2-bromo-N-methoxy-N-methylacetamide

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

実験手順: The title compound was prepared from (S)-1-(tert-butyldimethylsilyloxy)-3-cyclopropylbut-3-en-2-amine (Intermediate 234, 4.61 g, 19.09 mmol) and 2-bromo-N-methoxy-N-methylacetamide (Intermediate 4, 3.16 g, 17.36 mmol) following the procedure described for Intermediate 5. The desired product was obtained as a light yellow oil (4.94 g, 64%).

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

実験手順: The title compound was prepared from (S)-1-(tert-butyldimethylsilyloxy)-3-methylbut-3-en-2-amine (Intermediate 187, 5.57 g, 25.86 mmol) and 2-bromo-N-methoxy-N-methylacetamide (Intermediate 4, 4.28 g, 23.53 mmol) following the procedure described for Intermediate 5. Silica gel chromatography (0%-20% ethyl acetate/hexanes) afforded the desired product as a colorless oil (4.24 g, 39%).

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

実験手順: The title compound was prepared from (S)-1-(tert-butyldimethylsilyloxy)-3-methylbut-3-en-2-amine (Intermediate 187, 5.57 g, 25.86 mmol) and 2-bromo-N-methoxy-N-methylacetamide (Intermediate 4, 4.28 g, 23.53 mmol) following the procedure described for Intermediate 5. Silica gel chromatography (0%-20% ethyl acetate/hexanes) afforded the desired product as a colorless oil (4.24 g, 39%).

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

実験手順: To a stirred solution of 3-(6-(3-((tert-Butyldimethylsilyl)oxy)-2-hydroxypropyl)-1,3-dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (Example 9a, step 1) (280 mg, 0.597 mmol) in THF (5975 μL) was added sodium hydride (60% in mineral oil) (71.7 mg, 1.792 mmol) at 0° C. The resulting red solution was warmed to room temperature and stirred for 20 minutes, before being cooled to 0° C. 2-Bromo-N-methoxy-N-methylacetamide (Example 13, step 1) (141 mg, 0.777 mmol) was then added dropwise over 5 minutes. The reaction mixture was warmed to room temperature over 3 hours and then cooled to 0° C. and quenched with saturated aqueous ammonium chloride solution (5 mL). DCM (10 mL) was added to the biphasic solution. The aqueous phase was separated and extracted with DCM (3×10 mL); the combined organic extracts were dried (MgSO4) and concentrated under reduced pressure to afford a yellow oil. The oil was purified using Teledyne ISCO (12 g, SiO2) eluting with 0-65% EtOAc/hexanes to afford the title compound as an amorphous white solid. before being cooled to 0° C The reaction mixture was warmed to room temperature over 3 hours cooled to 0° C. quenched with saturated aqueous ammonium chloride solution (5 mL) DCM (10 mL) was added to the biphasic solution The aqueous phase was separated extracted with DCM (3×10 mL) the combined organic extracts were dried (MgSO4) concentrated under reduced pressure to afford a yellow oil The oil was purified eluting with 0-65% EtOAc/hexanes

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

実験手順: The above amide (1 equiv) is dissolved in THF. Piperidine (1.1 equiv) is added and the reaction solution is stirred at ambient temperature for 48 h. The reaction mixture is concentrated and the product is purified by flash chromatography on silica using MeOH/CH2Cl2 as the mobile phase to yield N-methoxy-N-methyl-2-(piperid-1-yl)-ethanamide. The reaction mixture is concentrated the product is purified by flash chromatography on silica

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

実験手順: Scheme 1, steps A and B: Bromoacetyl bromide (1.06 equiv.) is added to a solution of N,O-dimethylhydroxylamine hydrochloride (1.0 equiv.) (Volumes are in mL/g of this compound) in a stirring mixture of water (4 mL/g), toluene (4 mL/g), and K2CO3 (1.15 equiv.) at 0° C. After warming to room temperature over 1 hour, the layers are separated and the aqueous layer is extracted with toluene (2 mL/g). The combined organic layers are concentrated to give the intermediate 2-bromo-N-methoxy-N-methyl-acetamide containing about 20% toluene. 2-Bromo-N-methoxy-N-methyl-acetamide is added to a mixture of allyl alcohol (6.3 equiv) and K2CO3 (2 equiv.) over 3 hours at 30° C. After 2 hours at 30° C., toluene (4 mL/g) is added, the mixture is cooled to 0° C., and filtered. The filter cake is rinsed with cold (0° C.) toluene (2.7 mL/g) and the combined filtrate is washed with a 3 weight % solution of KHSO4 in water (0.6 mL/g). The toluene solution is concentrated while additional toluene (11 mL/g) is added to remove water and allyl alcohol. The concentrated toluene solution is washed with water (0.5 g/g), further concentrated to remove most of the toluene, and then distilled to give the title compound. LC-MS (m/z): 160 (M+H). filtered The filter cake is rinsed with cold (0° C.) toluene (2.7 mL/g) the combined filtrate is washed with a 3 weight % solution of KHSO4 in water (0.6 mL/g) The toluene solution is concentrated while additional toluene (11 mL/g) is added to remove water and allyl alcohol The concentrated toluene solution is washed with water (0.5 g/g) further concentrated to remove most of the toluene distilled

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

実験手順: Scheme 1, steps A and B: Bromoacetyl bromide (1.06 equiv.) is added to a solution of N,O-dimethylhydroxylamine hydrochloride (1.0 equiv.) (Volumes are in mL/g of this compound) in a stirring mixture of water (4 mL/g), toluene (4 mL/g), and K2CO3 (1.15 equiv.) at 0° C. After warming to room temperature over 1 hour, the layers are separated and the aqueous layer is extracted with toluene (2 mL/g). The combined organic layers are concentrated to give the intermediate 2-bromo-N-methoxy-N-methyl-acetamide containing about 20% toluene. 2-Bromo-N-methoxy-N-methyl-acetamide is added to a mixture of allyl alcohol (6.3 equiv) and K2CO3 (2 equiv.) over 3 hours at 30° C. After 2 hours at 30° C., toluene (4 mL/g) is added, the mixture is cooled to 0° C., and filtered. The filter cake is rinsed with cold (0° C.) toluene (2.7 mL/g) and the combined filtrate is washed with a 3 weight % solution of KHSO4 in water (0.6 mL/g). The toluene solution is concentrated while additional toluene (11 mL/g) is added to remove water and allyl alcohol. The concentrated toluene solution is washed with water (0.5 g/g), further concentrated to remove most of the toluene, and then distilled to give the title compound. LC-MS (m/z): 160 (M+H). filtered The filter cake is rinsed with cold (0° C.) toluene (2.7 mL/g) the combined filtrate is washed with a 3 weight % solution of KHSO4 in water (0.6 mL/g) The toluene solution is concentrated while additional toluene (11 mL/g) is added to remove water and allyl alcohol The concentrated toluene solution is washed with water (0.5 g/g) further concentrated to remove most of the toluene distilled

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

実験手順: This bromoacetamide was dissolved in acetonitrile and to the solution were added 10.75 gm (71.15 mMol) 4-acetamidophenol followed by 23.10 gm (71.1 mMol) cesium carbonate. The reaction mixture was heated at reflux for 3 hours and then concentrated under reduced pressure. The residue was partitioned between dichloromethane and 1N aqueous sodium hydroxide. The organic phase was separated, washed sequentially with water and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 10.34 gm (74%) of the desired compound. The reaction mixture was heated at reflux for 3 hours concentrated under reduced pressure The residue was partitioned between dichloromethane and 1N aqueous sodium hydroxide The organic phase was separated washed sequentially with water and saturated aqueous sodium chloride dried over magnesium sulfate concentrated under reduced pressure eluting with ethyl acetate Fractions containing product concentrated under reduced pressure

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

実験手順: In analogy to the procedure described in intermediate 1D, 3-bromopropionic acid gave the title compound as a light yellow liquid. MS: 195.9 (MH+, 1Br).

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

実験手順: A suspension of 5.01 g (16.00 mmol) of 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one and 3.20 g (17.60 mmol) of 2-bromo-N-methoxy-N-methyl-acetamide (intermediate 1D) in 110 ml of THF was treated at 0° C. with 0.84 g (19.20 mmol) of NaH (55% in oil) in two portions. The reaction was warmed up to RT over night and stirred for 2.5 h at 75° C. The reaction was cooled and neutralized with cold aqueous 10% KHSO4 and extracted with EtOAc (3×). The organic phases were washed with aqueous saturated NaHCO3, aqueous 10% NaCl, dried over Na2SO4 evaporated and purified by flash silica gel column (CH2Cl2/MeOH 99:1 to 97.5:2.5) to yield 3.49 g (53%) of the light yellow crystalline title compound. MS: 414.1 (MH+, 2Cl). The reaction was cooled extracted with EtOAc (3×) The organic phases were washed with aqueous saturated NaHCO3, aqueous 10% NaCl dried over Na2SO4 evaporated purified by flash silica gel column (CH2Cl2/MeOH 99:1 to 97.5:2.5)

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

実験手順: Scheme 1, steps A and B: Bromoacetyl bromide (1.06 equiv.) is added to a solution of N,O-dimethylhydroxylamine hydrochloride (1.0 equiv.) (Volumes are in mL/g of this compound) in a stirring mixture of water (4 mL/g), toluene (4 mL/g), and K2CO3 (1.15 equiv.) at 0° C. After warming to room temperature over 1 hour, the layers are separated and the aqueous layer is extracted with toluene (2 mL/g). The combined organic layers are concentrated to give the intermediate 2-bromo-N-methoxy-N-methyl-acetamide containing about 20% toluene. 2-Bromo-N-methoxy-N-methyl-acetamide is added to a mixture of allyl alcohol (6.3 equiv) and K2CO3 (2 equiv.) over 3 hours at 30° C. After 2 hours at 30° C., toluene (4 mL/g) is added, the mixture is cooled to 0° C., and filtered. The filter cake is rinsed with cold (0° C.) toluene (2.7 mL/g) and the combined filtrate is washed with a 3 weight % solution of KHSO4 in water (0.6 mL/g). The toluene solution is concentrated while additional toluene (11 mL/g) is added to remove water and allyl alcohol. The concentrated toluene solution is washed with water (0.5 g/g), further concentrated to remove most of the toluene, and then distilled to give the title compound. LC-MS (m/z): 160 (M+H). filtered The filter cake is rinsed with cold (0° C.) toluene (2.7 mL/g) the combined filtrate is washed with a 3 weight % solution of KHSO4 in water (0.6 mL/g) The toluene solution is concentrated while additional toluene (11 mL/g) is added to remove water and allyl alcohol The concentrated toluene solution is washed with water (0.5 g/g) further concentrated to remove most of the toluene distilled

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

実験手順: The title compound was prepared from (S)-1-(tert-butyldimethylsilyloxy)-3-cyclopropylbut-3-en-2-amine (Intermediate 234, 4.61 g, 19.09 mmol) and 2-bromo-N-methoxy-N-methylacetamide (Intermediate 4, 3.16 g, 17.36 mmol) following the procedure described for Intermediate 5. The desired product was obtained as a light yellow oil (4.94 g, 64%).