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Triphenylphosphine → 1-(5-tert-Butyl-2-{3-[2-(4-hydroxy-piperidin-1-yl)-ethoxy]-phenyl}-2H-pyrazol-3-yl)-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea Formate Salt

HRID 75605
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Druckvorschau

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Reaktionsgleichung von HRID 75605
CC([O:4][C:5](/N=N/C(OC(C)C)=O)=[O:6])C.[C:15]([C:19]1[CH:20]=[C:21]([NH:31][C:32]([NH:34][C@@H:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C@H:38]([O:45][C:46]3[CH:47]=[CH:48][C:49]4[N:50]([C:52]([CH:55]([CH3:57])[CH3:56])=[N:53][N:54]=4)[CH:51]=3)[CH2:37][CH2:36]2)=[O:33])[N:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)[N:23]=1)([CH3:18])([CH3:17])[CH3:16].[OH:58][CH:59]1[CH2:64][CH2:63][N:62]([CH2:65][CH2:66]O)[CH2:61][CH2:60]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH:5]([OH:6])=[O:4].[C:15]([C:19]1[CH:20]=[C:21]([NH:31][C:32]([NH:34][C@@H:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C@H:38]([O:45][C:46]3[CH:47]=[CH:48][C:49]4[N:50]([C:52]([CH:55]([CH3:57])[CH3:56])=[N:53][N:54]=4)[CH:51]=3)[CH2:37][CH2:36]2)=[O:33])[N:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:66][CH2:65][N:62]3[CH2:63][CH2:64][CH:59]([OH:58])[CH2:60][CH2:61]3)[CH:25]=2)[N:23]=1)([CH3:18])([CH3:17])[CH3:16]
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Komponenten

6

Edukt 4

HCID 11776TriphenylphosphineHCID 5363146Diisopropyl azodicarboxylateHCID 147994684-Hydroxy-1-piperidineethanolHCID 866867021-[5-tert-Butyl-2-(3-hydroxy-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

Produkt 1

HCID 86686704
1-(5-tert-Butyl-2-{3-[2-(4-hydroxy-piperidin-1-yl)-ethoxy]-phenyl}-2H-pyrazol-3-yl)-3-[(1S,4R)-4-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea Formate Salt

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 8028TetrahydrofuranLösungsmittel

Versuchsvorschrift

DIAD (51.0 μL, 0.260 mmol) was added to a solution of Intermediate 22d (75.0 mg, 0.13 mmol), 4-hydroxy-1-piperidine-ethanol (28.0 mg, 0.19 mmol), and Ph3P (68.0 mg, 0.26 mmol) in THF (1.5 mL) at 0° C. The reaction was stirred at RT over the weekend then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM. Further purification by HPLC (C18 X-select column, 25-98% MeCN in H2O, 0.1% HCO2H) gave the title compound as a white powder after freeze-drying (57 mg, 62%). LCMS (Method 5): Rt 3.32 min, m/z 707.4 [MH+]. 1H NMR (400 MHz, d4-MeOD): 1.31 (9H, s), 1.42 (3H, d, J 6.8), 1.45 (3H, d, J 6.8), 1.62-1.72 (2H, m), 1.86-2.04 (4H, m), 2.04-2.14 (1H, m), 2.21-2.30 (1H, m), 2.69-2.79 (2H, m), 3.11-3.19 (4H, m), 3.51 (1H, sept, J 6.9), 3.70-3.78 (1H, m), 4.26 (2H, t, J 5.3), 4.89 (1H, dd, J 8.9, 5.8), 5.45 (1H, t, J 4.1), 6.33 (1H, s), 7.05 (1H, ddd, J 8.4, 2.7, 0.8), 7.09-7.13 (2H, m), 7.19-7.25 (3H, m), 7.26-7.33 (2H, m), 7.42 (1H, t, J 8.1), 7.61 (1H, dd, J 9.7, 0.6), 8.01 (1H, d, J 1.7), 8.42 (1H, br s).

Aufarbeitung

  1. customthen partitioned between EtOAc and water
  2. extractionThe aqueous layer was extracted with EtOAc (3×)
  3. washThe combined organic layers were washed with brine
  4. dry with materialdried (MgSO4)
  5. filtrationfiltered
  6. customevaporated in vacuo
  7. customThe residue was purified by FCC
  8. customFurther purification by HPLC (C18 X-select column, 25-98% MeCN in H2O, 0.1% HCO2H)

Quellen und Nachweise

ORD-Eintrag
ord-372384002cc14894afc9d61eb8852333
Quelldatensatz
uspto-grants-2014_09
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US08835431B2

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