Potassium Carbonate → Ethyl 4-((tert-butoxycarbonyl)amino)-2-(2-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-2-oxoethyl)-3-oxopentanoate

HRID 1056146Notes

Reaction equation

HRID 1056146 reaction equation
Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([NH:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:9]([CH3:15])=[N:10]2)=[O:4].[C:22]([O:26][C:27]([NH:29][C@H:30]([CH3:39])[C:31](=[O:38])[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:28])([CH3:25])([CH3:24])[CH3:23].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:22]([O:26][C:27]([NH:29][CH:30]([CH3:39])[C:31](=[O:38])[CH:32]([CH2:2][C:3]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([NH:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:9]([CH3:15])=[N:10]2)=[O:4])[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:28])([CH3:24])([CH3:25])[CH3:23]

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 11288402Ethyl (4R)-4-[[(1,1-dimethylethoxy)carbonyl]amino]-3-oxopentanoateHCID 897820082-Bromo-1-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)ethanone

Product 1

HCID 89782051Ethyl 4-((tert-butoxycarbonyl)amino)-2-(2-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-2-oxoethyl)-3-oxopentanoateYield 64%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A mixture of 2-bromo-1-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)ethanone (616) (300 mg, 0.83 mmol), ethyl 4-((tert-butoxycarbonyl)amino)-3-oxopentanoate (602) (258 mg, 0.99 mmol) and K2CO3 (286 mg, 2.07 mmol) in DMF (2.75 mL) was stirred at RT for 1 h. The reaction mixture was concentrated. Saturated NH4Cl (aq.) and EtOAc was added and the layers were separated. The aq. layer was extracted with EtOAc (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was purified by silica gel chromatography (0-50% EtOAc in hexanes) to provide ethyl 4-((tert-butoxycarbonyl)amino)-2-(2-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-2-oxoethyl)-3-oxopentanoate (293a) (285 mg, 64% yield). m/z (ESI, +ve) 541.1 (M+H)+. This material was put into a sealed tube with 2 mL of EtOH. AcOH (1 mL) and NH4OAc (511 mg, 6.63 mmol) were added and the mixture was stirred at 60° C. overnight (21 h). The reaction mixture was concentrated. The residue was put into solution with EtOAc and water. The layers were separated and the organic layer was washed with water, 1 M NaOH (aq.) and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude material was purified by silica gel chromatography (0-50% EtOAc in hexanes) to provide ethyl 2-(1-((tert-butoxycarbonyl)amino)ethyl)-5-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-1H-pyrrole-3-carboxylate (293b) (215 mg, 0.41 mmol, 50% yield) as a yellow foam. 1H NMR (400 MHz, CDCl3) δ ppm 7.87 (dt, J=7.53, 0.73 Hz, 1H), 7.29-7.44 (m, 2H), 7.12 (d, J=2.54 Hz, 1H), 5.00 (br. s., 1H), 4.25-4.53 (m, 4H), 2.14-2.30 (m, 2H), 1.64 (s, 3H), 1.58 (d, J=7.24 Hz, 3H), 1.36-1.48 (m, 12H). 19F NMR (377 MHz, CDCl3) δ ppm −70.80. m/z (ESI, +ve) 522.2 (M+H)+.

Workup

  1. concentrationThe reaction mixture was concentrated
  2. additionSaturated NH4Cl (aq.) and EtOAc was added
  3. customthe layers were separated
  4. extractionThe aq. layer was extracted with EtOAc (2×)
  5. dry with materialThe combined organic layers were dried over anhydrous Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe crude material was purified by silica gel chromatography (0-50% EtOAc in hexanes)

Sources & evidence

ORD record
ord-c291b058be5343b5bd12b19659e82805
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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