Methyl iodide → (2R,3S,5R)-5-[(1S,2S)-1-benzyloxy-2-dibenzylamino-3-(4-methyl-3,5-difluorophenyl)-propyl]-2-(2,2-dimethylpropoxy)-3-methylmorpholine-4-carboxylic acid tert-butyl ester

HRID 20464

Reaction equation

HRID 20464 reaction equation
[CH2:1]([Li])CCC.[C:6]([O:10][C:11]([N:13]1[C@@H:18]([C@@H:19]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C@@H:20]([N:30]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:21][C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=2)[CH2:17][O:16][C@@H:15]([O:53][CH2:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C@@H:14]1[CH3:59])=[O:12])([CH3:9])([CH3:8])[CH3:7].CC(C)([O-])C.[K+].IC.CN(P(N(C)C)N(C)C)C>O1CCCC1>[C:6]([O:10][C:11]([N:13]1[C@@H:18]([C@@H:19]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C@@H:20]([N:30]([CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:21][C:22]2[CH:27]=[C:26]([F:28])[C:25]([CH3:1])=[C:24]([F:29])[CH:23]=2)[CH2:17][O:16][C@@H:15]([O:53][CH2:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C@@H:14]1[CH3:59])=[O:12])([CH3:8])([CH3:7])[CH3:9]

Participants

7

Reactant 5

HCID 6328Methyl iodideHCID 15355Hexamethylphosphorous triamideHCID 23665647Potassium tert-butoxideHCID 68562066(2R,3S,5R)-5-[(1S,2S)-1-benzyloxy-2-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-2-(2,2-dimethylpropoxy)-3-methylmorpholine-4-carboxylic acid tert-butyl esterHCID 178418339Butyllithium

Product 1

HCID 68564308(2R,3S,5R)-5-[(1S,2S)-1-benzyloxy-2-dibenzylamino-3-(4-methyl-3,5-difluorophenyl)-propyl]-2-(2,2-dimethylpropoxy)-3-methylmorpholine-4-carboxylic acid tert-butyl esterYield 55.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

Add n-butyllithium (252 μL, 0.404 mmol, 1.6 M in hexanes) dropwise over 5 minutes to a solution of (2R,3S,5R)-5-[(1S,2S)-1-benzyloxy-2-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-2-(2,2-dimethylpropoxy)-3-methylmorpholine-4-carboxylic acid tert-butyl ester (0.30 g, 0.404 mmol) in tetrahydrofuran (0.6 mL) at −78° C. Add potassium tert-butoxide (0.404 mL, 1 M in tetrahydrofuran) dropwise over 10 minutes and stir the reaction mixture for an additional 10 minutes. Add iodomethane (25.1 μL, 0.404 mmol) followed by a solution of hexamethylphosphorus triamide (53.7 μL, 0.294 mmol) in tetrahydrofuran (40.4 μL). Stir reaction mixture at −78° C. for 1 hour. Remove cooling bath and stir for 20 minutes. Add water (20 mL) and extract with ethyl acetate (2×50 mL). Wash combined organic layers with water (3×20 mL), dry over magnesium sulfate, and concentrate under reduced pressure. Subject residue to silica gel chromatography, eluting with hexanes containing 0-10% diethyl ether, to provide the desired compound 0.169 g (55.3%) as a white foam.

Workup

  1. stirringStir
  2. customreaction mixture at −78° C. for 1 hour
  3. customRemove
  4. temperaturecooling bath
  5. stirringstir for 20 minutes
  6. extractionAdd water (20 mL) and extract with ethyl acetate (2×50 mL)
  7. washWash
  8. dry with materialdry over magnesium sulfate
  9. concentrationconcentrate under reduced pressure
  10. washSubject residue to silica gel chromatography, eluting with hexanes containing 0-10% diethyl ether

Sources & evidence

ORD record
ord-3d156966dabb40ac83efaebac7fe08a2
Source dataset
uspto-grants-2010_06
Patent number
US07745438B2

Linked notes

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