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 75605Notes

Reaction equation

HRID 75605 reaction equation
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]

Participants

6

Reactant 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

Product 1

HCID 866867041-(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

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

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).

Workup

  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)

Sources & evidence

ORD record
ord-372384002cc14894afc9d61eb8852333
Source dataset
uspto-grants-2014_09
Patent number
US08835431B2

Reaction notes

Loading…