Binap, (A+-)- → HCID 11273431, compound

HRID 2374966Notes

Reaction equation

HRID 2374966 reaction equation
Br[C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([NH:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)=[N:15]3)=[C:10]([CH3:30])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:31][C:32]1[CH:33]=[C:34]([S:38]([NH:41][CH:42]2[CH2:44][CH2:43]2)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>CO.C(OCC)(=O)C.ClCCl.O1CCOCC1>[CH:42]1([NH:41][S:38]([C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([NH:31][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([C:8]4[N:16]5[C:11]([CH:12]=[N:13][C:14]([NH:17][C:18]6[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=6)=[N:15]5)=[C:10]([CH3:30])[N:9]=4)[CH:3]=3)[CH:33]=2)(=[O:40])=[O:39])[CH2:44][CH2:43]1

Participants

9

Reactant 4

HCID 634876Binap, (A+-)-HCID 53030613-amino-N-cyclopropylbenzenesulfonamideHCID 112135557-(3-bromophenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)-imidazo[5,1-f][1,2,4]triazin-2-amineHCID 23676156Sodium t-butoxide

Product 1

HCID 11273431HCID 11273431, compoundYield 30.1%

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
140 °C

Procedure

To a mixture of 7-(3-bromophenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)-imidazo[5,1-f][1,2,4]triazin-2-amine (Example 9) (20 mg, 0.042 mmol), 3-amino-N-cyclopropyl-benzenesulfonamide (10.8 mg, 0.051 mmol), (S)-(−)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl ((S)-BINAP) (15.9 mg, 0.026 mmol), Tris(dibenzylidineacetone)dipalladium (0) (7.8 mg, 0.008 mmol) and sodium t-butoxide (13.8mg, 0.144 mmol) was added 1,4-dioxane (1.5 mL). In a sealed reaction vessel, the mixture was heated with microwave radiation at 140° C. for 60 minutes. After cooling to room temperature, diluted mixture with methanol (5 mL) and ethyl acetate (5 mL) followed by filtration over celite. Removed solvent under reduced pressure and diluted brown residue in DMSO (1.0 mL). Injected (2×0.5mL) on an Agilent reverse phase prep LC subjected to a gradient elution using acetonitrile(0.1% Formic acid):water(0.1% Formic acid) (10:90 to 90:10). Combined appropriate fractions and removed solvent under reduced pressure. The solid material was dissolved in methanol and dichloromethane and added silica gel (100 mg). Followed by evaporation of the volatiles under reduced pressure, the pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using ethyl acetate:hexanes (30:70 to 90:10) using a RediSep silica gel cartridge (4.2 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give solid material that was again dissolved in dichlormethane and adsorbed onto a silica gel prep plate (20 cm×20 cm, 1000 μm). Eluted with ethyl acetate:hexanes (70:30), removed silica from plate and washed with ethyl acetate/methanol/dichloromethane (25 mL). Removed solvent under reduced pressure to give N-cyclopropyl-3-[(3-{5-methyl-2-[(3,4,5-trimethoxyphenyl)-amino]imidazo[5,1-f][1,2,4]triazin-7-yl}phenyl)amino]benzenesulfonamide (0.0076 g) as a yellow solid. 1H NMR (CD3OD) δ9.01 (s, 1H), 8.09 (dd, J=2.0, 1.6 Hz, 1H), 7.85-7.82 (m, 1H), 7.60-7.59 (m, 1H), 7.4 (dd, J=7.9, 8.0 Hz, 1H), 7.33-7.29 (m, 2H), 7.28-7.25 (m, 1H), 7.21 (ddd, J=8.2, 2.4, 1.1 Hz, 1H), 7.03 (s, 2H), 3.74 (s, 6H), 3.69 (s, 3H), 2.57 (s, 3H), 2.15-2.10 (m, 1H), 0.49-0.45 (m, 4H). MS m/z 602 (M+1).

Workup

  1. customIn a sealed reaction vessel
  2. temperatureAfter cooling to room temperature
  3. filtrationfollowed by filtration over celite
  4. additionRemoved solvent under reduced pressure and diluted brown residue in DMSO (1.0 mL)
  5. washsubjected to a gradient elution
  6. customremoved solvent under reduced pressure
  7. dissolutionThe solid material was dissolved in methanol
  8. additiondichloromethane and added silica gel (100 mg)
  9. customFollowed by evaporation of the volatiles under reduced pressure
  10. washsubjected to a gradient elution
  11. concentrationconcentrated under reduced pressure
  12. customto give solid material that
  13. washEluted with ethyl acetate:hexanes (70:30)
  14. customremoved silica from plate
  15. washwashed with ethyl acetate/methanol/dichloromethane (25 mL)

Sources & evidence

ORD record
ord-1bcb0a18bb554c72b84e0593c0076c96
Source dataset
uspto-grants-2008_12
Patent number
US07462614B2

Reaction notes

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