Lithium Hexamethyldisilazide → 3-(fluoro(phenylsulfonyl)methyl)-1-(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)-3-hydroxyindolin-2-one

HRID 573410Notes

Reaction equation

HRID 573410 reaction equation
[F:1][C:2]1[CH:19]=[C:18]([C:20]2[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=2)[CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[C:6]1=[O:15].[F:26][CH2:27][S:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:30])=[O:29].C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>C1COCC1>[F:26][CH:27]([S:28]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)(=[O:29])=[O:30])[C:7]1([OH:14])[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([CH2:4][C:3]2[CH:16]=[CH:17][C:18]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)=[CH:19][C:2]=2[F:1])[C:6]1=[O:15]

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 2759036Fluoromethyl Phenyl SulfoneHCID 442515561-(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)indoline-2,3-dione

Product 1

HCID 896769373-(fluoro(phenylsulfonyl)methyl)-1-(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)-3-hydroxyindolin-2-one

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

1-(2-Fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)indoline-2,3-dione (1 g, 3.0 mmol) was added to a flame-dried round bottom flask with stir bar and dissolved in THF (30 mL). Next, ((fluoromethyl)sulfonyl)benzene (780 mg, 4.5 mmol) was added, and the mixture was cooled to −78° C. Lithium hexamethyldisilazide (1M in THF, 4.5 mL, 4.5 mmol) was added dropwise to the cooled solution, and the mixture was allowed to gradually warm to room temperature overnight. The reaction was quenched by addition of excess saturated brine, and then extracted with 3×50 mL ethyl acetate. The organic layers were combined, dried over magnesium sulfate, evaporated and purified by silica gel chromatography (30-100% EtOAc in hexanes gradient) to afford 3-(fluoro(phenylsulfonyl)methyl)-1-(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)-3-hydroxyindolin-2-one as a yellowish foam. To a scintillation vial containing a magnetic stir bar was added 3-(fluoro(phenylsulfonyl)methyl)-1-(2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)benzyl)-3-hydroxyindolin-2-one (305 mg, 0.6 mmol), followed by DMF (6 mL), magnesium powder (150 mg, 6 mmol), and 3 mL of an acetic acid/sodium acetate (1:1) buffer solution (8 mol/L). The vial was sealed and allowed to stir at room temperature overnight. The mixture was diluted with water (100 mL), and then extracted with 5×25 mL ethyl acetate. The organic layers were combined, dried over magnesium sulfate, evaporated, and purified by reversed-phase HPLC using 0.1% TFA in water/acetonitrile as a mobile phase to afford the title compound. LCMS: RT=0.67 min, >99% @ 254 nm, >99% @ 215 nm; m/z (M+1)+=370. 1HNMR (400 MHz, CDCl3, δ (ppm)): 7.53 (s, 1H), 7.47 (s, 1H), 7.3 (dt, J=7.8, 1.1 Hz, 1H), 7.2-7.1 (m, 2H), 7.1-7.0 (m, 2H), 6.9 (d, J=7.9 Hz, 1H), 5.0 (d, J=15.8 Hz, 1H), 4.9 (d, J=15.8 Hz, 1H), 4.8 (quartet, J=3.6 Hz, 1H), 4.6 (quartet, J=9.1, 4.0 Hz, 1H), 3.9 (s, 3H), HRMS calculated for C20H18N3O2F2 (M+H)+ m/z: 370.1367, measured: 370.1366.

Workup

  1. temperatureto gradually warm to room temperature overnight
  2. customThe reaction was quenched by addition of excess saturated brine
  3. extractionextracted with 3×50 mL ethyl acetate
  4. dry with materialdried over magnesium sulfate
  5. customevaporated
  6. custompurified by silica gel chromatography (30-100% EtOAc in hexanes gradient)

Sources & evidence

ORD record
ord-5bbb2e8fcbf343d493c3a10bee97d666
Source dataset
uspto-grants-2015_05
Patent number
US09029563B2

Reaction notes

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