Tributylphosphine → 5-(R)-[1-(S)-benzyloxy-2-(S)-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-2-(S)-(3-methylbutyl)-morpholine-4-carboxylic acid tert-butyl ester

HRID 20355Notes

Reaction equation

HRID 20355 reaction equation
[C:1]([O:5][C:6](=[O:53])[N:7]([C@H:16]([CH2:51][OH:52])[C@@H:17]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C@@H:18]([N:28]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=1)[CH2:8][C@@H:9](O)[CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])([CH3:4])([CH3:3])[CH3:2].C(P(CCCC)CCCC)CCC>C1C=CC=CC=1>[C:1]([O:5][C:6]([N:7]1[C@@H:16]([C@@H:17]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C@@H:18]([N:28]([CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:19][C:20]2[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=2)[CH2:51][O:52][C@@H:9]([CH2:10][CH2:11][CH:12]([CH3:13])[CH3:14])[CH2:8]1)=[O:53])([CH3:3])([CH3:4])[CH3:2]

Participants

4

Reactant 2

HCID 13831TributylphosphineHCID 68564703HCID 68564703, compound

Product 1

HCID 685638025-(R)-[1-(S)-benzyloxy-2-(S)-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-2-(S)-(3-methylbutyl)-morpholine-4-carboxylic acid tert-butyl esterYield 77%

Reagents, catalysts & solvents 1

HCID 241BenzeneSolvent

Procedure

Dissolve [2-(S)-benzyloxy-3-(S)-dibenzylamino-4-(3,5-difluorophenyl)-1-(R)-hydroxymethylbutyl]-(2-(S)-hydroxy-5-methylhexyl)-carbamic acid tert-butyl ester (253 mg, 347 mmol) in benzene (3 mL). Deoxygenate the reaction mixture. Add tributyl phosphine (130 μL, 520 mmol), N,N-tetramethyl azodicarboxamide (TMAD) (89.5 mg, 520 mmol) and stir at room temperature 2.5 hours. Add deoxygenated tetrahydrofuran (5 mL), more tributyl phosphate (130 μL), more TMAD (90 mg) and stir 1.5 hours. Filter, rinse with hexanes, concentrate and purify (silica gel chromatography, eluting with 5:95 ethyl acetate:hexanes) to give the desired compound (191.7 mg, 77%).

Workup

  1. customDeoxygenate the reaction mixture
  2. additionAdd
  3. customdeoxygenated tetrahydrofuran (5 mL), more tributyl phosphate (130 μL), more TMAD (90 mg)
  4. filtrationFilter
  5. washrinse with hexanes
  6. concentrationconcentrate
  7. custompurify
  8. wash(silica gel chromatography, eluting with 5:95 ethyl acetate:hexanes)

Sources & evidence

ORD record
ord-5e1ffd8d9738461e92a9fa437e39e0b0
Source dataset
uspto-grants-2010_06
Patent number
US07745438B2

Reaction notes

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