Potassium Carbonate → Methyl 4-((tert-butoxycarbonyl)amino)-2-(2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-2-oxoethyl)-3-oxopentanoate

HRID 1056191Notes

Reaction equation

HRID 1056191 reaction equation
[C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:17])[C:10](=[O:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:19][C:20]([C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[N:24]=[C:25]([NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:26]([CH3:32])=[N:27]2)=[O:21].C([O-])([O-])=O.[K+].[K+]>C1COCC1.CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH3:17])[C:10](=[O:16])[CH:11]([CH2:19][C:20]([C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[N:24]=[C:25]([NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:26]([CH3:32])=[N:27]2)=[O:21])[C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:3])([CH3:4])[CH3:2]

Participants

7

Reactant 3

HCID 11430Potassium CarbonateHCID 14560628(R)-methyl 4-((tert-butoxycarbonyl)amino)-3-oxopentanoateHCID 897821422-Bromo-1-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)ethanone

Product 1

HCID 89782367Methyl 4-((tert-butoxycarbonyl)amino)-2-(2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-2-oxoethyl)-3-oxopentanoate

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

At RT, a solution of (R)-methyl 4-((tert-butoxycarbonyl)amino)-3-oxopentanoate (603) (5.38 g, 21.95 mmol) in 20 mL of THF and 20 mL of DMF was treated with 2-bromo-1-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)ethanone (606) (5.44 g, 16.18 mmol) and K2CO3 (5.59 g, 40.4 mmol) and stirred at RT for 6 h. It was diluted with 250 mL of EtOAc, filtered through a flitted funnel, rinsed with 2×15 mL of EtOAc. The filtrate was washed with sat NH4Cl (2×25 mL) followed by brine (15 mL). The organic solution was dried over Na2SO4 and concentrated. The residue was passed through a short column (35-75% EtOAc in hexanes) to get rid of the solvent front peaks and the base line peaks. Fractions with m/z (ESI, +ve) 501.2 (M+H)1 were collected and concentrated to give methyl 4-((tert-butoxycarbonyl)amino)-2-(2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-2-oxoethyl)-3-oxopentanoate (326a) as a brown residue. To the brown residue in a glass tube in 25 mL of EtOH and 10 mL of HOAc was added NH4OAc (8.46 g, 110 mmol). The tube was sealed and heated in an oil bath at 50° C. for 8 h. The mixture was concentrated to half of its volume, diluted with 250 mL of EtOAc, washed sequentially with 15 mL of water, 15 mL of 1 N NaOH and 5 mL of brine. The organic solution was concentrated and the residue was purified on a silica gel column (eluted with a gradient of 35-65% EtOAc in hexanes) to give methyl 2-(1-((tert-butoxycarbonyl)amino)ethyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (326b) (6.3 g, 71% yield) as a yellow amorphous. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.42 (1H, br.), 7.76 (1H, dd, J=7.4, 1.2 Hz), 7.63 (1H, dd, J=8.0, 1.2 Hz), 7.38 (2H, m), 7.03 (1H, d, J=7.8 Hz), 5.94 (1H, s), 5.44 (1H, m), 3.77 (3H, s), 2.56 (3H, s), 1.58 (9H, s), 1.40 (12H, m). m/z (ESI, +ve) 482.1 (M+H)+.

Workup

  1. filtrationfiltered through a flitted funnel
  2. washrinsed with 2×15 mL of EtOAc
  3. washThe filtrate was washed with sat NH4Cl (2×25 mL)
  4. dry with materialThe organic solution was dried over Na2SO4
  5. concentrationconcentrated
  6. customto get rid of the solvent front peaks
  7. customFractions with m/z (ESI, +ve) 501.2 (M+H)1 were collected
  8. concentrationconcentrated

Sources & evidence

ORD record
ord-ed1e64791b4f4378a5c31cfc8b11a1ac
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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