Dimethylformamide → Ethyl 5-(benzyloxy)-4-((tert-butoxycarbonyl)amino)-2-(2-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-2-oxoethyl)-3-oxopentanoate

HRID 1056241Notes

Reaction equation

HRID 1056241 reaction equation
[CH2:1]([O:8][CH2:9][C@@H:10]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:34][C:35]([C:37]1[C:46](F)=[CH:45][CH:44]=[C:43]2[C:38]=1[N:39]=[C:40]([NH:49][CH:50]1[CH2:52][CH2:51]1)[C:41]([CH3:48])=[N:42]2)=[O:36].CN(C=O)C>[NH4+].[Cl-]>[CH2:1]([O:8][CH2:9][CH:10]([NH:19][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[C:11](=[O:18])[CH:12]([CH2:34][C:35]([C:37]1[CH:46]=[CH:45][CH:44]=[C:43]2[C:38]=1[N:39]=[C:40]([NH:49][CH:50]1[CH2:52][CH2:51]1)[C:41]([CH3:48])=[N:42]2)=[O:36])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 11430Potassium CarbonateHCID 897821632-Bromo-1-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)ethanoneHCID 131736415(R)-ethyl 5-(benzyloxy)-4-((tert-butoxycarbonyl)amino)-3-oxopentanoate

Product 1

HCID 89782030Ethyl 5-(benzyloxy)-4-((tert-butoxycarbonyl)amino)-2-(2-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-2-oxoethyl)-3-oxopentanoate

Reagents, catalysts & solvents 1

HCID 25517Ammonium ChlorideSolvent

Procedure

To a 25-mL round-bottomed flask was added (R)-ethyl 5-(benzyloxy)-4-((tert-butoxycarbonyl)amino)-3-oxopentanoate (612) (0.78 g, 2.15 mmol), K2CO3 (0.67 g, 4.88 mmol), 2-bromo-1-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)ethanone (613) (0.62 g, 1.95 mmol), and DMF (4 mL). The reaction mixture was stirred at RT for 30 min. The reaction mixture was diluted with sat NH4Cl (5 mL) and extracted with EtOAc (10 mL). The organic extract was washed with water (5 mL), dried over Na2SO4, and concentrated. Ethyl 5-(benzyloxy)-4-((tert-butoxycarbonyl)amino)-2-(2-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-2-oxoethyl)-3-oxopentanoate (364a) was obtained as a yellow solid and used without further purification. m/z (ESI, +ve) 605.3 (M+H)+. To a 20-mL glass tube was added ethyl 5-(benzyloxy)-4-((tert-butoxycarbonyl)amino)-2-(2-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-2-oxoethyl)-3-oxopentanoate (364a), crude from previous step, NH4OAc (0.45 g, 5.85 mmol), EtOH (6 mL), and AcOH (1.5 mL). The tube was sealed and heated at 60° C. for 5 h. The reaction mixture was cooled to RT and was concentrated to half of its volume. The mixture was diluted with EtOAc (10 mL) and water (5 mL). The organic extract was washed with NaOH (1 N, 5 mL), water (5 mL), brine (5 mL), dried over Na2SO4, and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 10-30% EtOAc in hexanes to give ethyl 2-(2-(benzyloxy)-1-((tert-butoxycarbonyl)amino)ethyl)-5-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (364b) (0.48 g, 42% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.56 (br. s., 1H), 7.60 (dd, J=0.98, 8.02 Hz, 1H), 7.54 (d, J=1.96 Hz, 1H), 7.31-7.39 (m, 2H), 7.06 (br. s., 1H), 4.50 (d, J=5.48 Hz, 2H), 4.22 (q, J=7.04 Hz, 2H), 3.03 (br. s., 1H), 2.49 (s, 3H) 1.38 (s, 9H), 1.30 (t, J=7.04 Hz, 3H), 0.96-1.02 (m, 2H), 0.62-0.69 (m, 2H). m/z (ESI, +ve) 586.2 (M+H)+.

Workup

  1. extractionextracted with EtOAc (10 mL)
  2. extractionThe organic extract
  3. washwas washed with water (5 mL)
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated

Sources & evidence

ORD record
ord-ef43d5f990ea4610a1b1d4e81434817e
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

Loading…