Diisopropylethylamine → 4-Benzyl 1-tert-butyl (2S)-2-{[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl-amino]carbonyl}-1,4-piperazinedicarboxylate

HRID 2079759Notes

Reaction equation

HRID 2079759 reaction equation
[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:13]([C:24]([OH:26])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.[N:43]1(OC(N(C)C)=[N+](C)C)[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=2N=N1.O.ON1[C:66]2[CH:67]=CC=[CH:70][C:65]=2N=N1>CN(C=O)C.CCOC(C)=O>[C@H:47]1([NH:43][C:24]([C@@H:13]2[CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:16][CH2:15][N:14]2[C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])=[O:26])[C:46]2[C:51](=[CH:70][CH:65]=[CH:66][CH:67]=2)[CH2:50][CH2:49][CH2:48]1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 27960291-Hydroxybenzotriazole hydrateHCID 70106521-(1,1-Dimethylethyl) 4-(phenylmethyl) (2S)-1,2,4-piperazinetricarboxylate

Product 1

HCID 594403364-Benzyl 1-tert-butyl (2S)-2-{[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl-amino]carbonyl}-1,4-piperazinedicarboxylateYield 87%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

(2S)-4-[(benzyloxy)carbonyl]-1-(tert-butoxycarbonyl)-2-piperazinecarboxylic acid (1, 17.33 g, 47.5 mmol) is dissolved in DMF (800 mL), to which is added diisopropylethylamine (DIEA, 41.5 mL, 0.24 mol). This mixture is stirred at RT for 1.5 h. R-(−)-1,2,3,4-tetrahydro-1-naphthylamine (7.00 g, 47.5 mmol) is added, and stirring continued for a further hour. O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 19.84 g, 52.3 mmol) and 1-hydroxybenzotriazole hydrate (HOBt, 7.07 g, 52.3 mmol) are also added and the entire mixture stirred overnight at RT. The reaction mixture is then diluted with EtOAc (1.2 L) and washed sequentially with 1 M citric acid, brine, sat. NaHCO3, brine, water and brine (1 L of each solution). The EtOAc layer is then dried with Na2SO4, filtered, and the solvent removed under reduced pressure to afford a crude off-white solid (23.34 g). This material is purified by flash chromatography on silica gel (CH2Cl2 as eluent initially, followed by 5% Et2O/CH2Cl2 to elute the desired product). The desired coupled product 6 is isolated as a white foam (20.37 g, 87% yield): 1H NMR δ (CDCl3) 7.27-7.42 (m, 5H), 7.06-7.19 (m, 4H), 6.10 (brs, 1H), 5.11-5.25 (br m, 3H), 4.46-4.75 (br m, 2H), 3.77-4.02 (br m, 2H), 3.00-3.31 (br m, 3H), 2.68-2.84 (m, 2H), 1.97-2.07 (br m, 1H), 1.69-1.84 (br m, 3H), 1.43 (s, 9H). LCMS (APCl+) 494.8 (MH+), 438.5 (MH+-tBu), 394.4 (MH+-BOC).

Workup

  1. stirringstirring
  2. waitcontinued for a further hour
  3. stirringthe entire mixture stirred overnight at RT
  4. washwashed sequentially with 1 M citric acid, brine, sat. NaHCO3, brine, water and brine (1 L of each solution)
  5. dry with materialThe EtOAc layer is then dried with Na2SO4
  6. filtrationfiltered
  7. customthe solvent removed under reduced pressure
  8. customto afford a crude off-white solid (23.34 g)
  9. customThis material is purified by flash chromatography on silica gel (CH2Cl2 as eluent initially
  10. washto elute the desired product)

Sources & evidence

ORD record
ord-e8ea4aac54304dd8ae5748357824edec
Source dataset
uspto-grants-2011_04
Patent number
US07932255B2

Reaction notes

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