Bromide ion → 14-Amino-14-(3-methyl-3h-imidazol-4-yl)-2-oxa-10-aza-tricyclo[13.3.1.13,7]eicosa-1(18),3,5,7(20),15(19),16-hexaene-18-carbonitrile

HRID 413432Notes

Reaction equation

HRID 413432 reaction equation
[Mg].BrCCCO[Si]([C:10]([CH3:13])([CH3:12])[CH3:11])(C)C.[Br-].[C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:31]2[N:32]([CH3:36])[CH:33]=[N:34][CH:35]=2)=[N:24]S(CC(C)C)=O)=[CH:19][C:18]=1F)#[N:16].[CH2:38]1C[O:41][CH2:40][CH2:39]1>>[NH2:24][C:23]1([C:31]2[N:32]([CH3:36])[CH:33]=[N:34][CH:35]=2)[C:20]2=[CH:19][C:18](=[C:17]([C:15]#[N:16])[CH:22]=[CH:21]2)[O:41][C:40]2[CH:12]=[C:10]([CH:11]=[CH:38][CH:39]=2)[CH2:13][CH2:33][NH:32][CH2:31][CH2:23][CH2:20]1

Participants

6

Reactant 5

HCID 259Bromide ionHCID 8028Tetrahydrofuran2×HCID 607486(3-Bromopropoxy)(tert-butyl)dimethylsilaneHCID 5462224MagnesiumHCID 86584782N-[(4-cyano-3-fluoro-phenyl)-(3-methyl-3H-imidazol-4-yl)-methylene]-2-methylpropanesulfinamide

Product 1

HCID 1020023714-Amino-14-(3-methyl-3h-imidazol-4-yl)-2-oxa-10-aza-tricyclo[13.3.1.13,7]eicosa-1(18),3,5,7(20),15(19),16-hexaene-18-carbonitrile

Procedure

Magnesium (0.317 g, 12.03 mmol) was flame dried in a 50 mL RB flask equipped with addition funnel and magnetic stirrer under N2. When the flask had cooled, anhydrous THF (3 mL), a pinch of iodine, and a THF solution of Rieke magnesium (1 mL) were added, followed by a small portion of (3-bromopropoxy)-tert-butyldimethylsilane (3.048 g, 12.03 mmol) in THF (5 mL) with slight warming to initiate the reaction. The remainder of the bromide solution was added dropwise over 15 min. After 15 min. this Grignard solution was added to a solution of N-[(4-cyano-3-fluoro-phenyl)-(3-methyl-3H-imidazol-4-yl)-methylene]-2-methylpropanesulfinamide (Example 1, Step G) (1.00 g, 3.01 mmol) in THF (5 mL) with cooling in an ice-H2O bath. After 5 mL of Grignard solution was consumed, the reaction was complete by HPLC. The reaction mixture was quenched with H2O, diluted with saturated NaHCO3 solution and extracted with CH2Cl2 (2×20 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated to give the crude product. Purification on an ISCO Combiflash eluting with 1-3% MeOH/CH2Cl2 w/NH4OH gave the title compound.

Workup

  1. customdried in a 50 mL RB flask
  2. customequipped with addition funnel and magnetic stirrer under N2
  3. temperatureWhen the flask had cooled
  4. additionanhydrous THF (3 mL), a pinch of iodine, and a THF solution of Rieke magnesium (1 mL) were added
  5. temperaturewith slight warming
  6. customthe reaction
  7. temperaturewith cooling in an ice-H2O bath
  8. customAfter 5 mL of Grignard solution was consumed
  9. customThe reaction mixture was quenched with H2O
  10. additiondiluted with saturated NaHCO3 solution
  11. extractionextracted with CH2Cl2 (2×20 mL)
  12. washwashed with brine
  13. dry with materialdried (MgSO4)
  14. filtrationfiltered
  15. concentrationconcentrated
  16. customto give the crude product
  17. customPurification on an ISCO Combiflash
  18. washeluting with 1-3% MeOH/CH2Cl2

Sources & evidence

ORD record
ord-4c56b35cfe1a4c5f8b336fd00882c1c7
Source dataset
uspto-grants-2003_05
Patent number
US06566385B2

Reaction notes

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