Nitrogen → tert-Butyl 6-(4-(6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

HRID 587113Notes

Reaction equation

HRID 587113 reaction equation
Br[C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:20][C:9]3([CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]3)[CH2:8]2)[CH:6]=1.[Cl:21][C:22]1[C:27]([F:28])=[CH:26][CH:25]=[C:24]([Cl:29])[C:23]=1[CH:30]([O:32][C:33]1[C:34]([NH2:48])=[N:35][CH:36]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:38]=1)[CH3:31].N#N.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[NH2:48][C:34]1[N:35]=[CH:36][C:37]([C:2]2[CH:3]=[N:4][N:5]([CH:7]3[CH2:20][C:9]4([CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]4)[CH2:8]3)[CH:6]=2)=[CH:38][C:33]=1[O:32][CH:30]([C:23]1[C:24]([Cl:29])=[CH:25][CH:26]=[C:27]([F:28])[C:22]=1[Cl:21])[CH3:31]

Participants

7

Reactant 4

HCID 947Nitrogen2×HCID 10340Sodium CarbonateHCID 211113943-(1-(2,6-Dichloro-3-fluorophenyl)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amineHCID 71244309tert-butyl 6-(4-bromo-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

Product 1

HCID 71240178tert-Butyl 6-(4-(6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylateYield 45%

Reagents, catalysts & solvents 2

HCID 178418476HCID 178418476, compoundCatalystHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
90 °C

Procedure

tert-Butyl 6-(4-bromo-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (145 mg, 0.42 mmol) and (±)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (268 mg, 0.63 mmol) were added to a round bottom flask. It was vacuumed and refilled with N2 (3 times). DME (2.0 mL) and a solution of Na2CO3 (2.0 M, 1.0 mL) were sequentially added. It was vacuumed and refilled with N2 (3 times). Pd(PPh3)2Cl2 (14.7 mg, 0.021 mmol) was added. It was degassed again refilled with N2 (2 times). The mixture was stirred at 90° C. (heating bath) for 16 hrs. The reaction mixture was cooled to room temperature and H2O (30 mL) was added. The aqueous phase was extracted with EtOAc (30 mL) and DCM (3×30 mL). The combined organic phase was dried over anhydrous Na2SO4, concentrated by evaporation in vacuo to give black residue which was purified by CombiFlash (40 g silica gel column, Hexane/EtOAc) to afford (±)-tert-butyl 6-(4-(6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (106 mg, 45%) as a off-white solid.

Workup

  1. customIt was degassed again
  2. additionrefilled with N2 (2 times)
  3. temperature(heating bath) for 16 hrs
  4. temperatureThe reaction mixture was cooled to room temperature
  5. additionH2O (30 mL) was added
  6. extractionThe aqueous phase was extracted with EtOAc (30 mL) and DCM (3×30 mL)
  7. dry with materialThe combined organic phase was dried over anhydrous Na2SO4
  8. concentrationconcentrated by evaporation in vacuo
  9. customto give black residue which
  10. customwas purified by CombiFlash (40 g silica gel column, Hexane/EtOAc)

Sources & evidence

ORD record
ord-a37fc8f051724aec9244c9a4b3868890
Source dataset
uspto-grants-2016_01
Patent number
US09226923B2

Reaction notes

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