Potassium Carbonate → 6'-(5-Chloropyridin-3-yl)-4-(difluoromethyl)-5''-methyl-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazol]-4''-amine

HRID 1965151

Reaction equation

HRID 1965151 reaction equation
Br[C:2]1[CH:24]=[C:23]2[C:5]([CH2:6][C:7]3([C:16]42[N:20]=[C:19]([NH2:21])[C:18]([CH3:22])=[N:17]4)[CH2:12][CH2:11][CH:10]([CH:13]([F:15])[F:14])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[N:30][CH:31]=1.CC([PH+](C(C)(C)C)CCCS([O-])(=O)=O)(C)C.C([O-])([O-])=O.[K+].[K+]>[Na+].[Na+].Cl[Pd+2](Cl)(Cl)Cl>[Cl:25][C:26]1[CH:27]=[C:28]([C:2]2[CH:24]=[C:23]3[C:5]([CH2:6][C:7]4([C:16]53[N:20]=[C:19]([NH2:21])[C:18]([CH3:22])=[N:17]5)[CH2:8][CH2:9][CH:10]([CH:13]([F:14])[F:15])[CH2:11][CH2:12]4)=[CH:4][CH:3]=2)[CH:29]=[N:30][CH:31]=1

Participants

6

Reactant 4

HCID 11430Potassium CarbonateHCID 201118775-Chloropyridine-3-boronic acidHCID 249491873-(Di-tert-butylphosphonium)propane sulfonateHCID 679795776'-Bromo-4-(difluoromethyl)-5''-methyl-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazol]-4''-amine

Product 1

HCID 679793846'-(5-Chloropyridin-3-yl)-4-(difluoromethyl)-5''-methyl-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazol]-4''-amineYield 11.2%

Reagents, catalysts & solvents 1

HCID 178479786HCID 178479786, compoundCatalyst

Conditions

Temperature
100 °C

Procedure

6′-Bromo-4-(difluoromethyl)-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine (Example 128, 0.1 g, 0.25 mmol), 5-chloropyridin-3-yl boronic acid (0.048 g, 0.30 mmol), 3-(di-tert-butylphosphonium)propane sulfonate (6.77 mg, 0.03 mmol), sodium tetrachloro-palladate(II) (3.71 mg, 0.01 mmol), 2-Me THF (2 mL) and aq. K2CO3 (2.0 M, 0.379 mL, 0.76 mmol) were added to a microwave vial. The vial was sealed and evacuated and refilled with Ar (g) and then heated in the microwave reactor for 30 min at 100° C. The same amount of Pd-catalyst, ligand and boronic ester were added and the vial was sealed and evacuated and refilled with Ar (g). The vial was heated in the microwave reactor for 30 min at 100° C. EtOAc and water were added and the organic phase was extracted, dried through a phase separator and evaporated to dryness. The crude product was purified using preparative chromatography to give the title compound (12 mg, 11% yield): 1H NMR (500 MHz, CD3CN) δ ppm 1.24-1.41 (m, 4 H), 1.45-1.54 (m, 3 H), 1.71-1.86 (m, 1 H), 2.00 (dt, 1 H), 2.24 (s, 3 H), 2.98 (d, 1 H), 3.07 (d, 1 H), 5.32 (br. s., 2 H), 5.64 (d, 1 H), 6.86 (d, 1 H), 7.38 (d, 1 H), 7.50 (dd, 1 H), 7.93 (t, 1 H), 8.49 (d, 1 H), 8.65 (d, 1 H); MS (MM−ES+APCI)+ m/z 429 [M+H]+.

Workup

  1. customThe vial was sealed
  2. customevacuated
  3. additionrefilled with Ar (g)
  4. additionThe same amount of Pd-catalyst, ligand and boronic ester were added
  5. customthe vial was sealed
  6. customevacuated
  7. additionrefilled with Ar (g)
  8. temperatureThe vial was heated in the microwave reactor for 30 min at 100° C
  9. additionEtOAc and water were added
  10. extractionthe organic phase was extracted
  11. customdried through a phase separator
  12. customevaporated to dryness
  13. customThe crude product was purified

Sources & evidence

ORD record
ord-40ff2a9e26b446138c7fc2c12917a698
Source dataset
uspto-grants-2013_04
Patent number
US08415483B2

Linked notes

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