2,8,9-Triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo(3.3.3)undecane → Isopropyl 4-(6-(6-bromo-2,4-dimethylpyridin-3-ylamino)-5-methoxypyrimidin-4-yloxy)piperidine-1-carboxylate

HRID 1811586Notes

Reaction equation

HRID 1811586 reaction equation
Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[C:3]=1[O:21][CH3:22].[Br:23][C:24]1[N:29]=[C:28]([CH3:30])[C:27]([NH2:31])=[C:26]([CH3:32])[CH:25]=1.C(N1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2)C(C)C.O(C(C)(C)C)[Na]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].O>[Br:23][C:24]1[N:29]=[C:28]([CH3:30])[C:27]([NH:31][C:2]2[N:7]=[CH:6][N:5]=[C:4]([O:8][CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)[C:3]=2[O:21][CH3:22])=[C:26]([CH3:32])[CH:25]=1

Participants

8

Reactant 4

HCID 45712432,8,9-Triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo(3.3.3)undecaneHCID 288753476-Bromo-2,4-dimethylpyridin-3-amineHCID 51050526Isopropyl 4-[(6-chloro-5-methoxypyrimidin-4-yl)oxy]piperidine-1-carboxylateHCID 178418730sodium 2-methylpropan-2-olate

Product 1

HCID 58671560Isopropyl 4-(6-(6-bromo-2,4-dimethylpyridin-3-ylamino)-5-methoxypyrimidin-4-yloxy)piperidine-1-carboxylate

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
150 °C

Procedure

To a solution of isopropyl 4-(6-chloro-5-methoxypyrimidin-4-yloxy)piperidine-1-carboxylate (2.0 g, 6.1 mmol) in 10 ml of dioxane, were added 6-bromo-2,4-dimethylpyridin-3-amine (1.0 g, 5.1 mmol), 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane (0.35 g, 1.0 mmol), Pd(OAc)2 (0.11 g, 0.51 mmol), and NaO-t-Bu (1.2 g, 12 mmol) at an ambient temperature. The reaction was heated to 150° C. for 3 hrs. The reaction was cooled to room temperature and poured into H2O. The organics were extracted with ethyl acetate and dried over MgSO4. The ethyl acetate was concentrated under vacuum and purified over SiO2 to give isopropyl 4-(6-(6-bromo-2,4-dimethylpyridin-3-ylamino)-5-methoxy pyrimidin-4-yloxy)piperidine-1-carboxylate. 1HNMR (CDCl3, 400 MHz) δ 1.24-1.25 (d, J=6.2 Hz, 6H), 1.72-1.77 (m, 2H), 1.95-2.01 (m, 2H), 2.22 (s, 3H), 2.52 (s, 3H), 3.37-3.44 (m, 2H), 3.73-3.79 (m, 2H), 4.91-4.97 (m, 1H), 5.30-5.35 (m, 1H), 6.01 (s, 1H), 7.34-7.36 (d, J=8.5 Hz, 1H), 8.14-8.16 (d, J=8.5 Hz, 1H), 8.37 (s, 1H). Exact mass calculated for C21H28BrN5O4 494.31. found 495.2 (MH+).

Workup

  1. temperatureThe reaction was cooled to room temperature
  2. extractionThe organics were extracted with ethyl acetate
  3. dry with materialdried over MgSO4
  4. concentrationThe ethyl acetate was concentrated under vacuum
  5. custompurified over SiO2

Sources & evidence

ORD record
ord-a64c9db6907d413897e102c43b556cdf
Source dataset
uspto-grants-2013_01
Patent number
US08362248B2

Reaction notes

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