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

HRID 2079759
Notizen
Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 2079759
[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
KomponentenVersuchsvorschriftAufarbeitungQuellen und NachweiseNotizen zur Reaktion

Komponenten

7

Edukt 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

Produkt 1

HCID 59440336
4-Benzyl 1-tert-butyl (2S)-2-{[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl-amino]carbonyl}-1,4-piperazinedicarboxylate
Ausbeute 87 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 6228DimethylformamideLösungsmittelHCID 8857Ethyl AcetateLösungsmittel

Versuchsvorschrift

(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).

Aufarbeitung

  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)

Quellen und Nachweise

ORD-Eintrag
ord-e8ea4aac54304dd8ae5748357824edec
Quelldatensatz
uspto-grants-2011_04
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US07932255B2

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