Acetic Acid → 1-(5-tert-butyl-2-{3-[3-(tert-butyl-dimethyl-silanyloxy)-propylamino]-phenyl}-2H-pyrazol-3-yl)-3-[4-(pyridin-4-yloxy)-phenyl]-urea

HRID 1174869Notes

Reaction equation

HRID 1174869 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([NH:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)=[O:15])=[CH:11][C:10]([C:30]([CH3:33])([CH3:32])[CH3:31])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[Si:34]([O:41][CH2:42][CH2:43][CH:44]=O)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1COCC1>[C:30]([C:10]1[CH:11]=[C:12]([NH:13][C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)=[CH:21][CH:22]=2)=[O:15])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH2:44][CH2:43][CH2:42][O:41][Si:34]([C:37]([CH3:38])([CH3:40])[CH3:39])([CH3:35])[CH3:36])[CH:3]=2)[N:9]=1)([CH3:33])([CH3:32])[CH3:31]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 36623923-((Tert-butyldimethylsilyl)oxy)propanalHCID 5049666Sodium triacetoxyborohydrideHCID 536301941-[2-(3-amino-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)-phenyl]-urea

Product 1

HCID 536301951-(5-tert-butyl-2-{3-[3-(tert-butyl-dimethyl-silanyloxy)-propylamino]-phenyl}-2H-pyrazol-3-yl)-3-[4-(pyridin-4-yloxy)-phenyl]-ureaYield 84%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 1-[2-(3-amino-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)-phenyl]-urea (100 mg, 0.23 mmol), 3-[(tert-butyldimethylsilyl)oxy]-1-propanal (47 mg, 0.25 mmol, 1.1 eq), and sodium triacetoxyborohydride (67 mg, 0.32 mmol, 1.4 eq) in anhydrous THF (2 mL) was added acetic acid (16 mg, 0.27 mmol, 1.2 eq). The reaction mixture was stirred under N2 at room temperature for 2 h. The reaction mixture was quenched with saturated NaHCO3 and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated at reduced pressure. The crude residue was purified by MPLC (eluting with 40:60 to 60:40 EtOAc/hexanes) to give 117 mg (84%) of 1-(5-tert-butyl-2-{3-[3-(tert-butyl-dimethyl-silanyloxy)-propylamino]-phenyl}-2H-pyrazol-3-yl)-3-[4-(pyridin-4-yloxy)-phenyl]-urea. 1H-NMR (DMSO-d6) δ 9.17 (s, 1H), 8.40 (dd, J=1.5 & 4.6 Hz, 2H), 8.31 (s, 1H), 7.48 (d, J=8.8 Hz, 2H), 7.17 (t, J=8.1 Hz, 1H), 7.07 (d, J=8.8 Hz, 2H), 6.85 (dd, J=1.6 & 4.9 Hz, 2H), 6.61-6.56 (m, 3H), 6.32 (s, 1H), 5.92 (t, J=5.6 Hz, 1H), 3.66 (t, J=6.1 Hz, 2H), 3.07 (q, J=7.5 Hz, 2H), 1.72 (quintet, J=6.8 Hz, 2H), 1.26 (s, 9H), 0.84 (s, 9H), 0.02 (s, 6H); MS LC-MS [M+H]+=615.4, RT=3.28 min. Step 2: To a solution of 1-(5-tert-butyl-2-{3-[3-(tert-butyl-dimethyl-silanyloxy)-propylamino]-phenyl}-2H-pyrazol-3-yl)-3-[4-(pyridin-4-yloxy)-phenyl]-urea (117 mg, 0.19 mmol) in methanol (2 mL) was added a solution of 10% TFA in H2O (2 mL). The reaction was stirred at room temperature overnight. The mixture was then diluted with DCM, basified by the addition of saturated aq NaHCO3 and extracted with DCM. The combined organic phases were washed with brine, dried over MgSO4, and concentrated at reduced pressure. The crude residue was purified by MPLC (eluting with 4% to 5.5% MeOH in DCM) to give 82 mg (86%) of the desired product 1-{5-tert-butyl-2-[3-(3-hydroxy-propylamino)-phenyl]-2H-pyrazol-3-yl}-3-[4-(pyridin-4-yloxy)-phenyl]-urea. 1H-NMR (DMSO-d6) δ 9.18 (s, 1H), 8.40 (dd, J=1.7 & 4.7 Hz, 2H), 8.32 (s, 1H), 7.48 (d, J=9.0 Hz, 2H), 7.17 (t, J=7.9 Hz, 1H), 7.07 (d, J=9.1 Hz, 2H), 6.85 (dd, J=1.5 & 4.7 Hz, 2H), 6.63-6.56 (m, 3H), 6.33 (s, 1H), 5.91 (t, J=5.3 Hz, 1H), 4.47 (t, J=5.1 Hz, 1H), 3.48 (q, J=6.1 Hz, 2H), 3.06 (q, J=6.6 Hz, 2H), 1.69 (quintet, J=6.5 Hz, 2H), 1.26 (s, 9H); MS LC-MS [M+H]+=501.2, RT=2.29 min.

Workup

  1. customThe reaction mixture was quenched with saturated NaHCO3
  2. extractionextracted with EtOAc
  3. washThe combined organic phases were washed with brine
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated at reduced pressure
  6. customThe crude residue was purified by MPLC (eluting with 40:60 to 60:40 EtOAc/hexanes)

Sources & evidence

ORD record
ord-6c6ec60902974c91936a5e8c7603e3a3
Source dataset
uspto-grants-2010_11
Patent number
US07838524B2

Reaction notes

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