Potassium Carbonate → (4S,5R)-ethyl 4-((tert-butoxycarbonyl)amino)-5-((tert-butyldimethylsilyl)oxy)-2-(2-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)-2-oxoethyl)-3-oxohexanoate

HRID 1056230Notes

Reaction equation

HRID 1056230 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@@H:29]([C@H:38]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH3:39])[C:30](=[O:37])[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:27])([CH3:24])([CH3:23])[CH3:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:21]([O:25][C:26]([NH:28][C@@H:29]([C@H:38]([O:40][Si:41]([C:44]([CH3:46])([CH3:45])[CH3:47])([CH3:42])[CH3:43])[CH3:39])[C:30](=[O:37])[CH:31]([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:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:27])([CH3:24])([CH3:22])[CH3:23]

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 897821632-Bromo-1-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)ethanoneHCID 131736416(4S,5R)-ethyl 4-((tert-butoxycarbonyl)amino)-5-((tert-butyldimethylsilyl)oxy)-3-oxohexanoate

Product 1

HCID 131736422(4S,5R)-ethyl 4-((tert-butoxycarbonyl)amino)-5-((tert-butyldimethylsilyl)oxy)-2-(2-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)-2-oxoethyl)-3-oxohexanoateYield 22.3%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A solution of 2-bromo-1-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)ethanone (613) (566 mg, 1.674 mmol) and (4S,5R)-ethyl 4-((tert-butoxycarbonyl)amino)-5-((tert-butyldimethylsilyl)oxy)-3-oxohexanoate (614) (995 mg, 2.465 mmol) in DMF (9 mL) was cooled in an ice-water bath and treated with K2CO3 (509 mg, 3.68 mmol) The mixture was stirred for 16 h at RT then heated at 60° C. in an oil bath for 4 h. The mixture was extracted into CHCl3 (3×100 mL) from saturated aq. NaHCO3 (100 mL), dried (Na2SO4), concentrated, and purified by flash chromatography on silica gel (40 g) eluting with a gradient of 0-10% EtOAc in DCM to give (4S,5R)-ethyl 4-((tert-butoxycarbonyl)amino)-5-((tert-butyldimethylsilyl)oxy)-2-(2-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)-2-oxoethyl)-3-oxohexanoate (352a) (247 mg, 0.374 mmol, 22% yield) as a yellow foam. LC-MS m/z 661.1, [M+H]. A solution of (4S,5R)-ethyl 4-((tert-butoxycarbonyl)amino)-5-((tert-butyldimethylsilyl)oxy)-2-(2-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)-2-oxoethyl)-3-oxohexanoate (352a) (247 mg, 0.374 mmol) in EtOH (3.0 mL) and AcOH (1.5 mL) was treated with NH4OAc (Aldrich) (432 mg, 5.61 mmol). The resulting yellow solution was heated at 60° C. for 64 h. The mixture was concentrated and extracted into EtOAc (3×100 mL) from saturated aq. NaHCO3 (150 mL). The organic extracts were dried (Na2SO4), concentrated, and purified by flash chromatography on silica gel (gradient: 0-15% EtOAc in DCM) to give the title compound (352b) as a yellow foam (184.5 mg). LC-MS m/z 642.2, [M+H]+.

Workup

  1. temperaturethen heated at 60° C. in an oil bath for 4 h
  2. extractionThe mixture was extracted into CHCl3 (3×100 mL) from saturated aq. NaHCO3 (100 mL)
  3. dry with materialdried (Na2SO4)
  4. concentrationconcentrated
  5. custompurified by flash chromatography on silica gel (40 g)
  6. washeluting with a gradient of 0-10% EtOAc in DCM

Sources & evidence

ORD record
ord-79a5350119994412977b833028b6a1f8
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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