Tetrahydrofuran → Ethyl 4-((tert-butoxycarbonyl)amino)-2-(2-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-2-oxoethyl)-3-oxobutanoate

HRID 1056235Notes

Reaction equation

HRID 1056235 reaction equation
[C:1]([O:5][C:6]([NH:8][CH2:9][C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:25][C:26]([C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[N:30]=[C:31]([NH:39][C:40]1([CH3:43])[CH2:42][CH2:41]1)[C:32]([CH3:38])=[N:33]2)=[O:27].C1COCC1>[NH4+].[Cl-].CCO>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10](=[O:17])[CH:11]([CH2:25][C:26]([C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[N:30]=[C:31]([NH:39][C:40]1([CH3:43])[CH2:42][CH2:41]1)[C:32]([CH3:38])=[N:33]2)=[O:27])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:7])([CH3:3])([CH3:4])[CH3:2]

Participants

7

Reactant 4

HCID 8028TetrahydrofuranHCID 11430Potassium CarbonateHCID 111285644-((tert-Butoxycarbonyl)amino)-3-oxobutanoic acid ethyl esterHCID 897821052-Bromo-1-(2-methyl-3-((1-methylcyclopropyl)amino)-5-quinoxalinyl)ethanone

Product 1

HCID 89781945Ethyl 4-((tert-butoxycarbonyl)amino)-2-(2-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-2-oxoethyl)-3-oxobutanoate

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 25517Ammonium ChlorideSolvent

Procedure

To a 25-mL round-bottomed flask was added ethyl 4-((tert-butoxycarbonyl)amino)-3-oxobutanoate (601) (0.60 g, 2.44 mmol), K2CO3 (0.56 g, 4.07 mmol), 2-bromo-1-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)ethanone (611) (0.54 g, 1.63 mmol), THF (6 mL), and EtOH (6 mL). The reaction mixture was stirred at RT for 16 h and 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 4-((tert-butoxycarbonyl)amino)-2-(2-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-2-oxoethyl)-3-oxobutanoate (357a) was obtained as a light yellow oil and used without further purification. m/z (ESI, +ve) 499.2 (M+H)+. To a 15-mL glass tube was added ethyl 4-((tert-butoxycarbonyl)amino)-2-(2-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-2-oxoethyl)-3-oxobutanoate (357a), crude from previous step, NH4OAc (0.50 g, 6.51 mmol), EtOH (3 mL), and AcOH (1 mL). The tube was sealed and heated at 50° C. for 3 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 (24 g), eluting with a gradient of 10% to 30% EtOAc in hexanes to give ethyl 2-4(tert-butoxycarbonyl)amino)methyl)-5-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-1H-pyrrole-3-carboxylate (357b) (0.25 g, 32% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 12.24 (br. s., 1H), 7.97 (dd, J=1.17, 7.63 Hz, 1H), 7.54-7.63 (m, 3H), 7.34 (t, J=7.82 Hz, 1H), 6.94 (br. s., 1H), 4.51 (d, J=5.28 Hz, 2H), 4.22 (q, J=7.17 Hz, 2H), 2.48 (s, 3H), 1.56 (s, 3H), 1.38 (s, 9H), 1.29 (t, J=7.00 Hz, 3H), 0.91-0.94 (m, 2H), 0.84-0.89 (m, 2H). m/z (ESI, +ve) 480.4 (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-c256986a15da49bca1d2d6e2619541b8
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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