Acetic Acid → HCID 11315931, compound

HRID 1174804Notes

Reaction equation

HRID 1174804 reaction equation
P(C(C)(C)C)(C(C)(C)C)[C:2](C)(C)[CH3:3].N(C(C)C)C(C)C.[CH:21]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([O:33][C:34]2[C:39]([CH3:40])=[C:38]([O:41][C:42]3[CH:47]=[CH:46][C:45](Br)=[CH:44][C:43]=3[F:49])[N:37]=[CH:36][N:35]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])[CH3:22].[Si](C#C)(C)(C)C.[OH-].[Na+].CC(O)=O>O1CCOCC1.C1COCC1.CO.[Cu]I>[CH:21]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([O:33][C:34]2[C:39]([CH3:40])=[C:38]([O:41][C:42]3[CH:47]=[CH:46][C:45]([C:2]#[CH:3])=[CH:44][C:43]=3[F:49])[N:37]=[CH:36][N:35]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])[CH3:22]

Participants

11

Reactant 6

HCID 176Acetic AcidHCID 7912DiisopropylamineHCID 14798Sodium HydroxideHCID 66111TrimethylsilylacetyleneHCID 83681Tris(1,1-dimethylethyl)phosphineHCID 59856682HCID 59856682, compound

Product 1

HCID 11315931HCID 11315931, compound

Reagents, catalysts & solvents 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 887MethanolSolventHCID 8028TetrahydrofuranSolventHCID 312751,4-DioxaneSolvent

Procedure

Pd(II)(PhCN)2Cl2 (15 mg, 0.039 mmol) and CuI (9 mg, 0.047 mmol) were dissolved in anhydrous dioxane (3 mL), 10 wt % P(t-Bu)3 in hexanes (0.200 mL, 13.6 mg, 0.067 mmol), NH(i-Pr)2, (0.085 mL, 0.60 mmol), 4-[6-(4-bromo-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (243 mg, 0.50 mmol), and TMS-acetylene (0.083 mL, 0.60 mmol), were added and the reaction mixture was sealed, purged with nitrogen, and stirred at room temperature for 12 h. The reaction mixture was diluted with EtOAc (15 mL), the mixture was filtered through a silica pad, the solvent was evaporated in vacuo at 23 C to give a dark oil which was dissolved in THF (3.5 mL) and MeOH (1.5 mL). 1.0 N NaOH (0.75 mL, 0.75 mmol) was added and after 5 min glacial AcOH (0.086 mL, 1.5 mmol) was added. After addition of silica (2.4 g) the solvent was evaporated in vacuo at 25 C to give a solid which was pulverized with mortar and pestle. This crude product was adsorbed onto silica and purified by flash chromatography using hexanes-EtOAc, 82:18, then hexanes-EtOAc, 75:25, v/v, to give the title Compound C240 as a resin (67 mg, 32% over 2 steps). 1H NMR (400 MHz, CDCl3) δ 1.25 (d, J=6 Hz, 6H), 1.78 (m, 2H), 1.98 (m, 2H), 2.17 (s, 3H), 3.07 (s, 1H), 3.40 (m, 2H), 3.74 (m, 2H), 4.92 (m, 1H), 5.32 (m, 1H), 7.14 (m, 1H), 7.29 (m, 2H), 8.18 (s, 1H). LRMS calculated for C22H24FN3O4: 413.18. Found: 414.5 (M+H).

Workup

  1. customthe reaction mixture was sealed
  2. custompurged with nitrogen
  3. additionThe reaction mixture was diluted with EtOAc (15 mL)
  4. filtrationthe mixture was filtered through a silica pad
  5. customthe solvent was evaporated in vacuo at 23 C
  6. customto give a dark oil which
  7. additionwas added
  8. additionAfter addition of silica (2.4 g) the solvent
  9. customwas evaporated in vacuo at 25 C
  10. customto give a solid which
  11. custompurified by flash chromatography

Sources & evidence

ORD record
ord-00fd4f65084d445fae0b36c19aa6db15
Source dataset
uspto-grants-2010_11
Patent number
US07838525B2

Reaction notes

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