Diisopropylethylamine → HCID 78152116, compound

HRID 1056202Notes

Reaction equation

HRID 1056202 reaction equation
[NH2:1][CH:2]([C:4]1[NH:5][C:6]([C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[N:14]=[C:15]([NH:23][C:24]2([CH3:27])[CH2:26][CH2:25]2)[C:16]([CH3:22])=[N:17]3)=[CH:7][C:8]=1[C:9]([OH:11])=O)[CH3:3].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C([O-])(O)=O.[Na+]>CN(C=O)C.C(Cl)Cl>[CH3:3][CH:2]1[C:4]2[NH:5][C:6]([C:12]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:13]=3[N:14]=[C:15]([NH:23][C:24]3([CH3:27])[CH2:25][CH2:26]3)[C:16]([CH3:22])=[N:17]4)=[CH:7][C:8]=2[C:9](=[O:11])[NH:1]1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 2724699PyBOPHCID 89783805HCID 89783805, compound

Product 1

HCID 78152116HCID 78152116, compound

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °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

  1. customwas used in the next step without further purification
  2. additionpoured
  3. extractionextracted with EtOAc (3×200 mL)
  4. washThe combined extracts were washed with water (3×200 mL), and brine (100 mL)
  5. dry with materialdried (Na2SO4)
  6. concentrationconcentrated onto silica
  7. customPurification by silica gel chromatography (0-4% MeOH in CH2Cl2)

Sources & evidence

ORD record
ord-2e73e13155a143cf8d48489a1f6deee6
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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