Diisopropylethylamine → HCID 78162454, compound

HRID 1056147Notes

Reaction equation

HRID 1056147 reaction equation
F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.Cl.[NH2:35][CH:36]([C:38]1[NH:39][C:40]([C:46]2[CH:55]=[CH:54][CH:53]=[C:52]3[C:47]=2[N:48]=[C:49]([NH:57][CH2:58][C:59]([F:62])([F:61])[F:60])[C:50]([CH3:56])=[N:51]3)=[CH:41][C:42]=1[C:43](O)=[O:44])[CH3:37].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:37][CH:36]1[C:38]2[NH:39][C:40]([C:46]3[CH:55]=[CH:54][CH:53]=[C:52]4[C:47]=3[N:48]=[C:49]([NH:57][CH2:58][C:59]([F:60])([F:61])[F:62])[C:50]([CH3:56])=[N:51]4)=[CH:41][C:42]=2[C:43](=[O:44])[NH:35]1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 2724699PyBOPHCID 89783265HCID 89783265, compound

Product 1

HCID 78162454HCID 78162454, compoundYield 42.2%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) (AK Scientific, Inc., Union City, Calif.) (431 mg, 0.83 mmol) was added to a solution of 2-(1-aminoethyl)-5-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (293c) (274 mg, 0.64 mmol) and DIPEA (0.44 mL, 2.55 mmol) in CH2Cl2 (16 mL) and DMF (16 mL) at RT. After 30 min the reaction mixture was concentrated. The residue was diluted with EtOAc and washed sequentially with water, saturated NaHCO3 (aq.) and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by silica gel chromatography (0-5% MeOH in CH2Cl2), to provide rac-6-methyl-2-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (293d) (100 mg, 0.27 mmol, 42% yield) as a yellow solid. The mixture of enantiomers was subjected to chiral SFC (ChiralPak AS-H (21×250, 5 μm); additive in supercritical fluid CO2 was 25% MeOH with 20 mM NH3; 75 mL/min; column temperature 40° C.; outlet pressure 100 bar) to give separated enantiomers. Example 293 (first eluting peak): (S)-6-methyl-2-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (3 mg, 7.99 μmol, 1% yield, >99% ee) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.83-11.95 (m, 1H), 7.86-7.93 (m, 1H), 7.74 (t, J=6.26 Hz, 1H), 7.68 (dd, J=8.12, 1.47 Hz, 1H), 7.64 (d, J=0.39 Hz, 1H), 7.44 (t, J=7.82 Hz, 1H), 6.85-6.92 (m, 1H), 4.52-4.66 (m, 1H), 4.16-4.33 (m, 1H), 4.09 (q, J=5.15 Hz, 1H), 2.60 (s, 3H), 1.39 (d, J=6.65 Hz, 3H). 19F NMR (376 MHz, DMSO-d6) δ ppm −69.51 (s, 3F). m/z (ESI, +ve) 376.1 (M+H); and Example 294 (second eluting peak): (R)-6-methyl-2-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (44 mg, 0.12 mmol, 18% yield, >99% ee). m/z (ESI, +ve) 376.1 (M+H)+.

Workup

  1. concentrationAfter 30 min the reaction mixture was concentrated
  2. additionThe residue was diluted with EtOAc
  3. washwashed sequentially with water, saturated NaHCO3 (aq.) and brine
  4. dry with materialThe organic layer was dried over anhydrous Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe crude material was absorbed onto a plug of silica gel
  8. custompurified by silica gel chromatography (0-5% MeOH in CH2Cl2)

Sources & evidence

ORD record
ord-87ce27b0da164e8b97b47c301308461a
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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