N,N,N',N'-Tetramethylethylenediamine → 4-Benzyl-2-(R)-[(2-(R)-dibenzylamino-1-(S)-hydroxy-3-phenylpropyl)]-piperazine-1-carboxylic acid-tert-butyl ester

HRID 1436501Notes

Reaction equation

HRID 1436501 reaction equation
[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)CCN(C)C.C([Li])(CC)C.[CH2:34]([N:41]([CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C@@H:42]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH:43]=[O:44])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[Cl-].[NH4+]>C(OCC)C.C(OCC)(=O)C>[C:17]([O:16][C:14]([N:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][C@@H:12]1[C@@H:43]([OH:44])[C@H:42]([N:41]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH2:52][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:15])([CH3:20])([CH3:19])[CH3:18]

Participants

8

Reactant 5

HCID 8037N,N,N',N'-TetramethylethylenediamineHCID 25517Ammonium ChlorideHCID 584330Tert-butyl 4-benzylpiperazine-1-carboxylateHCID 9883943(alphaS)-alpha-[Bis(phenylmethyl)amino]benzenepropanalHCID 178418400CID 53628100

Product 1

HCID 690183394-Benzyl-2-(R)-[(2-(R)-dibenzylamino-1-(S)-hydroxy-3-phenylpropyl)]-piperazine-1-carboxylic acid-tert-butyl ester

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-78 °C

Procedure

Dissolve commercially available tert-butyl 4-benzyl-1-piperazinecarboxylate (2.9 g, 10.4 mmol) in diethyl ether (75 mL) under argon and cool to −78° C. Add tetramethylethylene diamine (1. 8 mL, 11.7 mmol) and sec-butyllithium (9 mL, 11.7 mmol) dropwise at −78° C. React for 1.5 h and add 2-(S)-dibenzylamino-3-phenylpropionaldehyde (2.6 g, 7.9 mmol) in diethyl ether (18 mL) dropwise over 10 min. Stir for 45 min. Add saturated aqueous ammonium chloride solution and ethyl acetate and let warm to room temperature, separate the layers, extract the aqueous layer with ethyl acetate, wash the organic layer with saturated aqueous sodium chloride solution, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 4:1 hexanes:ethyl acetate) to give the title compound (the first spot to elute) as a white solid (1.45 g, 30%) and a second diastereomer (the second spot to elute) as a white solid (1.1 g, 23%).

Workup

  1. customdropwise at −78° C
  2. customReact for 1.5 h
  3. customseparate the layers
  4. extractionextract the aqueous layer with ethyl acetate
  5. washwash the organic layer with saturated aqueous sodium chloride solution
  6. dry with materialdry (magnesium sulfate)
  7. concentrationconcentrate
  8. custompurify
  9. wash(silica gel chromatography, eluting with 4:1 hexanes:ethyl acetate)

Sources & evidence

ORD record
ord-630687f6a6684a57aff5e65c95a51ec5
Source dataset
uspto-grants-2009_11
Patent number
US07618978B2

Reaction notes

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