butanediamide

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

Procedure: To a solution of 10 (380 mg, 1.1 mmol), DIPEA (1 mL, 5.7 mmol), and 11 (0.37 g, 1.2 mmol) in DMF (30 mL) was added HATU (0.43 g, 1.1 mmol) and the solution was allowed to stir for 24 h at room temperature. The solution was diluted with EtOAc (150 mL) and washed with 5% aqueous solution of LiCl (3×100 mL), 1 N HCl (1×100 mL), saturated aqueous NaHCO3 (2×100 mL), brine, dried over anhydrous Na2SO4, filtered, and concentrated to yield an pale yellow oil. This residue was further purified by column chromatography (silica gel, 3:1 Hexanes/EtOAc) to yield 12 (0.31 g, 44%) as a white foam: 1H NMR (300 MHz, CDCl3) δ 7.86-6.91 (m, 9 H), 5.82 (m, 2 H) 5.67 (m, 1 H), 5.09 (m, 4 H), 3.48 (s, 3 H), 2.73-2.28 (m, 5 H), 1.92 (m, 1 H), 1.61 (m, 1 H), 1.42 (s, 9 H), 1.27 (m, 1 H), 0.93 (m, 6 H); ESI MS m/z=626 [C35H42F3N3O4+H]+. washed with 5% aqueous solution of LiCl (3×100 mL), 1 N HCl (1×100 mL), saturated aqueous NaHCO3 (2×100 mL), brine dried over anhydrous Na2SO4 filtered concentrated to yield an pale yellow oil This residue was further purified by column chromatography (silica gel, 3:1 Hexanes/EtOAc)

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

Procedure: 49.5 g of succinamide was dissolved in 750 ml of 2-butanone under heating. 187.9 g of dibromoethane and 138 g of anhydrous potassium carbonate were added to the solution and the mixture was heated under reflux for 9.5 h. under heating the mixture was heated under reflux for 9.5 h.

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

Procedure: To a solution of 10 (380 mg, 1.1 mmol), DIPEA (1 mL, 5.7 mmol), and 11 (0.37 g, 1.2 mmol) in DMF (30 mL) was added HATU (0.43 g, 1.1 mmol) and the solution was allowed to stir for 24 h at room temperature. The solution was diluted with EtOAc (150 mL) and washed with 5% aqueous solution of LiCl (3×100 mL), 1 N HCl (1×100 mL), saturated aqueous NaHCO3 (2×100 mL), brine, dried over anhydrous Na2SO4, filtered, and concentrated to yield an pale yellow oil. This residue was further purified by column chromatography (silica gel, 3:1 Hexanes/EtOAc) to yield 12 (0.31 g, 44%) as a white foam: 1H NMR (300 MHz, CDCl3) δ 7.86-6.91 (m, 9 H), 5.82 (m, 2 H), 5.67 (m, 1 H), 5.09 (m, 4 H), 3.48 (s, 3 H), 2.73-2.28 (m, 5 H), 1.92 (m, 1 H), 1.61 (m, 1 H), 1.42 (s, 9 H), 1.27 (m, 1 H), 0.93 (m, 6 H); ESI MS m/z=626 [C35H42F3N3O4+H]+. washed with 5% aqueous solution of LiCl (3×100 mL), 1 N HCl (1×100 mL), saturated aqueous NaHCO3 (2×100 mL), brine dried over anhydrous Na2SO4 filtered concentrated to yield an pale yellow oil This residue was further purified by column chromatography (silica gel, 3:1 Hexanes/EtOAc)

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

Procedure: 49.5 g of succinamide was dissolved in 750 ml of 2-butanone under heating. 187.9 g of dibromoethane and 138 g of anhydrous potassium carbonate were added to the solution and the mixture was heated under reflux for 9.5 h. under heating the mixture was heated under reflux for 9.5 h.

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

Procedure: Using the same reaction conditions as described in Example 20-step a except that methyl 4-chloro-3-oxobutyrate replaced methyl 3-chloro-3-oxopropionate, aniline (2.33 g, 25 mmol) was converted to the succinamide compound (5.18 g, 100%) after purification by chromatography over silica gel. 1H NMR (400 MHz, CDCl3) δ: 7.70 (s, 1H), 7.50 (d, 2H), 7.30 (t, 2H), 7.09 (m, 1H), 3.70 (s, 3H), 2.73–2.65 (m, 4H). the same reaction conditions after purification by chromatography over silica gel

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

Procedure: The synthesis of the succinamide analogs 29, 30, 31, 32, and 33 are described in Schemes 12, 13, and 14. N-Phenyl-succinamic acid was prepared via a two step reaction sequence analogous to the preparation of the N-phenyl-malonamic acid: 1) reaction of aniline with methyl 4-chloro-3-oxobutyrate followed by 2) treatment with lithium hydroxide. Coupling of N-phenyl-succinamic acid with 1-(2-methylamino-(S)-2-phenyl-ethyl)-pyrrolidin-(S)-3-ol, 1-(3-methyl-(S)-2-methylamino-butyl)-pyrrolidin-(S)-3-ol or 1-piperidin-(S)-2-ylmethyl-pyrrolidin-(S)-3-ol afforded 29, 30 and 31, respectively.

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

Procedure: To a solution of 10 (380 mg, 1.1 mmol), DIPEA (1 mL, 5.7 mmol), and 11 (0.37 g, 1.2 mmol) in DMF (30 mL) was added HATU (0.43 g, 1.1 mmol) and the solution was allowed to stir for 24 h at room temperature. The solution was diluted with EtOAc (150 mL) and washed with 5% aqueous solution of LiCl (3×100 mL), 1 N HCl (1×100 mL), saturated aqueous NaHCO3 (2×100 mL), brine, dried over anhydrous Na2SO4, filtered, and concentrated to yield an pale yellow oil. This residue was further purified by column chromatography (silica gel, 3:1 Hexanes/EtOAc) to yield 12 (0.31 g, 44%) as a white foam: 1H NMR (300 MHz, CDCl3) δ 7.86-6.91 (m, 9 H), 5.82 (m, 2 H) 5.67 (m, 1 H), 5.09 (m, 4 H), 3.48 (s, 3 H), 2.73-2.28 (m, 5 H), 1.92 (m, 1 H), 1.61 (m, 1 H), 1.42 (s, 9 H), 1.27 (m, 1 H), 0.93 (m, 6 H); ESI MS m/z=626 [C35H42F3N3O4+H]+. washed with 5% aqueous solution of LiCl (3×100 mL), 1 N HCl (1×100 mL), saturated aqueous NaHCO3 (2×100 mL), brine dried over anhydrous Na2SO4 filtered concentrated to yield an pale yellow oil This residue was further purified by column chromatography (silica gel, 3:1 Hexanes/EtOAc)