Lithium Hydroxide → HCID 89783565, compound

HRID 1056201Notes

Reaction equation

[C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]1[NH:12][C:13]([C:21]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:22]=2[N:23]=[C:24]([NH:32][C:33]2([CH3:36])[CH2:35][CH2:34]2)[C:25]([CH3:31])=[N:26]3)=[CH:14][C:15]=1[C:16]([O:18]CC)=[O:17])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCOCC1.[Li+].[OH-]>O>[C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[NH:12][C:13]([C:21]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:22]=2[N:23]=[C:24]([NH:32][C:33]2([CH3:36])[CH2:34][CH2:35]2)[C:25]([CH3:31])=[N:26]3)=[CH:14][C:15]=1[C:16]([OH:18])=[O:17])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]

Participants

Conditions

Temperature: 110 °C

Procedure

To a 250 mL round bottomed flask was added ethyl 2-((1S)-1-((tert-butoxycarbonyl)amino)ethyl)-5-(2-methyl-3-((1-methylcyclopropyl)amino)-5-quinoxalinyl)-1H-pyrrole-3-carboxylate (333a) (6.96 g, 14.1 mmol), dioxane (40 mL), water (40 mL) and LiOH (1.69 g, 70.5 mmol). The mixture was stirred and heated at 110° C. for 19 h. The solution was cooled to RT and then concentrated on the rotovap to afford 2-(1-((tert-butoxycarbonyl)amino)ethyl)-5-(2-methyl-3-((1-methylcyclopropyl)amino)-5-quinoxalinyl)-1H-pyrrole-3-carboxylic acid a tan solid which was used in the next step without further purification. m/z (ESI, +ve) 466.2 (M+H)+. The resulting material was treated with 1,4-dioxane (30 mL) and hydrogen chloride (4 M in 1,4-dioxane, 80 mL, 320 mmol) (Sigma-Aldrich). The solution was stirred at rt for 30 min and then concentrated on the rotovap to afford 2-(1-aminoethyl)-5-(2-methyl-3-((1-methylcyclopropyl)amino)-5-quinoxalinyl)-1H-pyrrole-3-carboxylic acid (333b) which was used in the next step without further purification. m/z (ESI, +ve) 349.1 (M−NH2)+. To the 2-(1-aminoethyl)-5-(2-methyl-3-((1-methylcyclopropyl)amino)-5-quinoxalinyl)-1H-pyrrole-3-carboxylic acid (333b) in a 250 mL round-bottomed flask was added DCM (40 mL), DMF (40 mL), and DIEA (7.80 mL, 44.9 mmol). The mixture was cooled to 0° C. and benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBop, 8.56 g, 16.5 mmol) (Matrix Innovation) was added. The solution was stirred at 0° C. for 40 min and then poured into sat NaHCO3 (200 mL) and extracted with EtOAc (3×200 mL). The combined extracts were washed with water (3×200 mL), and brine (100 mL) and then dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (0-4% MeOH in CH2Cl2) afforded 6-methyl-2-(2-methyl-3-((1-methylcyclopropyl)amino)-5-quinoxalinyl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (333c) as a yellow solid. m/z (ESI, +ve) 348.0 (M+H)+. The yellow solid (333c) was subjected to chiral preparative SFC purification (Column: Chiral Technologies, Inc., Chiralpak, AD-H (5 μm, 21 mm×25 cm). Eluent: 70% carbon dioxide and 30% organic modifier (MeOH with 20 mM NH3). Flow=60 mL/min, temperature=40° C., pressure=100 bar, detection wavelength=278 nm. Sample was dissolved in 45 mL DCM/MeOH (1:1), 0.8 mL per injection). Two peaks were collected: Peak 1: ee of peak 1 >99.5%, Peak 2: ee of peak 2 >99.5%. Peak 1 was concentrated to afford (6R)-6-methyl-2-(2-methyl-3-((1-methylcyclopropyl)amino)-5-quinoxalinyl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (333) (1.26 g, 3.63 mmol, 24% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.04 (s, 1H), 8.03 (dd, J=7.6, 1.2 Hz, 1H), 7.73 (br s, 2H), 7.59 (dd, J=8.0, 1.2 Hz, 1H), 7.35 (t, J=7.8 Hz, 1H), 7.05 (d, J=1.2 Hz, 1H), 4.66 (q, J=6.5 Hz, 1H), 2.49 (s, 3H) 1.54 (s, 3H), 1.38 (d, J=6.7 Hz, 3H), 0.92-1.02 (m, 2H), 0.84-0.92 (m, 2H). m/z (ESI, +ve) 348.0 (M+H)+. Peak 2 was concentrated to afford (6R)-6-methyl-2-(2-methyl-3((1-methylcyclopropyl)amino)-5-quinoxalinyl)-5,6-dihydropyrrolo[3,4-b]pyrrolo-4(1H)-one (328) (105 mg, 0.30 mmol, 2% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.04 (s, 1H), 8.03 (dd, J=7.6, 1.2 Hz, 1H), 7.73 (br s, 2H), 7.59 (dd, J=8.0, 1.2 Hz, 1H), 7.35 (t, J=7.8 Hz, 1H), 7.05 (d, J=1.2 Hz, 1H), 4.66 (q, J=6.5 Hz, 1H), 2.49 (s, 3H) 1.54 (s, 3H), 1.38 (d, J=6.7 Hz, 3H), 0.92-1.02 (m, 2H), 0.84-0.92 (m, 2H). m/z (ESI, +ve) 348.0 (M+H)+.

Workup

temperatureThe solution was cooled to RT
concentrationconcentrated on the rotovap

Sources & evidence

ORD record: ord-4e1860d8b80f4c3dae6a4aa8eefaa39e
Source dataset: uspto-grants-2016_07
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09394297B2

Reaction notes

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