Dimethyl Sulfate → 8-(1-((3,5-difluorophenyl)(methyl)amino)ethyl)-N-(2-hydroxyethyl)-N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide

HRID 1947351Notes

Reaction equation

HRID 1947351 reaction equation
[CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Li+].[Si:11]([O:28][CH2:29][CH2:30][N:31]([CH3:62])[C:32]([C:34]1[CH:35]=[C:36]2[C:41](=[C:42]([CH:44]([NH:46][C:47]3[CH:52]=[C:51]([F:53])[CH:50]=[C:49]([F:54])[CH:48]=3)[CH3:45])[CH:43]=1)[O:40][C:39]([N:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1)=[CH:38][C:37]2=[O:61])=[O:33])([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.S([O:68][CH3:69])(OC)(=O)=O.[NH4+].[Cl-]>C1COCC1>[Si:11]([O:28][CH2:29][CH2:30][N:31]([CH3:62])[C:32]([C:34]1[CH:35]=[C:36]2[C:41](=[C:42]([CH:44]([N:46]([C:47]3[CH:48]=[C:49]([F:54])[CH:50]=[C:51]([F:53])[CH:52]=3)[CH3:1])[CH3:45])[CH:43]=1)[O:40][C:39]([N:55]1[CH2:56][CH2:57][O:58][CH2:59][CH2:60]1)=[CH:38][C:37]2=[O:61])=[O:33])([C:24]([CH3:25])([CH3:27])[CH3:26])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1.[F:53][C:51]1[CH:52]=[C:47]([N:46]([CH3:1])[CH:44]([C:42]2[CH:43]=[C:34]([C:32]([N:31]([CH2:62][CH2:69][OH:68])[CH3:30])=[O:33])[CH:35]=[C:36]3[C:41]=2[O:40][C:39]([N:55]2[CH2:60][CH2:59][O:58][CH2:57][CH2:56]2)=[CH:38][C:37]3=[O:61])[CH3:45])[CH:48]=[C:49]([F:54])[CH:50]=1

Participants

7

Reactant 4

HCID 6497Dimethyl SulfateHCID 25517Ammonium ChlorideHCID 2733832Lithium HexamethyldisilazideHCID 67103917N-(2-(tert-butyldiphenylsilyloxy)ethyl)-8-(1-(3,5-difluorophenylamino)ethyl)-N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide

Product 2

HCID 582350098-(1-((3,5-difluorophenyl)(methyl)amino)ethyl)-N-(2-hydroxyethyl)-N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamideYield 261.7%HCID 67104069N-(2-(tert-butyldiphenylsilyloxy)ethyl)-8-(1-((3,5-difluorophenyl)(methyl)amino)ethyl)-N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-20 °C

Procedure

Lithium bis(trimethylsilyl)amide (0.539 mL, 0.54 mmol) was added to a stirred solution of N-(2-(tert-butyldiphenylsilyloxy)ethyl)-8-(1-(3,5-difluorophenylamino)ethyl)-N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (230 mg, 0.32 mmol) dissolved in dry THF (3 mL). The solution was stirred over a period of 10 minutes at −20° C. under nitrogen. Dimethyl sulfate (0.051 mL, 0.54 mmol) was added to the mixture and the resulting suspension was left to rise to RT for 1 h30 under nitrogen. A sat. aq. sol. of NH4Cl was added and the reaction mixture was extracted with DCM. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated. The crude product was diluted with DCM and purified by flash chromatography on silica gel eluting with 4% ethyl alcohol in DCM. The solvent was evaporated to dryness to afford N-(2-(tert-butyldiphenylsilyloxy)ethyl)-8-(1-((3,5-difluorophenyl)(methyl)amino)ethyl)-N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide enantiomer 1 (210 mg, 90%) as a white solid. Mass Spectrum: M+H+ 740.

Workup

  1. waitthe resulting suspension was left
  2. customto rise to RT for 1 h30 under nitrogen
  3. extractionthe reaction mixture was extracted with DCM
  4. washThe combined organic phases were washed with brine
  5. dry with materialdried over magnesium sulfate
  6. concentrationconcentrated
  7. additionThe crude product was diluted with DCM
  8. custompurified by flash chromatography on silica gel eluting with 4% ethyl alcohol in DCM
  9. customThe solvent was evaporated to dryness

Sources & evidence

ORD record
ord-b16466a9c7ac45d4adbd744bc6828ac3
Source dataset
uspto-grants-2013_03
Patent number
US08399460B2

Reaction notes

Loading…