2-cyclopropyl-N-methoxy-N-methylacetamide

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:; See reaction.notes.procedure_details.

実験手順: This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with 2-cyclopropyl-N-methoxy-N-methylacetamide. It is used in crude form in the following reaction. This compound is synthesized in the following reaction

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with 2-cyclopropyl-N-methoxy-N-methylacetamide. It is used in crude form in the following reaction. This compound is synthesized in the following reaction

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

実験手順: To a solution of 4-methyl-2-(methylthio)pyrimidine (5.63 mL, 40.4 mmol) in THF (20 mL) at −10° C., LiHMDS (60.6 mL, 60.6 mmol) (1N in MBTE) was added dropwise under nitrogen. The reaction mixture coagulated, and stopped stirring. For this, additional THF (40 mL) was added to dissolve the highly viscous mixture. The reaction was warmed up to rt and was stirred for 30 minutes. The reaction mixture was re-cooled to −10° C., then 2-cyclopropyl-N-methoxy-N-methylacetamide (7.47 g, 40.4 mmol) was added dropwise. The reaction mixture was warmed up to rt, then stirred for an additional 2 hours. The reaction was partitioned between ammonium chloride solution and EtOAc. The organic layer was separated, and the aqueous layer was back-extracted. The organic extracts were combined, washed with brine, dried over sodium sulfate, then concentrated in vacuo. The crude product was purified by Biotage™ silica gel chromatography [100 g SNAP column, 10% EtOAc/heptane to 100% EtOAc] to obtain the desired product, which was still contaminated significantly with the starting material, 4-methyl-2-(methylthio)pyrimidine (5.63 g, 48% yield). The product was carried on to the next step without further purification. MS (ES+): m/z=223.2/224.3 (100/50) [MH+]. HPLC: tR=0.84 minute over 3 minutes. Purity: 77% [HPLC (LC/MS) at 220 nm]. to dissolve the highly viscous mixture was stirred for 30 minutes The reaction mixture was re-cooled to −10° C. The reaction mixture was warmed up to rt stirred for an additional 2 hours The reaction was partitioned between ammonium chloride solution and EtOAc The organic layer was separated the aqueous layer was back-extracted washed with brine dried over sodium sulfate concentrated in vacuo The crude product was purified by Biotage™ silica gel chromatography [100 g SNAP column, 10% EtOAc/heptane to 100% EtOAc]

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

実験手順: Stir 1-bromo-2,4-bis-(tert-butyl-dimethyl-silanyloxy)-benzene (100 g, 240 mmol) in diethyl ether (1 L, anhydrous) at −60° C. and treat with 1.7M tert-butyllithium in pentane (290 mL, 493 mmol) via addition funnel over a 10 minute period. Stir for 15 min, then treat with 2-cyclopropyl-N-methoxy-N-methyl-acetamide (34 g, 237 mmol) in a minimum amount of ethyl ether. Remove cold bath, stir for 1 hr, treat with 1N aqueous hydrochloric acid (100 mL), and stir for an additional hour. Separate the layers and wash the organic layer with 1N aqueous hydrochloric acid (100 mL), brine, dry with magnesium sulfate, filter, and evaporate. Dissolve the residue in tetrahydrofuran (1 L), treat with 1N tetrabutylammonium fluoride solution in tetrahydrofuran (500 mL, 500 mmol), and stir for 3 hrs. Pour mixture into 1 L of water containing 120 mL of 5N hydrochloric acid, separate layers, and extract water layer twice with ethyl acetate. Wash organic layers with brine, dry with magnesium sulfate, filter, and evaporate. Chromatograph residue on silica gel (Biotage® Radial Compression fitted with a 75-L column) eluting with 25% ethyl acetate in hexanes to isolate the title compound (43 g, 94% yield). 1H NMR (CDCl3) δ 12.83 (s, 1H), 7.60 (d, J=8.0 Hz, 1H), 6.39 (m, 2H), 5.98 (s, 1H), 2.80 (d, J=4.0 Hz, 2H), 1.13 (m, 1H), 0.60 (m, 2H), 0.22 (m, 2H). Remove cold bath stir for 1 hr treat with 1N aqueous hydrochloric acid (100 mL) stir for an additional hour Separate the layers wash the organic layer with 1N aqueous hydrochloric acid (100 mL), brine dry with magnesium sulfate filter evaporate Dissolve the residue in tetrahydrofuran (1 L) stir for 3 hrs separate layers extract water layer twice with ethyl acetate Wash organic layers with brine, dry with magnesium sulfate filter evaporate Chromatograph residue on silica gel (Biotage® Radial Compression fitted with a 75-L column) eluting with 25% ethyl acetate in hexanes

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

実験手順: Stir 1-bromo-2,4-bis-(tert-butyl-dimethyl-silanyloxy)-benzene (100 g, 240 mmol) in diethyl ether (1 L, anhydrous) at −60° C. and treat with 1.7M tert-butyllithium in pentane (290 mL, 493 mmol) via addition funnel over a 10 minute period. Stir for 15 min, then treat with 2-cyclopropyl-N-methoxy-N-methyl-acetamide (34 g, 237 mmol) in a minimum amount of ethyl ether. Remove cold bath, stir for 1 hr, treat with 1N aqueous hydrochloric acid (100 mL), and stir for an additional hour. Separate the layers and wash the organic layer with 1N aqueous hydrochloric acid (100 mL), brine, dry with magnesium sulfate, filter, and evaporate. Dissolve the residue in tetrahydrofuran (1 L), treat with 1N tetrabutylammonium fluoride solution in tetrahydrofuran (500 mL, 500 mmol), and stir for 3 hrs. Pour mixture into 1 L of water containing 120 mL of 5N hydrochloric acid, separate layers, and extract water layer twice with ethyl acetate. Wash organic layers with brine, dry with magnesium sulfate, filter, and evaporate. Chromatograph residue on silica gel (Biotage® Radial Compression fitted with a 75-L column) eluting with 25% ethyl acetate in hexanes to isolate the title compound (43 g, 94% yield). 1H NMR (CDCl3) δ 12.83 (s, 1H), 7.60 (d, J=8.0 Hz, 1H), 6.39 (m, 2H), 5.98 (s, 1H), 2.80 (d, J=4.0 Hz, 2H), 1.13 (m, 1H), 0.60 (m, 2H), 0.22 (m, 2H). Remove cold bath stir for 1 hr treat with 1N aqueous hydrochloric acid (100 mL) stir for an additional hour Separate the layers wash the organic layer with 1N aqueous hydrochloric acid (100 mL), brine dry with magnesium sulfate filter evaporate Dissolve the residue in tetrahydrofuran (1 L) stir for 3 hrs separate layers extract water layer twice with ethyl acetate Wash organic layers with brine, dry with magnesium sulfate filter evaporate Chromatograph residue on silica gel (Biotage® Radial Compression fitted with a 75-L column) eluting with 25% ethyl acetate in hexanes

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

実験手順: Stir cyclopropaneacetic acid (30 g, 300 mmol) in dichloromethane (1 L) and treat with 1,1′-carbonyldiimidazole (52.5 g, 324 mmol) slowly. Stir for 2 hrs at room temperature and treat with N,O-dimethylhydroxylamine hydrochloride (30 g, 308 mmol), neat, in one portion; stir overnight. Pour mixture into water and extract twice with dichloromethane. Wash organic layers with water, dilute hydrochloric acid, saturated sodium bicarbonate solution, dry with magnesium sulfate, filter, and evaporate to provide the title compound (38 g, 89%). 1H NMR (CDCl3) δ 3.66 (s, 3H), 3.18 (s, 3H), 2.35 (d, J=8.0 Hz, 2H), 1.08 (m, 1H), 0.54 (m, 2H), 0.16 (m, 2H). stir overnight extract twice with dichloromethane Wash organic layers with water, dilute hydrochloric acid, saturated sodium bicarbonate solution, dry with magnesium sulfate filter evaporate

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

実験手順: Stir cyclopropaneacetic acid (30 g, 300 mmol) in dichloromethane (1 L) and treat with 1,1′-carbonyldiimidazole (52.5 g, 324 mmol) slowly. Stir for 2 hrs at room temperature and treat with N,O-dimethylhydroxylamine hydrochloride (30 g, 308 mmol), neat, in one portion; stir overnight. Pour mixture into water and extract twice with dichloromethane. Wash organic layers with water, dilute hydrochloric acid, saturated sodium bicarbonate solution, dry with magnesium sulfate, filter, and evaporate to provide the title compound (38 g, 89%). 1H NMR (CDCl3) δ 3.66 (s, 3H), 3.18 (s, 3H), 2.35 (d, J=8.0 Hz, 2H), 1.08 (m, 1H), 0.54 (m, 2H), 0.16 (m, 2H). stir overnight extract twice with dichloromethane Wash organic layers with water, dilute hydrochloric acid, saturated sodium bicarbonate solution, dry with magnesium sulfate filter evaporate