., Ltd.) was added dropwise in 236 g (0.5 moles) of a 25% toluene solution of triethylphosphine (HISHICOLIN (registered trademark) P-2, a trade name of Nippon Chemical Industrial Co., Ltd.), and the mixture was allowed to react at 70 to 80° C. for 6 hours. After completion of the reaction, hexane was added for crystallization, thereby obtaining 97 g (percent yield: 80%) of a crystal of triethyl(methoxymethyl)phosphonium bromide. 86 g (0.3 moles) of lithium bis(trifluoromethylsulfonyl)imide (a reagent available from Kanto Chemical Co., Inc.) was added to 73 g (0.3 moles) of this triethyl(methoxymethyl)phosphonium bromide, and the mixture was allowed to react in an aqueous system. Subsequently, the reaction mixture was stirred for aging at room temperature for 3 hours. After completion of stirring, a lower layer (product) was separated. The separated product was washed with pure water four times and then washed with hexane four times. After completion of washing, the product was dried in vacuo at 100° C. and at a degree of vacuum of 0.5 kPa for 5 hours. Confirmation of the obtained product was carried out by means of 1H-NMR, 13C-NMR, 31P-NMR and 19F-NMR. A yield of the product (colorless transparent liquid) was 104 g (percent yield: 78%), and it was confirmed by 3P-NMR that its purity was 98% or more. to react at 70 to 80° C. for 6 hours was added for crystallization

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

Procedure: To a stirring suspension of sodium hydride (1.2 g, 52.1 mmol, 60% dispersion in mineral oil) in DMF (75 mL) at 0° C. was added 2-bromophenol (6.0 g, 34.7 mmol) dropwise. After stirring for 20 min, bromomethyl methyl ether (4.3 g, 34.7 mmol) was added. After stirring for 16 h at room temperature, the mixture was poured into water (250 mL) and extracted with hexane. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography (silica gel, hexane) to yield the title compound as a colorless oil (4.0 g, 53%). 1HNMR (400 MHz, CDCl3) δ 7.55 (d, 1H), 7.28 (t, 1H), 7.16 (d, 1H), 6.91 (t, 1H), 5.25 (s, 2H), 3.54 (s, 3H). After stirring for 16 h at room temperature extracted with hexane The organic layer was washed with brine dried (MgSO4) filtered concentrated The residue was purified by column chromatography (silica gel, hexane)

Conditions: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add sodium hydride (0.031 g, 0.0013 mol) to a solution of 8-(2-chlorophenyl)-6-(4-ethylpiperazin-1-yl)-2-methyl-9H-purine (0.233 g, 0.00065 mol) in dry tetrahydrofuran (20 mL) at 0° C. Stir the reaction mixture for 15 min, then cool to −30° C. and add bromomethyl methyl ether (0.081 g, 0.00065 mol). Warm the reaction mixture to room temperature and stir for one hour. Quench the reaction mixture with water, remove the tetrahydrofuran by evaporation and then extract the reaction mixture with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to give the residue. Purify the residue through preparative reverse phase HPLC (X-Bridge column, 5 mM NH4OAc/acetonitrile) to give the title compound (0.029 g). ES/MS m/z 401 (M+1). Warm the reaction mixture to room temperature stir for one hour Quench the reaction mixture with water remove the tetrahydrofuran by evaporation extract the reaction mixture with dichloromethane Dry the organic layer over anhydrous sodium sulfate filter concentrate to give the residue Purify the residue through preparative reverse phase HPLC (X-Bridge column, 5 mM NH4OAc/acetonitrile)

Conditions: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 17.0 g quantity of N-methylpyrrolidine was dissolved in 160 g of dehydrated acetone (up to 0.1% in water content), followed by nitrogen replacement. To the solution was added dropwise 24.6 g of bromomethyl methyl ether (reagent, product of Tokyo Kasei Co., Ltd.) at 5° C. over a period of 1.5 hours. The mixture was stirred at 5 to not higher than 15° C. for 4 hours to terminate the reaction. The reaction mixture was filtered, and the resulting solids were washed with 160 g of acetone, and dried in a vacuum, affording 30.9 g of the desired product (white solid). to terminate the reaction The reaction mixture was filtered the resulting solids were washed with 160 g of acetone dried in a vacuum

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

Procedure: To a suspension of NaH (2.5 g, 0.06 mol) in dry DMF (100 mL) at 0° C. was added solution of 1-bromo-2-hydroxy-4-methoxybenzene (10.6 g, 0.05 mol). After stirring at 0° C. for 30 min. bromomethyl methyl ether (7.8 g, 0.06 mmol) were dropwise added. The mixture was warmed to room temperature over 20 min. and then stirred for 2 h, it was then quenched cautiously by the addition of cold dilute HCl and extracted with EtOAc. The EtOAc extract was washed successively with; H2O, 5% aqueous NaHCO3, H2O and finally brine. After drying (MgSO4) filtration and evaporation gave liquid. The product was purified by distillation (85° C., 0.2 mm Hg) to give the title compound as a colorless oil (13.7 g, 97%). were dropwise added it was then quenched cautiously by the addition of cold dilute HCl extracted with EtOAc The EtOAc extract was washed successively with After drying (MgSO4) filtration and evaporation gave liquid The product was purified by distillation (85° C., 0.2 mm Hg)

Conditions: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 17.0 g quantity of N-methylpyrrolidine was dissolved in 160 g of dehydrated acetone (up to 0.1% in water content), followed by nitrogen replacement. To the solution was added dropwise 24.6 g of bromomethyl methyl ether (reagent, product of Tokyo Kasei Co., Ltd.) at 5° C. over a period of 1.5 hours. The mixture was stirred at 5 to not higher than 15° C. for 4 hours to terminate the reaction. The reaction mixture was filtered, and the resulting solids were washed with 160 g of acetone, and dried in a vacuum, affording 30.9 g of the desired product (white solid). to terminate the reaction The reaction mixture was filtered the resulting solids were washed with 160 g of acetone dried in a vacuum

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

Procedure: To a suspension of 3,9-dimethylbenzo[f]quinazolin-1(2H)-one (1.0 g, 4.5 mmol) in DMF (25 ml) was added 80% NaH (0.15 g, 5.0 mmol) (Aldrich) portion wise and the mixture was stirred 35 minutes. Bromomethyl methyl ether (0.39 ml, 4.8 mmol) (Aldrich) was added in one portion and the solution was stirred at room temperature overnight. The solution was then diluted with water (100 ml) and extracted twice with methylene chloride (100, 40 ml). The combined methylene chloride extracts were washed with a small volume of water, dried (K2CO3), and concentrated in vacuo. The residue was purified by silica gel (4 0 g) chromatography eluting with ethyl acetate:methylene chloride (0 to 1:19) to give 3,9-dimethyl-2-methoxymethylbenzo[f]quinazolin-1(2H)-one and the corresponding O-alkylated material in a 4:1 ratio as determined by NMR (0.79 g). 1H NMR (DMSO-d6, 300 MHz) for major isomer δ: 2.57 (s, 3H, C9—CH3), 2.68 (s, 3H, C3—CH3), 3.38 (s, 3H, OCH3), 5.62 (s, 2H, NCH2O), 7.51 (dd, J=8,2 Hz, 1H, Ar), 7.56 (d, J=9 Hz, 1H, Ar), 7.96 (d, J=8 Hz, 1H, Ar), 8.24 (d, J=9 Hz, 1H, Ar), 9.63 (s, 1H, Ar). Anal. Calculated for C16H6N2O2: C, 71.62; H, 6.01; H, 10.44. Found: C, 71.55; H, 6.03; H, 10.43. the solution was stirred at room temperature overnight extracted twice with methylene chloride (100, 40 ml) The combined methylene chloride extracts were washed with a small volume of water dried (K2CO3) concentrated in vacuo The residue was purified by silica gel (4 0 g) chromatography eluting with ethyl acetate

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-Bromo-2-hydroxy-4-methoxybenzene (5.00 g, 24.60 mmol) in DMF was added 60% sodium hydride (1.97 g, 49.20 mmol) at 0° C. under argon. The mixture was allowed to stir at 0° C. for 15 minutes, then 90% bromomethyl methylether (4.10 g, 29.50 mmol) was added. After stirring for 1 h at 0° C. the reaction was quenched with water. The mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine and dried (Na2SO4). Removal of the solvent afforded the title compound as an oil (6.5 g, quantitative yield). 1H NMR (400 MHz, CDCl3) δ 7.41 (d, 2H), 6.76 (d, 1H), 6.47 (dd, 1H), 5.24 (s, 2H), 3.87 (s, 3H), 3.53 (s, 3H). After stirring for 1 h at 0° C. the reaction was quenched with water The mixture was extracted with ethyl acetate the combined organic extracts were washed with brine dried (Na2SO4) Removal of the solvent