Lithium Hexamethyldisilazide → 1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(6-(trifluoromethyl)pyrimidin-4-yl)isoquinoline-6-sulfonamide

HRID 1473635Notes

Reaction equation

HRID 1473635 reaction equation
[F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:22][O:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[C:34]1[C:43]2[C:38](=[CH:39][C:40]([S:44](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:46])=[O:45])=[CH:41][CH:42]=2)[CH:37]=[CH:36][N:35]=1>C1COCC1>[CH3:22][O:23][C:24]1[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=[CH:26][C:25]=1[C:34]1[C:43]2[C:38](=[CH:39][C:40]([S:44]([NH:9][C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:10])[F:11])[N:8]=[CH:7][N:6]=3)(=[O:46])=[O:45])=[CH:41][CH:42]=2)[CH:37]=[CH:36][N:35]=1

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 223857566-(Trifluoromethyl)pyrimidin-4-amineHCID 86687478Perfluorophenyl 1-(2-methoxy-4-(trifluoromethyl)phenyl)isoquinoline-6-sulfonate

Product 1

HCID 866877061-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(6-(trifluoromethyl)pyrimidin-4-yl)isoquinoline-6-sulfonamideYield 15.6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

A round-bottom flask was charged with 6-(trifluoromethyl)pyrimidin-4-amine (0.030 g, 0.182 mmol)) and THF (0.910 ml), and the vessel was cooled to −78° C. for 15 minutes. Lithium bis(trimethylsilyl)amide (0.218 ml, 0.218 mmol),) was then added drop wise over 1 minute. The reaction was stirred for 10 minutes, and then a solution of perfluorophenyl 1-(2-methoxy-4-(trifluoromethyl)phenyl)isoquinoline-6-sulfonate (Intermediate LLL; 0.100 g, 0.182 mmol) in THF (1.6 mL) was added drop wise. The bath was removed, and the resulting mixture was stirred for 45 minutes. The reaction was diluted with saturated ammonium chloride (aq.) solution (30 mL), and was washed with ethyl acetate (20 mL×3). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The resulting material was purified via silica gel chromatography (ISCO, 40 g), eluting with 0 to 100% ethyl acetate in heptanes. The fractions were concentrated under reduced pressure to yield 1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(6-(trifluoromethyl)pyrimidin-4-yl)isoquinoline-6-sulfonamide (0.015 g, 0.028 mmol, 15.60% yield). m/z (ESI) 528.9 (M+H)+.

Workup

  1. customThe bath was removed
  2. stirringthe resulting mixture was stirred for 45 minutes
  3. additionThe reaction was diluted with saturated ammonium chloride (aq.) solution (30 mL)
  4. washwas washed with ethyl acetate (20 mL×3)
  5. dry with materialdried over magnesium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe resulting material was purified via silica gel chromatography (ISCO, 40 g)
  9. washeluting with 0 to 100% ethyl acetate in heptanes
  10. concentrationThe fractions were concentrated under reduced pressure

Sources & evidence

ORD record
ord-84bedfc42f034c2fb84f7f0b9bdf34bc
Source dataset
uspto-grants-2015_04
Patent number
US09012443B2

Reaction notes

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