1-Bromo-2-methylpropane → (2R,3S,5R)-5-[(1S,2S)-2-Acetylamino-3-(3-fluoro-5-isobutoxy-phenyl)-1-hydroxypropyl]-2-(2,2-dimethyl-propoxy)-3-methyl-morpholine-4-carboxylic acid tert-butyl ester

HRID 20445

Reaction equation

HRID 20445 reaction equation
Br[CH2:2][CH:3]([CH3:5])[CH3:4].[C:6]([O:10][C:11]([N:13]1[C@@H:18]([C@@H:19]([OH:34])[C@@H:20]([NH:30][C:31](=[O:33])[CH3:32])[CH2:21][C:22]2[CH:27]=[C:26]([OH:28])[CH:25]=[C:24]([F:29])[CH:23]=2)[CH2:17][O:16][C@@H:15]([O:35][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C@@H:14]1[CH3:41])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:6]([O:10][C:11]([N:13]1[C@@H:18]([C@@H:19]([OH:34])[C@@H:20]([NH:30][C:31](=[O:33])[CH3:32])[CH2:21][C:22]2[CH:27]=[C:26]([O:28][CH2:2][CH:3]([CH3:5])[CH3:4])[CH:25]=[C:24]([F:29])[CH:23]=2)[CH2:17][O:16][C@@H:15]([O:35][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C@@H:14]1[CH3:41])=[O:12])([CH3:8])([CH3:9])[CH3:7]

Participants

6

Reactant 3

HCID 65551-Bromo-2-methylpropaneHCID 10796Cesium carbonateHCID 68560537(2R,3S,5R)-5-[(1S,2S)-2-Acetylamino-3-(3-fluoro-5-hydroxy-phenyl)-1-hydroxypropyl]-2-(2,2-dimethyl-propoxy)-3-methyl-morpholine-4-carboxylic acid tert-butyl ester

Product 1

HCID 68561946(2R,3S,5R)-5-[(1S,2S)-2-Acetylamino-3-(3-fluoro-5-isobutoxy-phenyl)-1-hydroxypropyl]-2-(2,2-dimethyl-propoxy)-3-methyl-morpholine-4-carboxylic acid tert-butyl esterYield 55%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
60 °C

Procedure

Add 1-bromo-2-methyl-propane (0.05 g, 0.35 mmol) to (2R,3S,5R)-5-[(1S,2S)-2-acetylamino-3-(3-fluoro-5-hydroxy-phenyl)-1-hydroxy-propyl]-2-(2,2-dimethyl-propoxy)-3-methyl-morpholine-4-carboxylic acid tert-butyl ester (0.12 g, 0.23 mmol) and cesium carbonate (0.15 g, 0.46 mmol) in N,N-dimethylformamide (3 mL) under nitrogen and heat in a 60° C. oil bath for 2.5 hours. Cool to room temperature and dilute with ethyl acetate. Wash (0.1N citric acid, 10% potassium carbonate, saturated aqueous sodium chloride), dry (magnesium sulfate), filter and concentrate. Purify on 12 g silica gel column eluting with 100:0 to 40:60 hexanes:ethyl acetate to give 0.072 g (54.5%) of the title compound as a white foam.

Workup

  1. temperatureCool to room temperature
  2. washWash (0.1N citric acid, 10% potassium carbonate, saturated aqueous sodium chloride)
  3. dry with materialdry (magnesium sulfate)
  4. filtrationfilter
  5. concentrationconcentrate
  6. customPurify on 12 g silica gel column
  7. washeluting with 100:0 to 40:60 hexanes

Sources & evidence

ORD record
ord-ca9cb4295a3b413c9a13f3b4c63cfdb0
Source dataset
uspto-grants-2010_06
Patent number
US07745438B2

Linked notes

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