3-Aminopropionitrile → 3-(4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-yl)propanenitrile

HRID 885741Notes

Reaction equation

HRID 885741 reaction equation
[Br:1][C:2]1[N:3]=[C:4]([CH:22]2[CH2:24][CH2:23]2)[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9](Cl)[N:8]=1.[NH2:25][CH2:26][CH2:27][C:28]#N.C(N(C(C)C)CC)(C)C.C([O-])([O-])=O.[Na+].[Na+]>CN1C(=O)CCC1>[Br:1][C:2]1[N:3]=[C:4]([CH:22]2[CH2:24][CH2:23]2)[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:28][CH2:27][C:26]#[N:25])[N:8]=1

Participants

6

Reactant 4

HCID 16473-AminopropionitrileHCID 10340Sodium CarbonateHCID 81531DiisopropylethylamineHCID 866514084-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy) methyl)-1H-imidazol-5-yl)-2-chloropyrimidine

Product 1

HCID 698129173-(4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-yl)propanenitrileYield 77.1%

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of 4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine (I-1a, step 5, 3.50 g, 8.14 mmol), 3-aminopropionitrile (1.79 mL, 24.4 mmol), diisopropylethylamine (2.84 ml, 16.3 mmol) and Na2CO3 (1.73 g, 16.3 mmol) in dry NMP (4 mL) was heated at 90° C. for 8 hours. The reaction was cooled to room temperature, and then partitioned between EtOAc (100 mL) and water (100 mL), and the layers separated. The organic portion was washed with water (100 mL), saturated aqueous NaHCO3 solution (100 ml), brine (100 mL), dried (Na2SO4) and concentrated. The crude residue was purified by flash chromatography (SiO2, 0-50% EtOAc in heptane) to furnish 3-(4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-yl)propanenitrile as a pale yellow foam (2.91 g, 6.28 mmol). LCMS(m/z) 463.1 (MH+), tR=0.98 minute, 1H NMR (CDCl3) δ ppm-0.09 (s, 9H) 0.73-0.85 (m, 2H) 0.99-1.11 (m, 2H) 1.12-1.21 (m, 2H) 1.90-2.05 (m, 1H) 2.75 (t, J=6.7 Hz, 2H) 3.36-3.48 (m, 2H) 3.76 (q, J=6.5 Hz, 3H) 5.50 (br s, 1H) 5.85 (s, 2H) 7.20 (d, J=5.1 Hz, 1H) 8.37 (d, J=5.1 Hz, 1H).

Workup

  1. temperatureThe reaction was cooled to room temperature
  2. custompartitioned between EtOAc (100 mL) and water (100 mL)
  3. customthe layers separated
  4. washThe organic portion was washed with water (100 mL), saturated aqueous NaHCO3 solution (100 ml), brine (100 mL)
  5. dry with materialdried (Na2SO4)
  6. concentrationconcentrated
  7. customThe crude residue was purified by flash chromatography (SiO2, 0-50% EtOAc in heptane)

Sources & evidence

ORD record
ord-337b8a278e474aeab50da2cf6864d242
Source dataset
uspto-grants-2012_08
Patent number
US08242260B2

Reaction notes

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