2-amino-3-cyclopropyloxy-N-methoxy-N-methylbenzamide

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of Intermediate A1D (6.61 g, 34.2 mmol) N,O-dimethylhydroxylamine hydrochloride (10.01 g, 103 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.87 g, 41.1 mmol) and 1-hydroxybenzotriazole hydrate (6.29 g, 41.1 mmol) in 50 ml of DMF was added triethylamine (19.07 mL, 137 mmol). The reaction solution was stirred at 60° C. overnight and then cooled to room temperature. The reaction mixture was partitioned between water and ethyl acetate and transferred to a separatory funnel and washed with 10% LiCl, water, and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide a dark oil. The crude product mixture was purified via silica gel chromatography (hexanes/EtOAc) to give Intermediate A1E (5.2 g, 22.01 mmol, 64.3% yield). HPLC: RT=1.975 min (H2O/MeOH with TFA, SunFire C18 3.5 μm, 2.1×30 mm, gradient=4 min, wavelength=220 nm); MS(ES): m/z=237.12 [M+H]+; 1H NMR (400 MHz, chloroform-d) δ 7.17 (dd, J=8.0, 1.2 Hz, 1H), 7.02 (dd, J=7.9, 1.3 Hz, 1H), 6.67 (t, J=7.9 Hz, 1H), 4.78 (br. s., 2H), 3.88-3.73 (m, 1H), 3.69-3.56 (m, 3H), 3.36 (s, 3H), 0.92-0.72 (m, 4H)). cooled to room temperature The reaction mixture was partitioned between water and ethyl acetate transferred to a separatory funnel washed with 10% LiCl, water, and brine The organic phase was dried over anhydrous sodium sulfate filtered concentrated to provide a dark oil The crude product mixture was purified via silica gel chromatography (hexanes/EtOAc) to give Intermediate A1E (5.2 g, 22.01 mmol, 64.3% yield)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of Intermediate A1D (6.61 g, 34.2 mmol) N,O-dimethylhydroxylamine hydrochloride (10.01 g, 103 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.87 g, 41.1 mmol) and 1-hydroxybenzotriazole hydrate (6.29 g, 41.1 mmol) in 50 ml of DMF was added triethylamine (19.07 mL, 137 mmol). The reaction solution was stirred at 60° C. overnight and then cooled to room temperature. The reaction mixture was partitioned between water and ethyl acetate and transferred to a separatory funnel and washed with 10% LiCl, water, and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide a dark oil. The crude product mixture was purified via silica gel chromatography (hexanes/EtOAc) to give Intermediate A1E (5.2 g, 22.01 mmol, 64.3% yield). HPLC: RT=1.975 min (H2O/MeOH with TFA, SunFire C18 3.5 μm, 2.1×30 mm, gradient=4 min, wavelength=220 nm); MS(ES): m/z=237.12 [M+H]+; 1H NMR (400 MHz, chloroform-d) δ 7.17 (dd, J=8.0, 1.2 Hz, 1H), 7.02 (dd, J=7.9, 1.3 Hz, 1H), 6.67 (t, J=7.9 Hz, 1H), 4.78 (br. s., 2H), 3.88-3.73 (m, 1H), 3.69-3.56 (m, 3H), 3.36 (s, 3H), 0.92-0.72 (m, 4H)). cooled to room temperature The reaction mixture was partitioned between water and ethyl acetate transferred to a separatory funnel washed with 10% LiCl, water, and brine The organic phase was dried over anhydrous sodium sulfate filtered concentrated to provide a dark oil The crude product mixture was purified via silica gel chromatography (hexanes/EtOAc) to give Intermediate A1E (5.2 g, 22.01 mmol, 64.3% yield)

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

Procedure: A solution of 1-fluoro-3-iodobenzene (1.009 mL, 8.59 mmol) in tetrahydrofuran (100 mL) was cooled to −78° C. in a dry ice/acetone bath under nitrogen. Then a solution of n-BuLi (1.8 M in hexanes, 5.37 mL, 8.59 mmol) was added via syringe over 15 minutes and stirred for 60 minutes to give gave a dark-yellow suspension. Then a solution of 2-amino-3-cyclopropoxy-N-methoxy-N-methylbenzamide (0.58 g, 2.455 mmol) in 10 mL of THF was added via syringe and the reaction mixture was stirred for 40 minutes at −78° C. After 40 minutes the mixture was poured into a mixture of ice and 1N HCl and extracted into ethyl acetate to give a light-yellow solution. The organic layer was washed with water and brine and concentrated to give a dark-yellow oil residue. The crude product mixture was purified via ISCO (0%-100% of EtOAC/heptane in 15 minutes, 40 g column) to give (2-amino-3-cyclopropoxyphenyl)(3-fluorophenyl)methanone (0.46 g, 1.696 mmol, 69.1% yield). HPLC: RT=3.481 min (H2O/MeOH with TFA, SunFire C18 3.5 μm, 2.1×30 mm, gradient=4 min, wavelength=220 nm); MS(ES):m/z=272.16 [M+H]+; 1H NMR (400 MHz, chloroform-d) δ 7.48-7.40 (m, 2H), 7.36 (ddd, J=9.3, 1.9, 1.1 Hz, 1H), 7.27-7.18 (m, 2H), 7.08 (dd, J=8.3, 1.2 Hz, 1H), 6.58 (t, J=8.0 Hz, 1H), 6.39 (br. s., 2H), 3.83 (t, J=4.5 Hz, 1H), 0.86 (d, J=4.4 Hz, 4H). to give gave a dark-yellow suspension the reaction mixture was stirred for 40 minutes at −78° C extracted into ethyl acetate to give a light-yellow solution The organic layer was washed with water and brine concentrated to give a dark-yellow oil residue The crude product mixture was purified via ISCO (0%-100% of EtOAC/heptane in 15 minutes, 40 g column)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a flask at room temperature, was added 2-amino-3-cyclopropoxybenzoic acid (6.61 g, 34.2 mmol) N,O-dimethylhydroxylamine hydrochloride (10.01 g, 103 mmol), N-ethyl-N″-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.87 g, 41.1 mmol) and 1-hydroxybenzotriazole hydrate (6.29 g, 41.1 mmol) in 50 ml of DMF. To the solution was added triethylamine (19.07 mL, 137 mmol). The reaction solution was stirred at 60° C. overnight and then cooled to room temperature. The reaction mixture was partitioned between water and ethyl acetate and transferred to a separatory funnel and washed with 10% LiCl, water, and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide dark oil. The crude product mixture was purified via ISCO (0%-50% of EtOAC/DCM in 15 minutes, 120 g column) to give 2-amino-3-cyclopropoxy-N-methoxy-N-methylbenzamide (5.2 g, 22.01 mmol, 64.3% yield). HPLC: RT=1.975 min (H2O/MeOH with TFA, SunFire C18 3.5 μm, 2.1×30 mm, gradient=4 min, wavelength=220 nm); MS(ES):m/z=237.12 [M+H]+; 1H NMR (400 MHz, chloroform-d) δ 7.17 (dd, J=8.0, 1.2 Hz, 1H), 7.02 (dd, J=7.9, 1.3 Hz, 1H), 6.67 (t, J=7.9 Hz, 1H), 4.78 (br. s., 2H), 3.88-3.73 (m, 1H), 3.69-3.56 (m, 3H), 3.36 (s, 3H), 0.92-0.72 (m, 4H)). cooled to room temperature The reaction mixture was partitioned between water and ethyl acetate transferred to a separatory funnel washed with 10% LiCl, water, and brine The organic phase was dried over anhydrous sodium sulfate filtered concentrated to provide dark oil The crude product mixture was purified via ISCO (0%-50% of EtOAC/DCM in 15 minutes, 120 g column)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a flask at room temperature, was added 2-amino-3-cyclopropoxybenzoic acid (6.61 g, 34.2 mmol) N,O-dimethylhydroxylamine hydrochloride (10.01 g, 103 mmol), N-ethyl-N″-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.87 g, 41.1 mmol) and 1-hydroxybenzotriazole hydrate (6.29 g, 41.1 mmol) in 50 ml of DMF. To the solution was added triethylamine (19.07 mL, 137 mmol). The reaction solution was stirred at 60° C. overnight and then cooled to room temperature. The reaction mixture was partitioned between water and ethyl acetate and transferred to a separatory funnel and washed with 10% LiCl, water, and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide dark oil. The crude product mixture was purified via ISCO (0%-50% of EtOAC/DCM in 15 minutes, 120 g column) to give 2-amino-3-cyclopropoxy-N-methoxy-N-methylbenzamide (5.2 g, 22.01 mmol, 64.3% yield). HPLC: RT=1.975 min (H2O/MeOH with TFA, SunFire C18 3.5 μm, 2.1×30 mm, gradient=4 min, wavelength=220 nm); MS(ES):m/z=237.12 [M+H]+; 1H NMR (400 MHz, chloroform-d) δ 7.17 (dd, J=8.0, 1.2 Hz, 1H), 7.02 (dd, J=7.9, 1.3 Hz, 1H), 6.67 (t, J=7.9 Hz, 1H), 4.78 (br. s., 2H), 3.88-3.73 (m, 1H), 3.69-3.56 (m, 3H), 3.36 (s, 3H), 0.92-0.72 (m, 4H)). cooled to room temperature The reaction mixture was partitioned between water and ethyl acetate transferred to a separatory funnel washed with 10% LiCl, water, and brine The organic phase was dried over anhydrous sodium sulfate filtered concentrated to provide dark oil The crude product mixture was purified via ISCO (0%-50% of EtOAC/DCM in 15 minutes, 120 g column)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a flask at room temperature, was added 2-amino-3-cyclopropoxybenzoic acid (6.61 g, 34.2 mmol) N,O-dimethylhydroxylamine hydrochloride (10.01 g, 103 mmol), N-ethyl-N″-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.87 g, 41.1 mmol) and 1-hydroxybenzotriazole hydrate (6.29 g, 41.1 mmol) in 50 ml of DMF. To the solution was added triethylamine (19.07 mL, 137 mmol). The reaction solution was stirred at 60° C. overnight and then cooled to room temperature. The reaction mixture was partitioned between water and ethyl acetate and transferred to a separatory funnel and washed with 10% LiCl, water, and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide dark oil. The crude product mixture was purified via ISCO (0%-50% of EtOAC/DCM in 15 minutes, 120 g column) to give 2-amino-3-cyclopropoxy-N-methoxy-N-methylbenzamide (5.2 g, 22.01 mmol, 64.3% yield). HPLC: RT=1.975 min (H2O/MeOH with TFA, SunFire C18 3.5 μm, 2.1×30 mm, gradient=4 min, wavelength=220 nm); MS(ES):m/z=237.12 [M+H]+; 1H NMR (400 MHz, chloroform-d) δ 7.17 (dd, J=8.0, 1.2 Hz, 1H), 7.02 (dd, J=7.9, 1.3 Hz, 1H), 6.67 (t, J=7.9 Hz, 1H), 4.78 (br. s., 2H), 3.88-3.73 (m, 1H), 3.69-3.56 (m, 3H), 3.36 (s, 3H), 0.92-0.72 (m, 4H)). cooled to room temperature The reaction mixture was partitioned between water and ethyl acetate transferred to a separatory funnel washed with 10% LiCl, water, and brine The organic phase was dried over anhydrous sodium sulfate filtered concentrated to provide dark oil The crude product mixture was purified via ISCO (0%-50% of EtOAC/DCM in 15 minutes, 120 g column)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a flask, at room temperature, was added Intermediate A-1D (6.61 g, 34.2 mmol), N,O-dimethylhydroxylamine hydrochloride (10.01 g, 103 mmol), N-Ethyl-N″-(3-Dimethylaminopropyl)carbodiimide hydrochloride (7.87 g, 41.1 mmol) and 1-hydroxybenzotriazole hydrate (6.29 g, 41.1 mmol) in 50 mL of DMF. To the solution was added triethylamine (19.07 mL, 137 mmol). The reaction solution was stirred at 60° C. overnight and then cooled to room temperature. The reaction mixture was partitioned between water and ethyl acetate and transferred to a separatory funnel and the organic layer was washed with 10% LiCl, water, and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide a dark oil. The crude product mixture was purified via silica gel chromatography (0%-50% of EtOAc/DCM over 15 minutes, 120 g column) to give Intermediate A-1E (5.2 g, 22.01 mmol, 64.3% yield). HPLC: RT=1.975 min (H2O/MeOH with TFA, SunFire C18 3.5 μm, 2.1×30 mm, gradient=4 min, wavelength=220 nm); MS(ES):m/z=237.12 [M+H]+; 1H NMR (400 MHz, chloroform-d) δ 7.17 (dd, J=8.0, 1.2 Hz, 1H), 7.02 (dd, J=7.9, 1.3 Hz, 1H), 6.67 (t, J=7.9 Hz, 1H), 4.78 (br. s., 2H), 3.88-3.73 (m, 1H), 3.69-3.56 (m, 3H), 3.36 (s, 3H), 0.92-0.72 (m, 4H). cooled to room temperature The reaction mixture was partitioned between water and ethyl acetate transferred to a separatory funnel the organic layer was washed with 10% LiCl, water, and brine The organic phase was dried over anhydrous sodium sulfate filtered concentrated to provide a dark oil The crude product mixture was purified via silica gel chromatography (0%-50% of EtOAc/DCM over 15 minutes, 120 g column) to give Intermediate A-1E (5.2 g, 22.01 mmol, 64.3% yield)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of Intermediate A1D (6.61 g, 34.2 mmol) N,O-dimethylhydroxylamine hydrochloride (10.01 g, 103 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.87 g, 41.1 mmol) and 1-hydroxybenzotriazole hydrate (6.29 g, 41.1 mmol) in 50 ml of DMF was added triethylamine (19.07 mL, 137 mmol). The reaction solution was stirred at 60° C. overnight and then cooled to room temperature. The reaction mixture was partitioned between water and ethyl acetate and transferred to a separatory funnel and washed with 10% LiCl, water, and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide a dark oil. The crude product mixture was purified via silica gel chromatography (hexanes/EtOAc) to give Intermediate A1E (5.2 g, 22.01 mmol, 64.3% yield). HPLC: RT=1.975 min (H2O/MeOH with TFA, SunFire C18 3.5 μm, 2.1×30 mm, gradient=4 min, wavelength=220 nm); MS(ES): m/z=237.12 [M+H]+; 1H NMR (400 MHz, chloroform-d) δ 7.17 (dd, J=8.0, 1.2 Hz, 1H), 7.02 (dd, J=7.9, 1.3 Hz, 1H), 6.67 (t, J=7.9 Hz, 1H), 4.78 (br. s., 2H), 3.88-3.73 (m, 1H), 3.69-3.56 (m, 3H), 3.36 (s, 3H), 0.92-0.72 (m, 4H)). cooled to room temperature The reaction mixture was partitioned between water and ethyl acetate transferred to a separatory funnel washed with 10% LiCl, water, and brine The organic phase was dried over anhydrous sodium sulfate filtered concentrated to provide a dark oil The crude product mixture was purified via silica gel chromatography (hexanes/EtOAc) to give Intermediate A1E (5.2 g, 22.01 mmol, 64.3% yield)