Ammonia → 4,4-difluoro-5''-methyl-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazole]-4'',6'-diamine

HRID 539345Notes

Reaction equation

HRID 539345 reaction equation
Br[C:2]1[CH:23]=[C:22]2[C:5]([CH2:6][C:7]3([C:15]42[N:19]=[C:18]([NH2:20])[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][C:10]([F:14])([F:13])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1.O[C@H]1C[NH:28][C@H](C(O)=O)C1.C([O-])([O-])=O.[K+].[K+].N>CS(C)=O.CCOC(C)=O.[Cu]I>[F:14][C:10]1([F:13])[CH2:9][CH2:8][C:7]2([C:15]3([N:19]=[C:18]([NH2:20])[C:17]([CH3:21])=[N:16]3)[C:22]3[C:5](=[CH:4][CH:3]=[C:2]([NH2:28])[CH:23]=3)[CH2:6]2)[CH2:12][CH2:11]1

Participants

8

Reactant 4

HCID 222AmmoniaHCID 5810L-Hydroxyproline2×HCID 11430Potassium CarbonateHCID 573858836'-Bromo-4,4-difluoro-5''-methyl-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazol]-4''-amine

Product 1

HCID 573861504,4-difluoro-5''-methyl-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazole]-4'',6'-diamineYield 48.2%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)Catalyst2×HCID 679Dimethyl SulfoxideSolventHCID 8857Ethyl AcetateSolvent

Procedure

6′-Bromo-4,4-difluoro-5″-methyl-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazol]-4″-amine (Example 27, 116 mg, 0.30 mmol), trans-4-hydroxy-L-proline (40 mg, 0.30 mmol), copper(I) iodide (29 mg, 0.15 mmol) and K2CO3 (126 mg, 0.91 mmol) were mixed in dry dimethylsulfoxide (3 mL) in a microwave vial. The mixture was stirred under argon at r.t. for 30 min. Ammonia (30-33% in H2O) (0.285 mL, 4.55 mmol) was added, the vial was sealed and heated at 110° C. for 3 h in a microwave synthesizer. Additional copper(I) iodide (29 mg, 0.15 mmol) and trans-4-hydroxy-L-proline (40 mg, 0.30 mmol) were added and the mixture was then heated to 110° C. for 4 h. The mixture was diluted with EtOAc (10 mL) and washed with brine (10 mL). The aqueous layer was extracted with EtOAc (2×10 mL). The organic layers were combined and concentrated in vacuo. The residue was applied on a short column of silica (4 g SiO2) and eluted with 0-100% (7 M NH3 in MeOH and DCM 1:9) in DCM to give the title compound (46 mg, 48% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 1.17 (t, 1 H), 1.48 (br. s., 2 H), 1.64-1.96 (m, 5 H), 2.11-2.17 (m, 3 H), 2.83 (d, 1 H), 2.90 (d, 1 H), 4.75 (s, 2 H), 5.83 (d, 1 H), 6.37 (dd, 1 H), 6.50 (s, 2 H), 6.90 (d, 1 H); MS (ES+) m/z 319.1 [M+H]+.

Workup

  1. customthe vial was sealed
  2. temperatureheated at 110° C. for 3 h in a microwave synthesizer
  3. temperaturethe mixture was then heated to 110° C. for 4 h
  4. washwashed with brine (10 mL)
  5. extractionThe aqueous layer was extracted with EtOAc (2×10 mL)
  6. concentrationconcentrated in vacuo
  7. washeluted with 0-100% (7 M NH3 in MeOH and DCM 1:9) in DCM

Sources & evidence

ORD record
ord-058c6b884473462b8ad062af79011684
Source dataset
uspto-grants-2014_10
Patent number
US08865911B2

Reaction notes

Loading…