Potassium Carbonate → 3-(4''-Amino-5''-methyl-3',4'-dihydrodispiro[cyclopropane-1,2'-naphthalene-1',2''-imidazol]-7'-yl)-5-fluorobenzonitrile

HRID 1468235Notes

Reaction equation

HRID 1468235 reaction equation
[C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2].Br[C:14]1[CH:31]=[C:30]2[C:17]([CH2:18][CH2:19][C:20]3([C:23]42[N:27]=[C:26]([NH2:28])[C:25]([CH3:29])=[N:24]4)[CH2:22][CH2:21]3)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CC([PH+](C(C)(C)C)CCCS([O-])(=O)=O)(C)C>[Cl-].[Na+].O.[Na+].[Na+].Cl[Pd+2](Cl)(Cl)Cl.CCOC(C)=O.O>[NH2:28][C:26]1[C:25]([CH3:29])=[N:24][C:23]2([C:30]3[C:17](=[CH:16][CH:15]=[C:14]([C:5]4[CH:4]=[C:3]([CH:8]=[C:7]([F:9])[CH:6]=4)[C:1]#[N:2])[CH:31]=3)[CH2:18][CH2:19][C:20]32[CH2:21][CH2:22]3)[N:27]=1

Participants

9

Reactant 4

HCID 11430Potassium CarbonateHCID 23435605(3-Cyano-5-fluorophenyl)boronic acidHCID 249491873-(Di-tert-butylphosphonium)propane sulfonateHCID 727146587'-Bromo-5''-methyl-3',4'-dihydrodispiro[cyclopropane-1,2'-naphthalene-1',2''-imidazol]-4''-amine

Product 1

HCID 727146593-(4''-Amino-5''-methyl-3',4'-dihydrodispiro[cyclopropane-1,2'-naphthalene-1',2''-imidazol]-7'-yl)-5-fluorobenzonitrileYield 86.4%

Reagents, catalysts & solvents 4

HCID 178479786HCID 178479786, compoundCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
100 °C

Procedure

3-Cyano-5-fluorophenylboronic acid (83 mg, 0.50 mmol) was added to 7′-bromo-5″-methyl-3′,4′-dihydrodispiro[cyclopropane-1,2′-naphthalene-1′,2″-imidazol]-4″-amine (Example 1, 100 mg, 0.31 mmol) in dry 2-Me THF (2.85 mL), followed by aq. potassium carbonate (2.0 M, 0.471 mL, 0.94 mmol). Argon was bubbled through the mixture for one min. and then sodium tetrachloropalladate(II) (9.3 mg, 0.03 mmol) and 3-(di-tert-butylphosphonium)propane sulfonate (16.9 mg, 0.06 mmol) were added and the mixture was heated in a microwave reactor for 60 min at 100° C. Water, brine, 2-Me THF and EtOAc were added to the mixture and the phases were separated. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine and water. The organic phase was dried (Na2SO4), filtered and concentrated. Recrystallization from MeOH and CHCl3 and purification by preparative HPLC gave the title compound (96 mg, 85% yield).

Workup

  1. customArgon was bubbled through the mixture for one min.
  2. customthe phases were separated
  3. extractionThe aqueous phase was extracted with EtOAc
  4. washThe combined organic phases were washed with brine and water
  5. dry with materialThe organic phase was dried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customRecrystallization
  9. customfrom MeOH and CHCl3 and purification by preparative HPLC

Sources & evidence

ORD record
ord-324eb7a67a21415dbeed41a9f9928ae1
Source dataset
uspto-grants-2015_04
Patent number
US09000184B2

Reaction notes

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