Tetrabutylammonium Fluoride → 1-[5-tert-Butyl-2-(3-chloro-4-hydroxy-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-urea

HRID 711155Notes

Reaction equation

HRID 711155 reaction equation
[C:1]([C:5]1[CH:6]=[C:7]([NH:28][C:29]([NH:31][C@@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C@H:35]([O:42][C:43]3[CH:44]=[CH:45][C:46]4[N:47]([C:49]([N:52]5[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]5)=[N:50][N:51]=4)[CH:48]=3)[CH2:34][CH2:33]2)=[O:30])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][Si](C(C)C)(C(C)C)C(C)C)=[C:12]([Cl:27])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:28][C:29]([NH:31][C@@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C@H:35]([O:42][C:43]3[CH:44]=[CH:45][C:46]4[N:47]([C:49]([N:52]5[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]5)=[N:50][N:51]=4)[CH:48]=3)[CH2:34][CH2:33]2)=[O:30])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([Cl:27])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]

Participants

4

Reactant 2

HCID 2724141Tetrabutylammonium FluorideHCID 123226521HCID 123226521, compound

Product 1

HCID 863448091-[5-tert-Butyl-2-(3-chloro-4-hydroxy-phenyl)-2H-pyrazol-3-yl]-3-[(1S,4R)-4-(3-piperidin-1-yl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-ureaYield 35%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A solution of Intermediate 49a (152 mg, 0.19 mmol) and TBAF (1M in THF, 0.225 mL, 0.225 mmol) in THF (4 mL) was stirred at RT for 10 min. The solution was concentrated in vacuo, suspended in water (5 mL) and extracted with EtOAc (2×5 mL). The combined organics were washed with brine (5 mL), dried (Na2SO4), filtered and concentrated in vacuo. FCC, using 5-15% [2M NH3 in MeOH] in DCM, gave a solid. Further purification by HPLC (XBridge C18 column, 25-75% MeCN in H2O, 0.1% NH4OH) gave the title compound (42.9 mg, 35%). LCMS (Method 5): Rt 4.46 min, m/z 655 [MH+]. NMR (400 MHz, d6-DMSO): 1.26 (9H, s), 1.60-1.66 (2H, m), 1.69-1.76 (4H, m), 1.82-1.96 (2H, m), 1.99-2.07 (1H, m), 2.09-2.16 (1H, m), 3.14 (4H, t, J=5.2 Hz), 4.78-4.84 (1H, m), 5.54 (1H, t, J=4.3 Hz), 6.28 (1H, s), 7.05 (2H, d, J=8.6 Hz), 7.16 (1H, dd, J=2.2, 9.8 Hz), 7.29-7.27 (4H, m), 7.38 (1H, d, J=7.6 Hz), 7.43 (1H, d, J=2.5 Hz), 7.61 (1H, dd, J=0.7, 11.9 Hz), 7.62 (1H, s), 8.00 (1H, s), 10.46 (1H, br s).

Workup

  1. concentrationThe solution was concentrated in vacuo
  2. extractionextracted with EtOAc (2×5 mL)
  3. washThe combined organics were washed with brine (5 mL)
  4. dry with materialdried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customgave a solid
  8. customFurther purification by HPLC (XBridge C18 column, 25-75% MeCN in H2O, 0.1% NH4OH)

Sources & evidence

ORD record
ord-9288362f87814eb18c1764317a71733b
Source dataset
uspto-grants-2015_11
Patent number
US09181242B2

Reaction notes

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