Methanesulfonic Acid → Dibenzyl-{(1S,2S)-2-benzyloxy-1-(3,5-difluorobenzyl)-2-[(3R,5S,6R)-6-(2,2-dimethylpropoxy)-5-methylmorpholin-3-yl]-ethyl}-amine

HRID 20415

Reaction equation

HRID 20415 reaction equation
[CH2:1]([O:8][C@@H:9]([C@@H:35]1[NH:40][C@@H:39]([CH3:41])[CH:38]([OH:42])[O:37][CH2:36]1)[C@@H:10]([N:20]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:43](O)[C:44]([CH3:47])([CH3:46])[CH3:45].CS(O)(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:28]([N:20]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@@H:10]([CH2:11][C:12]1[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=1)[C@@H:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:35]1[CH2:36][O:37][C@@H:38]([O:42][CH2:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C@H:39]([CH3:41])[NH:40]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1

Participants

6

Reactant 4

HCID 6395Methanesulfonic AcidHCID 6404Neopentyl alcoholHCID 516892Sodium BicarbonateHCID 68561049(3S,5R)-5-[(1S,2S)-1-benzyloxy-2-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-3-methylmorpholin-2-ol

Product 1

HCID 68558842Dibenzyl-{(1S,2S)-2-benzyloxy-1-(3,5-difluorobenzyl)-2-[(3R,5S,6R)-6-(2,2-dimethylpropoxy)-5-methylmorpholin-3-yl]-ethyl}-amineYield 56%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

Mix (3S,5R)-5-[(1S,2S)-1-benzyloxy-2-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-3-methylmorpholin-2-ol (1.06 g, 1.85 mmol) with neopentanol (1.63 g, 18.5 mmol,) in dichloromethane (0.2 mL). Add 4 Å molecular sieves (850 mg), then methanesulphonic acid (2.4 mL, 37 mmol) and heat at 50° C. for 4 hours. Cool to room temperature, dilute with dichloromethane and add slowly to a solution of saturated aqueous sodium bicarbonate. Extract the aqueous layer with dichloromethane, dry (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 100:0 to 90:10 hexanes:ethyl acetate) to give the desired compound as a white solid (665 mg, 56% yield).

Workup

  1. additionAdd 4 Å molecular sieves (850 mg)
  2. extractionExtract the aqueous layer with dichloromethane
  3. dry with materialdry (sodium sulfate)
  4. filtrationfilter
  5. concentrationconcentrate
  6. custompurify
  7. wash(silica gel chromatography, eluting with 100:0 to 90:10 hexanes:ethyl acetate)

Sources & evidence

ORD record
ord-03e6d70683a04b5cb357034188aa7430
Source dataset
uspto-grants-2010_06
Patent number
US07745438B2

Linked notes

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