Diisopropylamine → Tert-butyl 4-((4-amino-6-chloro-2-methylpyrimidin-5-YL)ethynyl)piperidine-1-carboxylate

HRID 575525Notes

Reaction equation

HRID 575525 reaction equation
[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[C:3]=1I.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]#[CH:25])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(NC(C)C)(C)C>C1COCC1.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.[Cu]I>[NH2:9][C:4]1[C:3]([C:25]#[C:24][CH:21]2[CH2:20][CH2:19][N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH2:23][CH2:22]2)=[C:2]([Cl:1])[N:7]=[C:6]([CH3:8])[N:5]=1

Participants

7

Reactant 3

HCID 7912DiisopropylamineHCID 15550481tert-Butyl 4-ethynylpiperidine-1-carboxylate2×HCID 885808566-Chloro-5-iodo-2-methylpyrimidin-4-amine

Product 1

HCID 118060900Tert-butyl 4-((4-amino-6-chloro-2-methylpyrimidin-5-YL)ethynyl)piperidine-1-carboxylateYield 86.8%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)Catalyst2×HCID 178418476HCID 178418476, compoundCatalyst2×HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
52.5 °C

Procedure

Dissolve 6-chloro-5-iodo-2-methyl-pyrimidin-4-amine (20 g, 74.22 mmol), 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (18.64 g, 89.06 mmol), and diisopropylamine (10.44 mL, 74.22 mmol) in THF (200 mL) in a 3-neck flask. Alternately evacuate and charge the flask with nitrogen 3 times. Add bis(triphenylphosphine)palladium(II) chloride (2.63 g, 3.71 mmol) and copper(I) iodide (0.713 g, 3.71 mmol) to the solution. Heat the mixture to between 50 to 55° C. for 16 h. Cool the mixture to RT and add more bis(triphenylphosphine)palladium(II) chloride (1.31 g, 1.86 mmol), copper(I) iodide (0.356 g, 1.86 mmol) and 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (1.55 g, 7.42 mmol). Heat the mixture to 60° C. for 3.5 h. Cool the mixture to RT and concentrate under reduced pressure. Dilute the material with DCM (300 mL) and wash with saturated aqueous ammonium chloride solution (100 mL), water (100 mL), and saturated aqueous sodium chloride (100 mL). Dry the solution over MgSO4, filter, and concentrate under reduced pressure. Purify the residue using silica gel chromatography (800 g silica gel column) eluting with 20% to 100% EtOAc in hexanes. Concentrate the purified fractions to give the title compound as a pale orange powder (22.6 g, 86%). LC-ES/MS m/z (35Cl/37Cl) 351.2/353.1 (M+1).

Workup

  1. customAlternately evacuate
  2. additioncharge the flask with nitrogen 3 times
  3. temperatureCool the mixture to RT
  4. temperatureHeat the mixture to 60° C. for 3.5 h
  5. temperatureCool the mixture to RT
  6. concentrationconcentrate under reduced pressure
  7. additionDilute the material with DCM (300 mL)
  8. washwash with saturated aqueous ammonium chloride solution (100 mL), water (100 mL), and saturated aqueous sodium chloride (100 mL)
  9. dry with materialDry the solution over MgSO4
  10. filtrationfilter
  11. concentrationconcentrate under reduced pressure
  12. customPurify the residue
  13. washeluting with 20% to 100% EtOAc in hexanes
  14. concentrationConcentrate the purified fractions

Sources & evidence

ORD record
ord-9a05370e426c4fadbd583627ebdfacac
Source dataset
uspto-grants-2015_05
Patent number
US09035051B1

Reaction notes

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