HCID 86613210, compound → HCID 86613209, compound

Participants

Reaction Steps

Coupling In a 100-mL flask acrylic acid (0.17 g, 2.4 mmol), N-benzyl-1-(2-trans-methylcyclopropyl)methanamine (0.5 g, 2.4 mmol) and DIPEA (0.64 g, 4.9 mmol) were dissolved in 20 mL of dichloromethane. To this solution at room temperature EDC (0.68 g, 3.5 mmol) was added as a solid portionwise and stirred 15 hours. The reaction was partitioned between 1M HCl and methylene chloride. The organics were dried over sodium sulfate, filtered, concentrated in vacuo and carried into next reaction crude. Step B: Michael Addition. In a 50-mL flask acrylamide (crude from step A) in methanol (10 mL) was treated with dimethylamine (4.5 mmol, 2.2 mL of a 2M solution in methanol). The reaction was stirred for 1 hour at ambient temperature then concentrated in vacuo. The residue was purified by flash column chromatography (2.5-15% MeOH/methylene chloride) to provide N1-benzyl-N3,N3-dimethyl-N1-[(2-methylcyclopropyl)-methyl]-β-alaninamide as a clear oil: 1H NMR (400 MHz, CDCl3) δ 7.24 (m, 5H), 4.68 (m, 2H), 3.21 (m, 2H), 2.67 (m, 4H), 2.34 (s, 3H), 2.24 (s, 3H), 0.97 (m, 3H), 0.58 (m, 2H), 0.29 m, 2H). LCMS [M+H]+=275.4. Step C: Reduction In a round-bottom flask N1-benzyl-N3,N3-dimethyl-N1-[(2-methylcyclopropyl)-methyl]-β-alaninamide (0.47 g, 1.7 mmol) was dissolved in 10 mL anhydrous THF. To this solution was added BH3-THF (5.1 mmol, 5.1 mL of a 1M solution in THF). The reaction was equipped with a reflux condenser and heated to reflux for 16 hours. The reaction was cooled to 0° C. and quenched with methanol followed by concentrated HCl (5 mL). The resulting mixture was heated to reflux for 16 hours. The crude mixture was then concentrated in vacuo and partitioned between 10% NaOH/ethyl acetate. The organics were dried over sodium sulfate, filtered and evaporated in vacuo. Purification by reverse phase chromatography gave N1-benzyl-N3,N3-dimethyl-N1-[(2-methylcyclopropyl)methyl]propane-1,3-diaminium bis(trifluoroacetate) as a clear oil: LCMS [M+H]+=261.5. Step D: Hydrogenation A solution of N1-benzyl-N3,N3-dimethyl-N1-[(2-methylcyclopropyl)methyl]propane-1,3-diaminium bis(trifluoroacetate) (0.42 g, 0.86 mmol) in ethanol (50 mL) was degassed with nitrogen and treated with palladium hydroxide (75 mg). The reaction was placed under a hydrogen atmosphere and stirred vigorously for 1 hour. The reaction was filtered through celite, washed with methanol and concentrated in vacuo to give N,N-dimethyl-N′-[(2-methylcyclopropyl)methyl]propane-1,3-diaminium bis(trifluoroacetate) as a pale yellow oil.

Provenance & Evidence