Lithium Hexamethyldisilazide → N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-3H-imidazol-4-yl)-pyrazol-1-yl]-benzamide

HRID 2109221Notes

Reaction equation

HRID 2109221 reaction equation
[NH2:1][C:2]1[C:3]([O:17][CH3:18])=[C:4]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.[Li]CCCC.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C([O:36][C:37](=O)[C:38]1[CH:43]=[CH:42][C:41]([CH3:44])=[C:40]([N:45]2[CH:49]=[C:48]([C:50]3[N:51]([CH3:55])[CH:52]=[N:53][CH:54]=3)[CH:47]=[N:46]2)[CH:39]=1)C>C1COCC1.CO>[C:8]([C:6]1[CH:5]=[C:4]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:3]([O:17][CH3:18])=[C:2]([NH:1][C:37](=[O:36])[C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[C:40]([N:45]3[CH:49]=[C:48]([C:50]4[N:51]([CH3:55])[CH:52]=[N:53][CH:54]=4)[CH:47]=[N:46]3)[CH:39]=2)[CH:7]=1)([CH3:10])([CH3:11])[CH3:9]

Participants

7

Reactant 4

HCID 2733832Lithium HexamethyldisilazideHCID 10214710N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamideHCID 588612804-methyl-3-[4-(3-methyl-3H-imidazol-4-yl)-pyrazol-1-yl]-benzoic acid ethyl esterHCID 178418339Butyllithium

Product 1

HCID 21097201N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-3H-imidazol-4-yl)-pyrazol-1-yl]-benzamideYield 33.6%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

A solution of N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide (81 mg, 0.261 mmol) in THF (4 mL) was stirred in a bath cooled to −78° C., and n-BuLi (0.22 mL, 0.548 mmol) was added slowly. The cold bath was removed, and the reaction was allowed to stir for 30 min. LHMDS (0.261 mmol) was then added slowly. The suspension was transferred dropwise to a stirring solution of compound 4-methyl-3-[4-(3-methyl-3H-imidazol-4-yl)-pyrazol-1-yl]-benzoic acid ethyl ester (81 mg, 0.261 mmol) in THF at 0° C. After 30 min cole MeOH was added and the mixture was partitioned between saturated NH4Cl and EtOAc, then extracted with EtOAc (3×). The organic combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated, and chromatographed (1% MeOH (with 5% NH4OH)/CH2Cl2 to 5% MeOH (with 5% NH4OH)/CH2Cl2) to afford N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-3-[4-(3-methyl-3H-imidazol-4-yl)-pyrazol-1-yl]-benzamide (47 mg, 33%) as an orange foam: ESI MS m/z=537 [C27H32N6O4S+H]+.

Workup

  1. customThe cold bath was removed
  2. customthe mixture was partitioned between saturated NH4Cl and EtOAc
  3. extractionextracted with EtOAc (3×)
  4. washThe organic combined extracts were washed with brine
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customchromatographed (1% MeOH (with 5% NH4OH)/CH2Cl2 to 5% MeOH (with 5% NH4OH)/CH2Cl2)

Sources & evidence

ORD record
ord-143e69599c0b40b7a3d5a0ef9ef973d4
Source dataset
uspto-grants-2009_04
Patent number
US07514458B2

Reaction notes

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