Potassium Carbonate → Ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropanecarbonyl)-4-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)-4-oxobutanoate

HRID 1056134Notes

Reaction equation

HRID 1056134 reaction equation
Br[CH2:2][C:3]([C:5]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([NH:17][CH:18]1[CH2:20][CH2:19]1)[C:9]([CH3:16])=[N:10]2)=[O:4].[C:21]([O:25][C:26]([NH:28][C:29]1([C:32](=[O:39])[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:31][CH2:30]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C([O-])(O)=O.[Na+].C(Cl)(Cl)Cl>[C:21]([O:25][C:26]([NH:28][C:29]1([C:32]([CH:33]([CH2:2][C:3]([C:5]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]3[C:6]=2[N:7]=[C:8]([NH:17][CH:18]2[CH2:20][CH2:19]2)[C:9]([CH3:16])=[N:10]3)=[O:4])[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:39])[CH2:31][CH2:30]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]

Participants

7

Reactant 3

HCID 11430Potassium CarbonateHCID 89781999Ethyl 3-(1-{[(tert-butoxy)carbonyl]amino}cyclopropyl)-3-oxopropanoateHCID 897821632-Bromo-1-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)ethanone

Product 1

HCID 118512012Ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropanecarbonyl)-4-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)-4-oxobutanoateYield 37.2%

Reagents, catalysts & solvents 3

HCID 6212ChloroformSolventHCID 6228DimethylformamideSolventHCID 516892Sodium BicarbonateSolvent

Procedure

At RT, to a mixture of 2-bromo-1-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)ethanone (283c) (1.18 g, 3.49 mmol) and ethyl 3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-3-oxopropanoate (604) (1.14 g, 4.19 mmol) dissolved in DMF (10.26 mL) was added K2CO3 (1.21 g, 8.72 mmol). The overall mixture was stirred overnight. The mixture was diluted with saturated NaHCO3 (100 mL) and CHCl3 (100 mL). The layers were separated and the aq. layer was extracted with CHCl3 (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by chromatography through an Interchim puriFlash UP (25 micron) pre-packed silica-gel column (80 grams), eluting with a gradient of 0-30% EtOAc in DCM, to provide ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropanecarbonyl)-4-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)-4-oxobutanoate (0.69 g, 1.30 mmol, 37% yield) as a yellow oil. The yellow oil was put into a sealed tube with 2:1 mixture of EtOH/AcOH (3 mL) and NH4OAc (Sigma) (0.80 g, 10.5 mmol) was added and the mixture was stirred at 60° C. overnight. The precipitate solid was filtered and washed with Et2O (3×2 mL) to give ethyl 2-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-5-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (0.41 g, 23% yield) as a yellow solid. m/z (ESI, +ve) 510 (M+H).

Workup

  1. customThe layers were separated
  2. extractionthe aq. layer was extracted with CHCl3 (3×)
  3. dry with materialThe combined organic extracts were dried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe crude material was purified by chromatography through an Interchim puriFlash UP (25 micron) pre-packed silica-gel column (80 grams)
  7. washeluting with a gradient of 0-30% EtOAc in DCM

Sources & evidence

ORD record
ord-a5deaca978bf467ea9b5a1aed13c4c97
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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