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

HRID 20430Notes

Reaction equation

HRID 20430 reaction equation
ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[CH2:13]([O:20][C@H:21]([C@@H:47]1[NH:52][C@@H:51]([CH3:53])[CH:50]([OH:54])[O:49][CH2:48]1)[C@@H:22]([N:32]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.[F:62][C:63]1([CH2:69]O)[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH2:40]([N:32]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:22]([CH2:23][C:24]1[CH:25]=[C:26]([F:31])[CH:27]=[C:28]([F:30])[CH:29]=1)[C@H:21]([O:20][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C@H:47]1[CH2:48][O:49][C@@H:50]([O:54][CH2:69][C:63]2([F:62])[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]2)[C@H:51]([CH3:53])[NH:52]1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1

Participants

8

Reactant 6

HCID 8471TriethylamineHCID 11430Potassium CarbonateHCID 65367Trimethylsilyl triflate2×HCID 94429TriphosgeneHCID 18342450(1-Fluorocyclohexyl)methanolHCID 68564040(3S,5R)-5-[(1R,2S)-1-benzyloxy-2-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-3-methylmorpholin-2-ol

Product 1

HCID 68560341Dibenzyl-{(1S,2R)-2-benzyloxy-1-(3,5-difluorobenzyl)-2-[(3R,5S,6S)-6-(1-fluorocyclohexylmethoxy)-5-methylmorpholin-3-yl]-ethyl}-amineYield 31.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

Add triphosgene (246 mg, 0.79 mmol) at room temperature to a solution of (3S,5R)-5-[(1R,2S)-1-benzyloxy-2-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-3-methylmorpholin-2-ol (1 g, 1.75 mmol) and triethylamine (0.99 mL, 7 mmol) in anhydrous dichloromethane (17 mL). Stir for 30 min, cool to 0° C. and add (1-fluorocyclohexyl)-methanol (1.16 g, 8.75 mmol) and trimethylsilyl trifluoromethanesulfonate (TMSOTf) (0.64 mL, 3.5 mmol). Stir at 0° C. for 1 hour and at room temperature for 2 hours. Add more trimethylsilyl trifluoromethanesulfonate (0.16 mL, 0.87 mmol) and stir at room temperature for 30 min. Add 10% aqueous potassium carbonate, separate the organic layer and extract the aqueous layer with dichloromethane. Combine the organic layers, dry (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 0:100 to 20:80 hexanes:ethyl acetate), to give the title compound as a colorless oil (375 mg).

Workup

  1. stirringStir at 0° C. for 1 hour and at room temperature for 2 hours
  2. stirringstir at room temperature for 30 min
  3. customseparate the organic layer
  4. extractionextract the aqueous layer with dichloromethane
  5. dry with materialdry (sodium sulfate)
  6. filtrationfilter
  7. concentrationconcentrate
  8. custompurify
  9. wash(silica gel chromatography, eluting with 0:100 to 20:80 hexanes:ethyl acetate)

Sources & evidence

ORD record
ord-ff70de919aa443f1927ba715ffc76ddf
Source dataset
uspto-grants-2010_06
Patent number
US07745438B2

Reaction notes

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