1,4-Dioxane → HCID 53377726, compound

HRID 2091925Notes

Reaction equation

HRID 2091925 reaction equation
Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[F:29][C:30]([F:42])([F:41])[CH2:31][C:32]1[NH:36][C:35]2[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=2[N:33]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:26]1[CH2:27][CH2:28][N:23]([C:4]2[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=[C:2]([N:33]3[C:34]4[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=4[N:36]=[C:32]3[CH2:31][C:30]([F:29])([F:42])[F:41])[N:3]=2)[CH2:24][CH2:25]1

Participants

8

Reactant 5

HCID 312751,4-DioxaneHCID 62657Potassium Phosphate, TribasicHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 431321902-(2,2,2-Trifluoroethyl)-1H-benzimidazoleHCID 584049702-(1-((2-Chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol

Product 1

HCID 53377726HCID 53377726, compoundYield 53%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolvent

Conditions

Temperature
155 °C

Procedure

A small vial was charged with 2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 (0.070 g, 0.17 mmol), 2-(2,2,2-trifluoro-ethyl)-1H-benzoimidazole (0.042 g, 0.21 mmol), XPhos (0.012 g, 0.026 mmol) and Potassium phosphate (0.110 g, 0.519 mmol). Dry 1,4-dioxane (1.9 mL, 0.024 mol) was added. The whole was sparged with nitrogen for 3 min. Tris(dibenzylideneacetone)dipalladium(0) (0.012 g, 0.013 mmol) was added under nitrogen. The vial was sealed and heated at 155° C. (heating block temp) for 4 h. LC/MS indicates complete reaction. The solution was diluted with water and extracted with dichloromethane 3 times. The combined organics were washed with brine and dried over sodium sulfate. The material was purified by reverse phase HPLC to give 51.3 mg (53% yield) of 173 as a white solid. LCMS (MH+)=570.3. 1H NMR (400 MHz, DMSO) δ 8.25-8.15 (m, 2H), 7.91 (d, J=8.7 Hz, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.42-7.31 (m, 2H), 4.65 (q, J=10.7 Hz, 2H), 4.90-4.25 (br m, 4H), 4.05 (s, 1H), 3.88-3.80 (m, 4H), 3.74 (s, 2H), 2.92 (d, J=11.1 Hz, 2H), 1.99 (t, J=11.1 Hz, 2H), 1.67 (d, J=11.2 Hz, 2H), 1.37-1.23 (m, 2H), 1.22-1.12 (m, 1H), 1.04 (s, 6H)

Workup

  1. customThe whole was sparged with nitrogen for 3 min
  2. customThe vial was sealed
  3. temperature(heating block temp) for 4 h
  4. customreaction
  5. extractionextracted with dichloromethane 3 times
  6. washThe combined organics were washed with brine
  7. dry with materialdried over sodium sulfate
  8. customThe material was purified by reverse phase HPLC

Sources & evidence

ORD record
ord-d5fa8a6624ad43d389bc8286c7958685
Source dataset
uspto-grants-2013_05
Patent number
US08440651B2

Reaction notes

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