methyl 2-[(2R)-3-oxo-2,4-dihydro-1H-quinoxalin-2-yl]acetate

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

Procedure: A mixture of 2-(R)-(2-nitrophenylamino)succinic acid dimethyl ester (2.15 g, 7.62 mmol) (prepared below), and PtO2 (210 mg) in methanol (35 mL) was shaken on a Parr apparatus at 48 psi for 6 hours. The reaction was filtered through celite, rinsed with methanol and was evaporated in vacuo to a very sticky oil as the title compound (1.69 g, 100%): 1H NMR (CDCl3) δ=8.23 (bs, 1H), 6.91 (dt, 1H, J=1.8, 7.5 Hz), 6.80–6.70 (m, 3H), 4.74 (bs, 1H), 4.34 (dt, 1H, J=2.4, 10.5 Hz), 3.75 (s, 3H), 3.14 (dd, 1H, J=2.4, 17.4 Hz), 2.75 (dd, 1H, J=10.5, 17.4 Hz). The reaction was filtered through celite rinsed with methanol was evaporated in vacuo to a very sticky oil as the title compound (1.69 g, 100%)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl [(2R)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]acetate (Example 1, Step 2, 650 mg, 2.95 mmol) in DMF (5 mL) at 0° C. was added NaH (142 mg, 3.54 mmol). After stirring at 0° C. for 20 minutes, MeI (220 uL, 3.54 mmol) was added and the reaction mixture was stirred for an additional 15 minutes at 0° C. The reaction mixture was then diluted with water (10 mL) and extracted with EtOAc (2×50 mL). Combined organics were washed with water (1×50 mL), dried over sodium sulfate, filtered, and concentrated to give methyl [(2R)-4-methyl-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]acetate, which was used without further purification. LCMS (ES) 235.1 m/z (M+H)+. the reaction mixture was stirred for an additional 15 minutes at 0° C extracted with EtOAc (2×50 mL) Combined organics were washed with water (1×50 mL) dried over sodium sulfate filtered concentrated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl [(2R)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]acetate (Example 1, Step 2, 650 mg, 2.95 mmol) in DMF (5 mL) at 0° C. was added NaH (142 mg, 3.54 mmol). After stirring at 0° C. for 20 minutes, MeI (220 uL, 3.54 mmol) was added and the reaction mixture was stirred for an additional 15 minutes at 0° C. The reaction mixture was then diluted with water (10 mL) and extracted with EtOAc (2×50 mL). Combined organics were washed with water (1×50 mL), dried over sodium sulfate, filtered, and concentrated to give methyl [(2R)-4-methyl-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]acetate, which was used without further purification. LCMS (ES) 235.1 m/z (M+H)+. the reaction mixture was stirred for an additional 15 minutes at 0° C extracted with EtOAc (2×50 mL) Combined organics were washed with water (1×50 mL) dried over sodium sulfate filtered concentrated

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

Procedure: To a solution of methyl [(2R)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]acetate (Example 1, Step 2, 299 mg, 1.36 mmol) in DMF (5 mL), Cs2CO3 (885 mg, 2.72 mmol) and then (bromomethyl)benzene (0.48 mL, 4.07 mmol) were added. After overnight stirring, the crude reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with EtOAc (3×50 mL). The combined organics were then washed with water (2×50 mL) and brine (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was subjected to silica gel chromatography eluting with 15%-25% EtOAc in Hexanes to give 131 mg (31%) methyl [(2R)-1-benzyl-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]acetate. LCMS (ES) 311.3 m/z (M+H)+. the crude reaction mixture extracted with EtOAc (3×50 mL) The combined organics were then washed with water (2×50 mL) and brine (1×50 mL) dried over sodium sulfate filtered concentrated in vacuo eluting with 15%-25% EtOAc in Hexanes

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

Procedure: A mixture of 2-(R)-(2-nitrophenylamino)succinic acid dimethyl ester (2.15 g, 7.62 mmol) (prepared below), and PtO2 (210 mg) in methanol (35 mL) was shaken on a Parr apparatus at 48 psi for 6 hours. The reaction was filtered through celite, rinsed with methanol and was evaporated in vacuo to a very sticky oil as the title compound (1.69 g, 100%): 1H NMR (CDCl3) δ=8.23 (bs, 1H), 6.91 (dt, 1H, J=1.8, 7.5 Hz), 6.80–6.70 (m, 3H), 4.74 (bs, 1H), 4.34 (dt, 1H, J=2.4, 10.5 Hz), 3.75 (s, 3H), 3.14 (dd, 1H, J=2.4, 17.4 Hz), 2.75 (dd, 1H, J=10.5, 17.4 Hz). The reaction was filtered through celite rinsed with methanol was evaporated in vacuo to a very sticky oil as the title compound (1.69 g, 100%)

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

Procedure: A mixture of 2-(R)-(2-nitrophenylamino)succinic acid dimethyl ester (2.15 g, 7.62 mmol) (prepared below), and PtO2 (210 mg) in methanol (35 mL) was shaken on a Parr apparatus at 48 psi for 6 hours. The reaction was filtered through celite, rinsed with methanol and was evaporated in vacuo to a very sticky oil as the title compound (1.69 g, 100%): 1H NMR (CDCl3) δ=8.23 (bs, 1H), 6.91 (dt, 1H, J=1.8, 7.5 Hz), 6.80-6.70 (m, 3H), 4.74 (bs, 1H), 4.34 (dt, 1H, J=2.4, 10.5 Hz), 3.75 (s, 3H), 3.14 (dd, 1H, J=2.4, 17.4 Hz), 2.75 (dd, 1H, J=10.5, 17.4 Hz). The reaction was filtered through celite rinsed with methanol was evaporated in vacuo to a very sticky oil as the title compound (1.69 g, 100%)

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

Procedure: A mixture of 2-(R)-(2-nitrophenylamino)succinic acid dimethyl ester (2.15 g, 7.62 mmol) (prepared above), and PtO2 (210 mg) in methanol (35 mL) was shaken on a Parr apparatus at 48 psi for 6 hours. The reaction was filtered through celite, rinsed with methanol and was evaporated in vacuo to a very sticky oil as the title compound (1.69 g, 100%): 1H NMR (CDCl3) δ=8.23 (bs, 1H), 6.91 (dt, 1H, J=1.8, 7.5 Hz), 6.80–6.70 (m, 3H), 4.74 (bs, 1H), 4.34 (dt, 1H, J2.4, 10.5 Hz), 3.75 (s, 3H), 3.14 (dd, 1H, J=2.4, 17.4 Hz), 2.75 (dd, 1H, J=10.5, 17.4 Hz). The reaction was filtered through celite rinsed with methanol was evaporated in vacuo to a very sticky oil as the title compound (1.69 g, 100%)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl [(2R)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]acetate (Example 1, Step 2, 650 mg, 2.95 mmol) in DMF (5 mL) at 0° C. was added NaH (142 mg, 3.54 mmol). After stirring at 0° C. for 20 minutes, MeI (220 uL, 3.54 mmol) was added and the reaction mixture was stirred for an additional 15 minutes at 0° C. The reaction mixture was then diluted with water (10 mL) and extracted with EtOAc (2×50 mL). Combined organics were washed with water (1×50 mL), dried over sodium sulfate, filtered, and concentrated to give methyl [(2R)-4-methyl-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]acetate, which was used without further purification. LCMS (ES) 235.1 m/z (M+H)+. the reaction mixture was stirred for an additional 15 minutes at 0° C extracted with EtOAc (2×50 mL) Combined organics were washed with water (1×50 mL) dried over sodium sulfate filtered concentrated

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

Procedure: To a solution of methyl [(2R)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]acetate (Example 1, Step 2, 299 mg, 1.36 mmol) in DMF (5 mL), Cs2CO3 (885 mg, 2.72 mmol) and then (bromomethyl)benzene (0.48 mL, 4.07 mmol) were added. After overnight stirring, the crude reaction mixture was poured into saturated NaHCO3 (50 mL) and extracted with EtOAc (3×50 mL). The combined organics were then washed with water (2×50 mL) and brine (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was subjected to silica gel chromatography eluting with 15%-25% EtOAc in Hexanes to give 131 mg (31%) methyl [(2R)-1-benzyl-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]acetate. LCMS (ES) 311.3 m/z (M+H)+. the crude reaction mixture extracted with EtOAc (3×50 mL) The combined organics were then washed with water (2×50 mL) and brine (1×50 mL) dried over sodium sulfate filtered concentrated in vacuo eluting with 15%-25% EtOAc in Hexanes

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

Procedure: A mixture of 2-(R)-(2-nitrophenylamino)succinic acid dimethyl ester (2.15 g, 7.62 mmol) (prepared below), and PtO2 (210 mg) in methanol (35 mL) was shaken on a Parr apparatus at 48 psi for 6 hours. The reaction was filtered through celite, rinsed with methanol and was evaporated in vacuo to a very sticky oil as the title compound (1.69 g, 100%): 1H NMR (CDCl3) δ=8.23 (bs, 1H), 6.91 (dt, 1H, J=1.8, 7.5 Hz), 6.80–6.70 (m, 3H), 4.74 (bs, 1H), 4.34 (dt, 1H, J=2.4, 10.5 Hz), 3.75 (s, 3H), 3.14 (dd, 1H, J=2.4, 17.4 Hz), 2.75 (dd, 1H, J=10.5, 17.4 Hz). The reaction was filtered through celite rinsed with methanol was evaporated in vacuo to a very sticky oil as the title compound (1.69 g, 100%)