Dichloromethane → 3-(5-(2-chloropyrimidin-4-yl)-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-2-fluoroaniline

HRID 1043726Notes

Reaction equation

HRID 1043726 reaction equation
Br[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:13])[N:8]=1.[F:25][C:26]1[C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=[CH:29][C:27]=1[NH2:28].C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>[NH4+].[Cl-].COCCOC>[Cl:13][C:9]1[N:8]=[C:7]([C:6]2[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:4]([CH:22]3[CH2:24][CH2:23]3)=[N:3][C:2]=2[C:32]2[C:26]([F:25])=[C:27]([CH:29]=[CH:30][CH:31]=2)[NH2:28])[CH:12]=[CH:11][N:10]=1

Participants

7

Reactant 4

HCID 6344DichloromethaneHCID 10340Sodium CarbonateHCID 581644342-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)anilineHCID 866514084-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy) methyl)-1H-imidazol-5-yl)-2-chloropyrimidine

Product 1

HCID 866514093-(5-(2-chloropyrimidin-4-yl)-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-2-fluoroanilineYield 38%

Reagents, catalysts & solvents 2

HCID 80711,2-DimethoxyethaneSolventHCID 25517Ammonium ChlorideSolvent

Procedure

To a microwave vial with stir bar was added 4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine (I-1a, step 5, 0.55 g, 1.3 mmol), 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.61 g, 2.6 mmol), 2.0 M aqueous sodium carbonate solution (3.2 mL, 6.4 mmol) and DME (6.4 mL). The resulting mixture was sparged with nitrogen followed by the addition of PdCl2(dppf).DCM adduct (0.052 g, 0.06 mmol). The reaction was sealed and irradiated in microwave reactor for 20 minutes at 120° C. The reaction mixture was diluted with a saturated aqueous NH4Cl solution and extracted with EtOAc. The organic phase was washed with water, brine, dried (Na2SO4), filtered, concentrated, and adsorbed onto silica gel. Purification by flash chromatography (SiO2, 0-100% EtOAc in heptane) yielded 3-(5-(2-chloropyrimidin-4-yl)-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-2-fluoroaniline (223 mg, 0.48 mmol, 38%) as a viscous yellow oil: LCMS (m/z) 460.1 (MH+), tR=0.95 minute.

Workup

  1. customThe resulting mixture was sparged with nitrogen
  2. additionfollowed by the addition of PdCl2(dppf)
  3. customThe reaction was sealed
  4. customirradiated in microwave reactor for 20 minutes at 120° C
  5. extractionextracted with EtOAc
  6. washThe organic phase was washed with water, brine
  7. dry with materialdried (Na2SO4)
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customPurification by flash chromatography (SiO2, 0-100% EtOAc in heptane)

Sources & evidence

ORD record
ord-5473ab7257c249f58cf72312a6d4550f
Source dataset
uspto-grants-2013_10
Patent number
US08563553B2

Reaction notes

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