1-dipyrrolidin-1-ylphosphorylpyrrolidine

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

Procedure: To a mixture of 2-(1-aminoethyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (326c) (⅔ of the crude material from previous step, estimated to be 9.4 mmol) in 30 mL of DMF and 25 mL of DCM at 0° C. was added DIEA (0.98 mL, 56.4 mmol) and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (Sigma-Aldrich Chemical Company, Inc.) (6.11 g, 11.75 mmol). The resulting homogeneous solution was stirred at RT for 8 h. It was diluted with 300 mL of DCM, washed sequentially with 15 mL of water, 2×10 mL of 1 N NaOH, and 10 mL of brine. The organic solution was concentrated and the residue was purified on a silica gel column (eluted with a gradient of 1-5% MeOH in DCM) to provide a brown amorphous solid containing 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6-methyl-5,6-dihydropyrrolo[3,4-b]pyrrolo-4(1H)-one (326d), m/z (ESI, +ve) 350.0 (M+H)+; and a significant amount of undesired side product, tri(pyrrolidin-1-yl)phosphine oxide, m/z (ESI, +ve) 258.0 (M+H)+. The individual enantiomers of Example 326d were obtained by chiral SFC (Column: Chiralcel OJH (250×20 mm, 5μ); Mobile Phase: 85:15 (A:B); A: Liquid CO2; B: MeOH (20 mM NH3); Flow Rate: 70 mL/min; Oven Temp: 40° C.; Inlet Pressure: 100 bar; Wavelength: 278 nm) to give Example 326 (first eluting product) and Example 327 (second eluting product). Example 326: (6R)-2-(3-(tert-butylamino)-2-methyl-5-quinoxalinyl)-6-methyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (810 mg, 25% yield, >99% ee) as a yellow crystalline solid was obtained. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.00 (1H, br.), 7.83 (1H, dd, J=7.4, 1.2 Hz), 7.64 (2H, m), 7.37 (1H, t, J=7.7 Hz), 6.85 (1H, d, J=1.4 Hz), 6.02 (1H, s), 4.57 (1H, q, J=6.6 Hz), 2.58 (3H, s), 1.56 (9H, s), 1.40 (3H, d, J=6.7 Hz). m/z (ESI, +ve) 350.0 (M+H)+. Example 327: (65)-2-(3-(tert-butylamino)-2-methyl-5-quinoxalinyl)-6-methyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (85 mg, 2.6% yield, >99% ee) as a brown crystalline solid was obtained. m/z (ESI, +ve) 350.0 (M+H)+. washed sequentially with 15 mL of water, 2×10 mL of 1 N NaOH, and 10 mL of brine The organic solution was concentrated the residue was purified on a silica gel column ( eluted with a gradient of 1-5% MeOH in DCM) to provide a brown amorphous solid The individual enantiomers of Example 326d were obtained by chiral SFC (Column 40° C. Wavelength: 278 nm) to give Example 326 (first eluting product) and Example 327 (second eluting product)

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

Procedure: To a mixture of 2-(1-aminoethyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (326c) (⅔ of the crude material from previous step, estimated to be 9.4 mmol) in 30 mL of DMF and 25 mL of DCM at 0° C. was added DIEA (0.98 mL, 56.4 mmol) and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (Sigma-Aldrich Chemical Company, Inc.) (6.11 g, 11.75 mmol). The resulting homogeneous solution was stirred at RT for 8 h. It was diluted with 300 mL of DCM, washed sequentially with 15 mL of water, 2×10 mL of 1 N NaOH, and 10 mL of brine. The organic solution was concentrated and the residue was purified on a silica gel column (eluted with a gradient of 1-5% MeOH in DCM) to provide a brown amorphous solid containing 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6-methyl-5,6-dihydropyrrolo[3,4-b]pyrrolo-4(1H)-one (326d), m/z (ESI, +ve) 350.0 (M+H)+; and a significant amount of undesired side product, tri(pyrrolidin-1-yl)phosphine oxide, m/z (ESI, +ve) 258.0 (M+H)+. The individual enantiomers of Example 326d were obtained by chiral SFC (Column: Chiralcel OJH (250×20 mm, 5μ); Mobile Phase: 85:15 (A:B); A: Liquid CO2; B: MeOH (20 mM NH3); Flow Rate: 70 mL/min; Oven Temp: 40° C.; Inlet Pressure: 100 bar; Wavelength: 278 nm) to give Example 326 (first eluting product) and Example 327 (second eluting product). Example 326: (6R)-2-(3-(tert-butylamino)-2-methyl-5-quinoxalinyl)-6-methyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (810 mg, 25% yield, >99% ee) as a yellow crystalline solid was obtained. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.00 (1H, br.), 7.83 (1H, dd, J=7.4, 1.2 Hz), 7.64 (2H, m), 7.37 (1H, t, J=7.7 Hz), 6.85 (1H, d, J=1.4 Hz), 6.02 (1H, s), 4.57 (1H, q, J=6.6 Hz), 2.58 (3H, s), 1.56 (9H, s), 1.40 (3H, d, J=6.7 Hz). m/z (ESI, +ve) 350.0 (M+H)+. Example 327: (65)-2-(3-(tert-butylamino)-2-methyl-5-quinoxalinyl)-6-methyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (85 mg, 2.6% yield, >99% ee) as a brown crystalline solid was obtained. m/z (ESI, +ve) 350.0 (M+H)+. washed sequentially with 15 mL of water, 2×10 mL of 1 N NaOH, and 10 mL of brine The organic solution was concentrated the residue was purified on a silica gel column ( eluted with a gradient of 1-5% MeOH in DCM) to provide a brown amorphous solid The individual enantiomers of Example 326d were obtained by chiral SFC (Column 40° C. Wavelength: 278 nm) to give Example 326 (first eluting product) and Example 327 (second eluting product)

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

Procedure: To a mixture of 2-(1-aminoethyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (326c) (⅔ of the crude material from previous step, estimated to be 9.4 mmol) in 30 mL of DMF and 25 mL of DCM at 0° C. was added DIEA (0.98 mL, 56.4 mmol) and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (Sigma-Aldrich Chemical Company, Inc.) (6.11 g, 11.75 mmol). The resulting homogeneous solution was stirred at RT for 8 h. It was diluted with 300 mL of DCM, washed sequentially with 15 mL of water, 2×10 mL of 1 N NaOH, and 10 mL of brine. The organic solution was concentrated and the residue was purified on a silica gel column (eluted with a gradient of 1-5% MeOH in DCM) to provide a brown amorphous solid containing 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6-methyl-5,6-dihydropyrrolo[3,4-b]pyrrolo-4(1H)-one (326d), m/z (ESI, +ve) 350.0 (M+H)+; and a significant amount of undesired side product, tri(pyrrolidin-1-yl)phosphine oxide, m/z (ESI, +ve) 258.0 (M+H)+. The individual enantiomers of Example 326d were obtained by chiral SFC (Column: Chiralcel OJH (250×20 mm, 5μ); Mobile Phase: 85:15 (A:B); A: Liquid CO2; B: MeOH (20 mM NH3); Flow Rate: 70 mL/min; Oven Temp: 40° C.; Inlet Pressure: 100 bar; Wavelength: 278 nm) to give Example 326 (first eluting product) and Example 327 (second eluting product). Example 326: (6R)-2-(3-(tert-butylamino)-2-methyl-5-quinoxalinyl)-6-methyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (810 mg, 25% yield, >99% ee) as a yellow crystalline solid was obtained. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.00 (1H, br.), 7.83 (1H, dd, J=7.4, 1.2 Hz), 7.64 (2H, m), 7.37 (1H, t, J=7.7 Hz), 6.85 (1H, d, J=1.4 Hz), 6.02 (1H, s), 4.57 (1H, q, J=6.6 Hz), 2.58 (3H, s), 1.56 (9H, s), 1.40 (3H, d, J=6.7 Hz). m/z (ESI, +ve) 350.0 (M+H)+. Example 327: (65)-2-(3-(tert-butylamino)-2-methyl-5-quinoxalinyl)-6-methyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (85 mg, 2.6% yield, >99% ee) as a brown crystalline solid was obtained. m/z (ESI, +ve) 350.0 (M+H)+. washed sequentially with 15 mL of water, 2×10 mL of 1 N NaOH, and 10 mL of brine The organic solution was concentrated the residue was purified on a silica gel column ( eluted with a gradient of 1-5% MeOH in DCM) to provide a brown amorphous solid The individual enantiomers of Example 326d were obtained by chiral SFC (Column 40° C. Wavelength: 278 nm) to give Example 326 (first eluting product) and Example 327 (second eluting product)