(2R)-2-amino-3-phenylpropanamide

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

Procedure: A solution of 3,5-dichloropyrazine-2-carbonitrile (86 mg, 0.494 mmol), D-phenylalaninamide (81 mg, 0.494 mmol) and DIEA (0.130 mL, 0.747 mmol) in DMF (2 mL) was stirred at room temperature for 20 h. Water and EtOAc were added. Organic phase was separated, washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-3-phenylpropanamide (128 mg) as an oil. Organic phase was separated washed with 1N HCl with 5% NaHCO3, dried over Na2SO4 concentrated in vacuo

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

Procedure: To a solution of D-Phenylalaninamide (1.83 g, 11.1 mmol) in acetonitrile (20 mL) was added 1,3-propane sultone (1.29 g, 10.6 mmol). The solution was stirred at reflux for 2.5 hours. The reaction mixture was cooled to room temperature. The solid was filtered and washed with acetonitrile (2×20 mL). The solid product was suspended in EtOH (75 mL). The suspension was stirred at reflux for 1 hours. The solid material was filtered, washed with acetone (1×25 mL) and dried in vacuo, affording the title compound (2.62 g, 89%). 1H NMR (D2O, 500 MHz) δ ppm 7.28 (m, 3H), 7.19 (m, 2H), 4.05 (m, 1H), 3.19 (dd, 1H, J=5.3 Hz, 14.2 Hz), 3.04 (m, 3H), 2.86 (t, 2H, J=5.8 Hz), 2.03 (m, 2H). 13C (D2O, 125 MHz) δ ppm 170.39, 133.73, 129.62, 129.26, 128.15, 61.57, 47.99, 45.57, 36.21, 21.45. [α]D=−20.7° (c=0.0038 in water), ES-MS 285 (M−1). at reflux for 2.5 hours The solid was filtered washed with acetonitrile (2×20 mL) The suspension was stirred at reflux for 1 hours The solid material was filtered washed with acetone (1×25 mL) dried in vacuo

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

Procedure: In accordance with the process described in JP Patent Application Laying Open (Kokai) No. 62-55097, Enterobacter cloacae N-7901 (FERM BP-873) was cultured. This culture solution, 500 mL, was centrifuged, and the wet cells were then suspended in distilled water to prepare a 1,140 g cell suspension. D, L-phenylalanine amide, 60 g, was dissolved in this suspension, and the mixture was then allowed to react at 40° C. for 24 hours. After the reaction, cells were removed by centrifugation and 1,150 g of an aqueous solution containing 2.5% by mass each of L-phenylalanine and D-phenylalanine amide was obtained. to prepare a 1,140 g cell suspension to react at 40° C. for 24 hours After the reaction, cells were removed by centrifugation and 1,150 g of an aqueous solution containing 2.5% by mass each of L-phenylalanine

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

Procedure: A solution of 3,5-dichloropyrazine-2-carbonitrile (86 mg, 0.494 mmol), D-phenylalaninamide (81 mg, 0.494 mmol) and DIEA (0.130 mL, 0.747 mmol) in DMF (2 mL) was stirred at room temperature for 20 h. Water and EtOAc were added. Organic phase was separated, washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-3-phenylpropanamide (128 mg) as an oil. Organic phase was separated washed with 1N HCl with 5% NaHCO3, dried over Na2SO4 concentrated in vacuo

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

Procedure: A solution of 3,5-dichloropyrazine-2-carbonitrile (86 mg, 0.494 mmol), D-phenylalaninamide (81 mg, 0.494 mmol) and DIEA (0.130 mL, 0.747 mmol) in DMF (2 mL) was stirred at room temperature for 20 h. Water and EtOAc were added. Organic phase was separated, washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-3-phenylpropanamide (128 mg) as an oil. Organic phase was separated washed with 1N HCl with 5% NaHCO3, dried over Na2SO4 concentrated in vacuo

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

Procedure: To a solution of D-Phenylalaninamide (1.83 g, 11.1 mmol) in acetonitrile (20 mL) was added 1,3-propane sultone (1.29 g, 10.6 mmol). The solution was stirred at reflux for 2.5 hours. The reaction mixture was cooled to room temperature. The solid was filtered and washed with acetonitrile (2×20 mL). The solid product was suspended in EtOH (75 mL). The suspension was stirred at reflux for 1 hours. The solid material was filtered, washed with acetone (1×25 mL) and dried in vacuo, affording the title compound (2.62 g, 89%). 1H NMR (D2O, 500 MHz) δ ppm 7.28 (m, 3H), 7.19 (m, 2H), 4.05 (m, 1H), 3.19 (dd, 1H, J=5.3 Hz, 14.2 Hz), 3.04 (m, 3H), 2.86 (t, 2H, J=5.8 Hz), 2.03 (m, 2H). 13C (D2O, 125 MHz) δ ppm 170.39, 133.73, 129.62, 129.26, 128.15, 61.57, 47.99, 45.57, 36.21, 21.45. [α]D=−20.7° (c=0.0038 in water), ES-MS 285 (M−1). at reflux for 2.5 hours The solid was filtered washed with acetonitrile (2×20 mL) The suspension was stirred at reflux for 1 hours The solid material was filtered washed with acetone (1×25 mL) dried in vacuo

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

Procedure: A solution of 2-bromo-4,5-difluorobenzonitrile (218 mg, 1.00 mmol), D-phenylalanine amide (185 mg, 1.12 mmol) and DIEA (0.600 mL, 3.45 mmol) in DMSO (3 mL) was stirred at 120 C for 18 h. Water and EtOAc were added. The organic phase was separated, washed with water, dried over Na2SO4, concentrated in vacuo to give (R)-2-(5-bromo-4-cyano-2-fluorophenylamino)-3-phenylpropanamide (362 mg). The organic phase was separated washed with water dried over Na2SO4 concentrated in vacuo

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

Procedure: A mixture of (R)-benzyl 1-amino-1-oxo-3-phenylpropan-2-ylcarbamate (910 mg, 3.05 mmol) and Pd—C (10%, 200 mg) in MeOH (20 mL) was hydrogenated under balloon H2 for 16 h. It was filtered through celite. The filtrate was concentrated in vacuo to give D-phenylalanine amide as a white solid (493 mg). It was filtered through celite The filtrate was concentrated in vacuo

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

Procedure: A solution of 2-bromo-4-fluorobenzonitrile (255 mg, 1.27 mmol), D-phenylalanine amide (220 mg, 1.34 mmol) and DIEA (0.466 mL, 2.68 mmol) in DMSO (3 mL) was stirred at 100 C for 18 h. The mixture was then purified by HPLC to give (R)-2-(3-bromo-4-cyanophenylamino)-3-phenylpropanamide (102 mg). The mixture was then purified by HPLC

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

Procedure: A solution of 3,5-dichloropyrazine-2-carbonitrile (86 mg, 0.494 mmol), D-phenylalaninamide (81 mg, 0.494 mmol) and DIEA (0.130 mL, 0.747 mmol) in DMF (2 mL) was stirred at room temperature for 20 h. Water and EtOAc were added. Organic phase was separated, washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-3-phenylpropanamide (128 mg) as an oil. Organic phase was separated washed with 1N HCl with 5% NaHCO3, dried over Na2SO4 concentrated in vacuo

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

Procedure: A solution of 2-bromo-4,5-difluorobenzonitrile (218 mg, 1.00 mmol), D-phenylalanine amide (185 mg, 1.12 mmol) and DIEA (0.600 mL, 3.45 mmol) in DMSO (3 mL) was stirred at 120 C for 18 h. Water and EtOAc were added. The organic phase was separated, washed with water, dried over Na2SO4, concentrated in vacuo to give (R)-2-(5-bromo-4-cyano-2-fluorophenylamino)-3-phenylpropanamide (362 mg). The organic phase was separated washed with water dried over Na2SO4 concentrated in vacuo

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

Procedure: A solution of 2-bromo-4-fluorobenzonitrile (255 mg, 1.27 mmol), D-phenylalanine amide (220 mg, 1.34 mmol) and DIEA (0.466 mL, 2.68 mmol) in DMSO (3 mL) was stirred at 100 C for 18 h. The mixture was then purified by HPLC to give (R)-2-(3-bromo-4-cyanophenylamino)-3-phenylpropanamide (102 mg). The mixture was then purified by HPLC