Ammonia → 1-(5-tert-Butyl-2-piperidin-4-yl-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

HRID 75597Notes

Reaction equation

HRID 75597 reaction equation
C(OC([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:21]([NH:22][C:23]([NH:25][C@@H:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C@H:29]([O:36][C:37]4[CH:38]=[CH:39][C:40]5[N:41]([C:43]([CH:46]([CH3:48])[CH3:47])=[N:44][N:45]=5)[CH:42]=4)[CH2:28][CH2:27]3)=[O:24])=[CH:20][C:19]([C:49]([CH3:52])([CH3:51])[CH3:50])=[N:18]2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.N.CO>CCO.[Pd]>[C:49]([C:19]1[CH:20]=[C:21]([NH:22][C:23]([NH:25][C@@H:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C@H:29]([O:36][C:37]3[CH:38]=[CH:39][C:40]4[N:41]([C:43]([CH:46]([CH3:48])[CH3:47])=[N:44][N:45]=4)[CH:42]=3)[CH2:28][CH2:27]2)=[O:24])[N:17]([CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)[N:18]=1)([CH3:52])([CH3:51])[CH3:50]

Participants

6

Reactant 3

HCID 222AmmoniaHCID 887MethanolHCID 86686695HCID 86686695, compound

Product 1

HCID 715986451-(5-tert-Butyl-2-piperidin-4-yl-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]-ureaYield 90.6%

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 702EthanolSolvent

Procedure

A suspension of Intermediate 16d (165 mg, 0.234 mmol), Pd/C (10%, 16 mg), and 2M NH3 in MeOH (0.117 mL, 0.234 mmol) in EtOH (5 mL) under N2 was evacuated and purged with H2 twice, then stirred at rt for 8 h. The suspension was filtered through Celite, then the filter-cake washed with EtOH (10 mL). The combined organics were concentrated in vacuo to ˜0.5 mL volume, then applied to an SCX-2 cartridge (5 g) and washed with MeOH (5 mL). The product was eluted with 2M NH3 in MeOH (25 mL); concentration in vacuo left a pale yellow solid that was triturated with diethyl ether (10 mL) to leave a buff solid (121 mg). Half of this material was purified by HPLC(XBridge C18, 25-98% MeCN in H2O, 0.1% NH4OH) to give the title compound as a white solid after freeze-drying (20.0 mg, 15%). LCMS (Method 5): Rt 3.16 min, m/z 571 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.16 (9H, s), 1.33 (3H, d, J 6.8), 1.35 (3H, d, J 6.8), 1.68 (2H, m), 1.79 (2H, m), 1.91 (2H, m), 2.09 (2H, m), 2.47 (2H, m), 2.98 (2H, d, J 12.3), 3.50 (1H, sept, J 6.8), 3.92 (1H, m), 4.82 (1H, m), 5.51 (1H, t, J 4.5), 5.97 (1H, s), 6.88 (1H, d, J 8.6), 7.14 (1H, dd, J 9.9, 2.1), 7.26 (1H, m), 7.31-7.38 (3H, m), 7.65 (1H, dd, J 9.8, 0.8), 8.07 (1H, br s), 8.18 (1H, d, J 2.0).

Workup

  1. customwas evacuated
  2. custompurged with H2 twice
  3. filtrationThe suspension was filtered through Celite
  4. washthe filter-cake washed with EtOH (10 mL)
  5. concentrationThe combined organics were concentrated in vacuo to ˜0.5 mL volume
  6. washwashed with MeOH (5 mL)
  7. washThe product was eluted with 2M NH3 in MeOH (25 mL)
  8. concentrationconcentration in vacuo
  9. waitleft a pale yellow solid
  10. customthat was triturated with diethyl ether (10 mL)

Sources & evidence

ORD record
ord-a27006266aa04704a7e3c35280d030e6
Source dataset
uspto-grants-2014_09
Patent number
US08835431B2

Reaction notes

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