Ethyl Acetate → 3-(S)-(2-(S)-Benzyloxycarbonylamino-4,4-dimethyl-pentanoylamino)-4-(5-fluoro-2,3-dihydro-indol-1-yl)-butyric acid tert-butyl ester

HRID 132143

Reaktionsgleichung

Reaktionsgleichung von HRID 132143
[C:1]([O:5][C:6](=[O:31])[CH2:7][C@H:8]([NH:20][C:21]([O:23]CC1C=CC=CC=1)=O)[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[H][H].[C:34](C(C)(C)C)([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35].CN(C(O[N:56]1N=N[C:58]2C=CC=N[C:57]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N([CH:78]([CH3:80])[CH3:79])CC)(C)C.[C:81](OCC)(=O)C>[OH-].[OH-].[Pd+2].CN(C=O)C.CO>[C:1]([O:5][C:6](=[O:31])[CH2:7][C@H:8]([NH:20][C:21](=[O:23])[C@@H:57]([NH:56][C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:35])[CH2:58][C:78]([CH3:79])([CH3:80])[CH3:81])[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)([CH3:3])([CH3:2])[CH3:4]

Komponenten

10

Edukt 6

HCID 8857Ethyl AcetateHCID 74977Benzyl pivalateHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 691957243-(s)-Benzyloxycarbonylamino-4-(5-fluoro-2,3-dihydro-indol-1-yl)-butyric acid tert-butyl esterHCID 178418361HCID 178418361, Verbindung

Produkt 1

HCID 691960933-(S)-(2-(S)-Benzyloxycarbonylamino-4,4-dimethyl-pentanoylamino)-4-(5-fluoro-2,3-dihydro-indol-1-yl)-butyric acid tert-butyl esterAusbeute 77 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 9942167Palladium hydroxideKatalysatorHCID 887MethanolLösungsmittelHCID 6228DimethylformamideLösungsmittel

Versuchsvorschrift

A sample of the product of step A (1.3 g, 3.0 mmol) was treated with 20% Pd(OH)2 on carbon (260 mg) and methanol (2 mL). The atmosphere in the reaction was exchanged for hydrogen by sparging the solution with a long needle for 3 minutes and the reaction was stirred under 1 atmosphere of hydrogen for 2 hours. The atmosphere was exchanged back to nitrogen by again sparging the solution with a long needle for 3 minutes. The reaction mixture was filtered through celite and the solvent was removed. The resulting oil was treated with Cbz-tBu-ala DCHA salt (1.8 g, 3.7 mmol), HATU (1.4 g, 3.8 mmol) and DMF (2 mL). The reaction was then treated with diisopropylethylamine (1.2 g, 9.2 mmol) and stirred overnight. The reaction was diluted with ethyl acetate and extracted with water twice and 1 M NaOH once. The organics were then dried over MgSO4 and the solvent was removed. The residue was purified over silica gel using a gradient of 0 to 100% ethyl acetate in hexane to afford 1.3 g (77%) of the title material as a solid; 1H NMR (CDCl3, 400 MHz) δ 0.92 (s, 9H), 1.39 (dd, 1H, J1=5.8, J2=14.4), 1.44 (s, 9H), 1.82 (dd, 1H, J1=3.7, J2=14.5), 2.51 (dd, 1H, J1=5.5, J2=16.2), 2.61 (dd, 1H, J1=4.7, J2=16.3), 2.92 (dd, 1H, J1=J2=8.2), 3.07 (dd, 1H, J1=7.4, J2=13.6), 3.17 (dd, 1H, J1=6.0, J2=13.8), 3.28-3.47 (m, 2H), 4.09-4.17 (m, 1H), 4.33-4.43 (m, 1H), 4.98-5.13 (m, 3H), 6.40 (dd, 1H, J1=4.0, J2=8.4), 6.69-6.84 (m, 3H), 7.26-7.37 (m, 5H); HPLC-MS calcd. for C31H42FN3O5 (M+H+) 556.3, found 556.5.

Aufarbeitung

  1. customby sparging the solution with a long needle for 3 minutes
  2. customby again sparging the solution with a long needle for 3 minutes
  3. filtrationThe reaction mixture was filtered through celite
  4. customthe solvent was removed
  5. stirringstirred overnight
  6. extractionextracted with water twice
  7. dry with materialThe organics were then dried over MgSO4
  8. customthe solvent was removed
  9. customThe residue was purified over silica gel using a gradient of 0 to 100% ethyl acetate in hexane

Quellen und Nachweise

ORD-Eintrag
ord-5bf9f010983044e8810652fd873541b0
Quelldatensatz
uspto-grants-2008_06
Patentnummer
US07384970B2

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