N-BUTYL-2-CHLORO-ACETAMIDE

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

Procedure: Tetraethyl methylenebisphosphonate (1.44 g, 5.0 mmol) in THF (1 mL) was added to a slurry of 80% sodium hydride (150 mg, 5.0 mmol) in THF (4 mL) at 0° C. The reaction was warmed to room temperature and stirred until all of the hydride was consumed. A solution of N-butyl-2-chloroacetamide (0.75 g, 5.0 mmol) in THF (1 ml) and potassium iodide (100 mg) were then added. The reaction mixture was then heated at 50° C. for 18 hours, during which time sodium chloride precipitated. Additional sodium hydride (20 mg) was added, and the reaction mixture was heated an additional 4 hours. After cooling, the mixture was poured into 1N HCl (10 mL) and diethyl ether (50 mL) was added. The diethyl ether layer was further extracted with water (3×10 mL). The combined aqueous fractions were extracted with dichloromethane (4×25 mL). The combined extracts were dried (Na2SO4) and concentrated to give the title compound (1.40 g, 70%) as an oil. was consumed precipitated Additional sodium hydride (20 mg) was added the reaction mixture was heated an additional 4 hours After cooling the mixture was poured into 1N HCl (10 mL) and diethyl ether (50 mL) was added The diethyl ether layer was further extracted with water (3×10 mL) The combined aqueous fractions were extracted with dichloromethane (4×25 mL) The combined extracts were dried (Na2SO4) concentrated

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

Procedure: Tetraethyl methylenebisphosphonate (1.44 g, 5.0 mmol) in THF (1 mL) was added to a slurry of 80% sodium hydride (150 mg, 5.0 mmol) in THF (4 mL) at 0° C. The reaction was warmed to room temperature and stirred until all of the hydride was consumed. A solution of N-butyl-2-chloroacetamide (0.75 g, 5.0 mmol) in THF (1 ml) and potassium iodide (100 mg) were then added. The reaction mixture was then heated at 50° C. for 18 hours, during which time sodium chloride precipitated. Additional sodium hydride (20 mg) was added, and the reaction mixture was heated an additional 4 hours. After cooling, the mixture was poured into 1N HCl (10 mL) and diethyl ether (50 mL) was added. The diethyl ether layer was further extracted with water (3×10 mL). The combined aqueous fractions were extracted with dichloromethane (4×25 mL). The combined extracts were dried (Na2SO4) and concentrated to give the title compound (1.40 g, 70%) as an oil. was consumed precipitated Additional sodium hydride (20 mg) was added the reaction mixture was heated an additional 4 hours After cooling the mixture was poured into 1N HCl (10 mL) and diethyl ether (50 mL) was added The diethyl ether layer was further extracted with water (3×10 mL) The combined aqueous fractions were extracted with dichloromethane (4×25 mL) The combined extracts were dried (Na2SO4) concentrated

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

Procedure: Following general procedure A, methyl hydrogen fumarate (MHF) (0.50 g, 3.84 mmol) dissolved in NMP was reacted at ca. 55° C. with N-butyl chloroacetamide (0.69 g, 4.61 mmol) in the presence of CsHCO3 (0.89 g, 4.61 mmol) to afford 0.19 g (21% yield) of the title compound (4) as a white solid after purification by mass-guided preparative HPLC and lyophilization. 1H NMR (CDCl3, 400 MHz): δ 6.98-6.92 (m, 2H), 6.09 (br s, 1H), 4.68 (s, 2H), 3.82 (s, 3H), 3.34-3.29 (q, 2H, J=6.4 Hz), 1.54-1.48 (m, 2H), 1.38-1.32 (m, 2H), 0.956-0.920 (t, J=7.6 Hz, 3H). MS (ESI): m/z 244.04 (M+H)+.

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

Procedure: Following general procedure A, methyl hydrogen fumarate (MHF) (0.50 g, 3.84 mmol) dissolved in NMP was reacted at ca. 55° C. with N-butyl chloroacetamide (0.69 g, 4.61 mmol) in the presence of CsHCO3 (0.89 g, 4.61 mmol) to afford 0.19 g (21% yield) of the title compound (4) as a white solid after purification by mass-guided preparative HPLC and lyophilization. 1H NMR (CDCl3, 400 MHz): δ 6.98-6.92 (m, 2H), 6.09 (br s, 1H), 4.68 (s, 2H), 3.82 (s, 3H), 3.34-3.29 (q, 2H, J=6.4 Hz), 1.54-1.48 (m, 2H), 1.38-1.32 (m, 2H), 0.956-0.920 (t, J=7.6 Hz, 3H). MS (ESI): m/z 244.04 (M+H)+.

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

Procedure: Following general procedure A, methyl hydrogen fumarate (MHF) (0.50 g, 3.84 mmol) dissolved in NMP was reacted at ca. 55° C. with N-butyl chloroacetamide (0.69 g, 4.61 mmol) in the presence of CsHCO3 (0.89 g, 4.61 mmol) to afford 0.19 g (21% yield) of the title compound (4) as a white solid after purification by mass-guided preparative HPLC and lyophilization. 1H NMR (CDCl3, 400 MHz): δ 6.98-6.92 (m, 2H), 6.09 (br s, 1H), 4.68 (s, 2H), 3.82 (s, 3H), 3.34-3.29 (q, 2H, J=6.4 Hz), 1.54-1.48 (m, 2H), 1.38-1.32 (m, 2H), 0.956-0.920 (t, J=7.6 Hz, 3H). MS (ESI): m/z 244.04 (M+H)+.

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

Procedure: Tetraethyl methylenebisphosphonate (1.44 g, 5.0 mmol) in THF (1 mL) was added to a slurry of 80% sodium hydride (150 mg, 5.0 mmol) in THF (4 mL) at 0° C. The reaction was warmed to room temperature and stirred until all of the hydride was consumed. A solution of N-butyl-2-chloroacetamide (0.75 g, 5.0 mmol) in THF (1 ml) and potassium iodide (100 mg) were then added. The reaction mixture was then heated at 50° C. for 18 hours, during which time sodium chloride precipitated. Additional sodium hydride (20 mg) was added, and the reaction mixture was heated an additional 4 hours. After cooling, the mixture was poured into 1N HCl (10 mL) and diethyl ether (50 mL) was added. The diethyl ether layer was further extracted with water (3×10 mL). The combined aqueous fractions were extracted with dichloromethane (4×25 mL). The combined extracts were dried (Na2SO4) and concentrated to give the title compound (1.40 g, 70%) as an oil. was consumed precipitated Additional sodium hydride (20 mg) was added the reaction mixture was heated an additional 4 hours After cooling the mixture was poured into 1N HCl (10 mL) and diethyl ether (50 mL) was added The diethyl ether layer was further extracted with water (3×10 mL) The combined aqueous fractions were extracted with dichloromethane (4×25 mL) The combined extracts were dried (Na2SO4) concentrated