3,5-dibromo-1-trityl-1H-1,2,4-triazole → 4-((5-bromo-2-trityl-2H-1,2,4-triazol-3-yl)(5-ethoxy-2-fluoro-3-isopropoxyphenyl)methylamino)benzonitrile

HRID 2105046Notes

Reaction equation

HRID 2105046 reaction equation
[Br:1][C:2]1[N:6]=[C:5](Br)[N:4]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[Li]CCCC.[CH2:32]([O:34][C:35]1[CH:36]=[C:37]([O:52][CH:53]([CH3:55])[CH3:54])[C:38]([F:51])=[C:39]([CH:50]=1)/[CH:40]=[N:41]/[C:42]1[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=1)[CH3:33]>C1COCC1>[Br:1][C:2]1[N:6]=[C:5]([N:41]([CH2:40][C:39]2[CH:50]=[C:35]([O:34][CH2:32][CH3:33])[CH:36]=[C:37]([O:52][CH:53]([CH3:55])[CH3:54])[C:38]=2[F:51])[C:42]2[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=2)[N:4]([C:8]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:3]=1

Participants

5

Reactant 3

HCID 578040363,5-dibromo-1-trityl-1H-1,2,4-triazoleHCID 178418339ButyllithiumHCID 178466720HCID 178466720, compound

Product 1

HCID 688145164-((5-bromo-2-trityl-2H-1,2,4-triazol-3-yl)(5-ethoxy-2-fluoro-3-isopropoxyphenyl)methylamino)benzonitrileYield 29.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a solution of Intermediate 359.1 (748 mg, 1.6 mmol) in THF (10 mL) was added BuLi (1.6 M in THF, 1.02 mL, 1.6 mmol). The mixture was stirred at −78° C. for 15 min, then a solution of Intermediate 7.3 (500 mg, 1.53 mmol) in THF (5 mL) was added dropwise. The mixture was stirred at −78° C. for 30 min, before warming to 23° C., and quenching with aqueous NH4Cl. The mixture was diluted with EtOAc, washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 40% EtOAc/hexanes gradient) followed by preparative HPLC purification to afford 320 mg of Intermediate 359.2. LCMS (2 min gradient) RT=2.45 min, 717.2 (M+H)+; 1H NMR (400 MHz, MeOD) δ ppm 1.25-1.33 (m, 9H) 3.93(q, 2H) 4.41 (m, 1H) 6.15 (d, 2H) 6.52 (m, 1H) 6.82 (m, 1H) 7.03-7.21 (m, 18H).

Workup

  1. stirringThe mixture was stirred at −78° C. for 30 min
  2. temperaturebefore warming to 23° C.
  3. customquenching with aqueous NH4Cl
  4. additionThe mixture was diluted with EtOAc
  5. washwashed with H2O and brine
  6. dry with materialdried (Na2SO4)
  7. concentrationconcentrated
  8. customThe crude product was purified by flash chromatography (0 to 40% EtOAc/hexanes gradient)
  9. customfollowed by preparative HPLC purification

Sources & evidence

ORD record
ord-95125d9ef7804b85bb081d5bfec09373
Source dataset
uspto-grants-2009_08
Patent number
US07576098B2

Reaction notes

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