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

HRID 1056347Notes

Reaction equation

HRID 1056347 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[CH:46]=[CH:45][CH:44]=[C:43]2[C:38]=1[N:39]=[C:40]([NH:48][C:49]([CH3:52])([CH3:51])[CH3:50])[C:41]([CH3:47])=[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:48][C:49]([CH3:52])([CH3:51])[CH3:50])[C:41]([CH3:47])=[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 897821422-Bromo-1-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)ethanoneHCID 131736415(R)-ethyl 5-(benzyloxy)-4-((tert-butoxycarbonyl)amino)-3-oxopentanoate

Product 1

HCID 89781972Ethyl 5-(benzyloxy)-4-((tert-butoxycarbonyl)amino)-2-(2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-2-oxoethyl)-3-oxopentanoate

Reagents, catalysts & solvents 1

HCID 25517Ammonium ChlorideSolvent

Procedure

To a 50-mL round-bottomed flask was added (R)-ethyl 5-(benzyloxy)-4-((tert-butoxycarbonyl)amino)-3-oxopentanoate (608) (1.21 g, 3.31 mmol), K2CO3 (1.04 g, 7.52 mmol), 2-bromo-1-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)ethanone (606) (1.01 g, 3.01 mmol), and DMF (8 mL). The reaction was stirred at RT for 4 h. The reaction mixture was diluted with sat. NH4Cl (20 mL) and extracted with EtOAc (30 mL). The organic extract was washed with water (10 mL), dried over Na2SO4, and concentrated. Ethyl 5-(benzyloxy)-4-((tert-butoxycarbonyl)amino)-2-(2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-2-oxoethyl)-3-oxopentanoate (468a) was obtained as a light yellow oil and used without further purification. m/z (ESI, +ve) 621.3 (M+H)+. To a 15-mL glass tube was added ethyl 5-(benzyloxy)-4-((tert-butoxycarbonyl)amino)-2-(2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-2-oxoethyl)-3-oxopentanoate (468a), crude from previous step, NH4OAc (0.93 g, 12.0 mmol), EtOH (10 mL), and AcOH (3 mL). The tube was sealed and heated at 60° C. for 2 h. The reaction mixture was cooled to RT and was concentrated to half of its volume. The mixture was diluted with EtOAc (20 mL) and water (10 mL). The organic extract was washed with brine (10 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-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (468b) (0.97 g, 53% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.43 (br. s., 1H), 7.73 (dd, J=1.27, 7.53 Hz, 1H), 7.62 (dd, J=1.37, 8.02 Hz, 1H), 7.55 (d, J=2.35 Hz, 1H), 7.36 (t, J=7.73 Hz, 1H), 7.21-7.31 (m, 5H), 7.09 (br. d, J=10.17 Hz, 1H), 5.67-5.80 (m, 1H), 4.37-4.59 (m, 2H), 4.15-4.25 (m, 2H), 3.51-3.67 (m, 2H), 2.46 (s, 3H), 1.56 (s, 9H), 1.39 (s, 9H), 1.29 (t, J=7.14 Hz, 3H). m/z (ESI, +ve) 602.3 (M+H)+.

Workup

  1. extractionextracted with EtOAc (30 mL)
  2. extractionThe organic extract
  3. washwas washed with water (10 mL)
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated

Sources & evidence

ORD record
ord-7787b4a03018453187692c72d69ec82d
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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