2-cyclopropylacetyl chloride

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: To a solution of intermediate compound D7 (0.73 g, 2.709 mmol) in dry DCM (8 ml), cooled at 0° C., were added triethylamine (0.562 ml, 4.064 mmol) and cyclopropyl-acetyl chloride (0.385 g, 3.251 mmol). The resulting reaction mixture was stirred at r.t. for 16 h. To this mixture was then added NaHCO3 (aqueous sat. solution). The resulting solution was then extracted with DCM. The organic layer was separated, dried (MgSO4) and concentrated in vacuo to yield intermediate compound D8 (0.94 g, 99%). The resulting reaction mixture The resulting solution was then extracted with DCM The organic layer was separated dried (MgSO4) concentrated in vacuo

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

Procedure: To a solution of intermediate compound D7 (0.73 g, 2.709 mmol) in dry DCM (8 ml), cooled at 0° C., were added triethylamine (0.562 ml, 4.064 mmol) and cyclopropyl-acetyl chloride (0.385 g, 3.251 mmol). The resulting reaction mixture was stirred at r.t. for 16 h. To this mixture was then added NaHCO3 (aqueous sat. solution). The resulting solution was then extracted with DCM. The organic layer was separated, dried (MgSO4) and concentrated in vacuo to yield intermediate compound D8 (0.94 g, 99%). The resulting reaction mixture The resulting solution was then extracted with DCM The organic layer was separated dried (MgSO4) concentrated in vacuo

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

Procedure: To a solution of intermediate compound D3 (4.099 g, 17.06 mmol) in dry DCM (112 ml) were added triethylamine (2.76 g, 27.294 mmol) and cyclopropyl-acetyl chloride (3.438 g, 29 mmol). The resulting reaction mixture was stirred at r.t. for 20 min, then concentrated in vacuo to yield intermediate compound D4 (5 g, 91%), which was used without further purification. The resulting reaction mixture concentrated in vacuo

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

Procedure: To a solution of intermediate compound D3 (4.099 g, 17.06 mmol) in dry DCM (112 ml) were added triethylamine (2.76 g, 27.294 mmol) and cyclopropyl-acetyl chloride (3.438 g, 29 mmol). The resulting reaction mixture was stirred at r.t. for 20 min, then concentrated in vacuo to yield intermediate compound D4 (5 g, 91%), which was used without further purification. The resulting reaction mixture concentrated in vacuo

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

Procedure: An ice-cooled mixture of 4-methyl-5-nitropyridin-2-amine (1 g, 6.5 mmol), triethylamine (1.31 g, 13 mmol) in tetrahydrofuran (20 mL) was treated with cyclopropyl acetyl chloride (0.75 g, 7.1 mmol) drop wise. After complete addition the reaction mixture was stirred at room temperature for 1 hour, cooled to 0° C. and added cyclopropyl acetyl chloride (0.75 g, 7.1 mmol) followed by stirring at room temperature for 1 hour. The solvent was evaporated under vacuum and water (100 mL) was poured into the reaction mixture and extracted with ethyl acetate (2×150 mL). The organic layer was washed with aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue (1.5 g) was taken-up in methanol and water (4:1, 40 mL). Potassium carbonate was added to it and stirred at room temperature for 20 hours. The mixture was concentrated under vacuum. Residue was taken up in water (100 mL) and extracted with ethyl acetate (2×150 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to get the crude compound, which upon purification by silica gel column chromatography using methanol in dichloromethane (1%) as eluent afforded N-(4-methyl-5-nitropyridin-2-yl)cyclopropanecarboxamide (0.6 g, 52%). After complete addition the reaction mixture cooled to 0° C. by stirring at room temperature for 1 hour The solvent was evaporated under vacuum and water (100 mL) was poured into the reaction mixture extracted with ethyl acetate (2×150 mL) The organic layer was washed with aqueous sodium bicarbonate solution dried over anhydrous sodium sulfate concentrated under vacuum Potassium carbonate was added to it stirred at room temperature for 20 hours The mixture was concentrated under vacuum extracted with ethyl acetate (2×150 mL) The organic layer was dried over anhydrous sodium sulfate concentrated under vacuum to get the crude compound, which upon purification by silica gel column chromatography

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

Procedure: An ice-cooled mixture of 4-methyl-5-nitropyridin-2-amine (1 g, 6.5 mmol), triethylamine (1.31 g, 13 mmol) in tetrahydrofuran (20 mL) was treated with cyclopropyl acetyl chloride (0.75 g, 7.1 mmol) drop wise. After complete addition the reaction mixture was stirred at room temperature for 1 hour, cooled to 0° C. and added cyclopropyl acetyl chloride (0.75 g, 7.1 mmol) followed by stirring at room temperature for 1 hour. The solvent was evaporated under vacuum and water (100 mL) was poured into the reaction mixture and extracted with ethyl acetate (2×150 mL). The organic layer was washed with aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue (1.5 g) was taken-up in methanol and water (4:1, 40 mL). Potassium carbonate was added to it and stirred at room temperature for 20 hours. The mixture was concentrated under vacuum. Residue was taken up in water (100 mL) and extracted with ethyl acetate (2×150 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to get the crude compound, which upon purification by silica gel column chromatography using methanol in dichloromethane (1%) as eluent afforded N-(4-methyl-5-nitropyridin-2-yl)cyclopropanecarboxamide (0.6 g, 52%). After complete addition the reaction mixture cooled to 0° C. by stirring at room temperature for 1 hour The solvent was evaporated under vacuum and water (100 mL) was poured into the reaction mixture extracted with ethyl acetate (2×150 mL) The organic layer was washed with aqueous sodium bicarbonate solution dried over anhydrous sodium sulfate concentrated under vacuum Potassium carbonate was added to it stirred at room temperature for 20 hours The mixture was concentrated under vacuum extracted with ethyl acetate (2×150 mL) The organic layer was dried over anhydrous sodium sulfate concentrated under vacuum to get the crude compound, which upon purification by silica gel column chromatography

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

Procedure: Following the procedure as describe in Example 6, making variations as required to replace 2-fluorobenzoyl chloride with 2-cyclopropylacetyl chloride to react with 2-amino-N-benzylisonicotinamide, N-benzyl-2-(2-cyclopropylacetamido)isonicotinamide was obtained as a colorless solid in 57% yield: 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.48 (s, 1H), 8.34 (d, J=5.1 Hz, 1H), 7.53 (dd, J=5.1, 1.4 Hz, 1H), 7.31-7.24 (m, 5H), 6.87 (br s, 1H), 4.60 (d, J=5.8 Hz, 2H), 2.31 (d, J=7.2 Hz, 2H), 1.08-0.99 (m, 1H), 0.70-0.62 (m, 2H), 0.25 (q, J=4.9 Hz, 2H); MS (ES+) m/z 310.6 (M+1).

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

Procedure: To a solution of D3 (4.099 g, 17.06 mmol) in dry DCM (112 ml) was added Et3N (2.76 g, 27.294 mmol) and cyclopropyl-acetyl chloride (3.438 g, 29 mmol). The resulting reaction mixture was stirred at r.t. for 20 min. The mixture was concentrated in vacuo to yield compound D4 (5 g, 91%). The resulting reaction mixture The mixture was concentrated in vacuo

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

Procedure: To a solution of D3 (4.099 g, 17.06 mmol) in dry DCM (112 ml) was added Et3N (2.76 g, 27.294 mmol) and cyclopropyl-acetyl chloride (3.438 g, 29 mmol). The resulting reaction mixture was stirred at r.t. for 20 min. The mixture was concentrated in vacuo to yield compound D4 (5 g, 91%). The resulting reaction mixture The mixture was concentrated in vacuo