Carbon Dioxide → (6R)-2-(3-(tert-butylamino)-2-methyl-5-quinoxalinyl)-6-methyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one

HRID 1056193Notes

Reaction equation

HRID 1056193 reaction equation
Cl.[NH2:2][CH:3]([C:5]1[NH:6][C:7]([C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[N:15]=[C:16]([NH:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:17]([CH3:23])=[N:18]3)=[CH:8][C:9]=1[C:10]([OH:12])=O)[CH3:4].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.N1(P(=O)(N2CCCC2)N2CCCC2)CCCC1.C(=O)=O>CN(C=O)C.C(Cl)Cl.CO>[C:25]([NH:24][C:16]1[C:17]([CH3:23])=[N:18][C:19]2[C:14]([N:15]=1)=[C:13]([C:7]1[NH:6][C:5]3[C@@H:3]([CH3:4])[NH:2][C:10](=[O:12])[C:9]=3[CH:8]=1)[CH:22]=[CH:21][CH:20]=2)([CH3:27])([CH3:28])[CH3:26]

Participants

9

Reactant 5

HCID 280Carbon DioxideHCID 808661,1',1''-Phosphinylidynetris(pyrrolidine)HCID 81531DiisopropylethylamineHCID 2724699PyBOPHCID 89783230HCID 89783230, compound

Product 1

HCID 71730241(6R)-2-(3-(tert-butylamino)-2-methyl-5-quinoxalinyl)-6-methyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-oneYield 25%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×

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)+.

Workup

  1. washwashed sequentially with 15 mL of water, 2×10 mL of 1 N NaOH, and 10 mL of brine
  2. concentrationThe organic solution was concentrated
  3. customthe residue was purified on a silica gel column (
  4. washeluted with a gradient of 1-5% MeOH in DCM)
  5. customto provide a brown amorphous solid
  6. customThe individual enantiomers of Example 326d were obtained by chiral SFC (Column
  7. custom40° C.
  8. customWavelength: 278 nm) to give Example 326 (first eluting product) and Example 327 (second eluting product)

Sources & evidence

ORD record
ord-1ab5e651c4ed4f8c97559fbaa4d10acf
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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