Lithium Hexamethyldisilazide → N-(3-(2-(2-chloropyriMidin-4-yl)acetyl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide

HRID 1942916Notes

Reaction equation

HRID 1942916 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH:12][C:13]1[C:14]([F:23])=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16](OC)=[O:17])(=[O:11])=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:34][C:35]1[N:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N:36]=1>O1CCCC1>[Cl:34][C:35]1[N:40]=[C:39]([CH2:41][C:16]([C:15]2[C:14]([F:23])=[C:13]([NH:12][S:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])(=[O:10])=[O:11])[CH:22]=[CH:21][CH:20]=2)=[O:17])[CH:38]=[CH:37][N:36]=1

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 116296072-Chloro-4-methylpyrimidineHCID 57989692Benzoic acid, 3-[[(2,6-difluorophenyl)sulfonyl]amino]-2-fluoro-, methyl ester

Product 1

HCID 57989720N-(3-(2-(2-chloropyriMidin-4-yl)acetyl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamideYield 33.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-5 °C

Procedure

To a solution of methyl 3-(2,6-difluorophenylsulfonamido)-2-fluorobenzoate (6.6 g, 19.11 mmol) in tetrahydrofuran (THF) (80 mL) stirred under nitrogen at −30° C. was added the solution of LiHMDS (65 mL, 65 mmol) in tetrahydrofuran dropwise over 40 mins. The reaction mixture was stirred at −5° C. for 2 hours. The reaction mixture was cooled again to −30° C. 2-Chloro-4-methylpyrimidine (2.95 g, 22.94 mmol) in tetrahydrofuran (THF) (10 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at −10° C. for 1 h, and warmed to room temperature for another 1.5 hours. The reaction mixture was cooled to 0° C. and quenched by addition of the satureated aqueous NH4Cl (80 mL) and extracted with ethyl acetate (100 ml×3). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product, which was purified by silica gel chromatography with petroleum ether/EtOAc (2:1) to produce the N-(3-(2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (5.05 g, 6.37 mmol, 33.3% yield). LCMS [M+H]+=442.

Workup

  1. temperatureThe reaction mixture was cooled again to −30° C
  2. stirringThe reaction mixture was stirred at −10° C. for 1 h
  3. temperaturewarmed to room temperature for another 1.5 hours
  4. temperatureThe reaction mixture was cooled to 0° C.
  5. customquenched by addition of the satureated aqueous NH4Cl (80 mL)
  6. extractionextracted with ethyl acetate (100 ml×3)
  7. washThe combined organic layers were washed with water and brine
  8. dry with materialdried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure
  11. customto afford the crude product, which
  12. customwas purified by silica gel chromatography with petroleum ether/EtOAc (2:1)

Sources & evidence

ORD record
ord-1d0aad73ee034eac817b79e141130d02
Source dataset
uspto-grants-2013_03
Patent number
US08389723B1

Reaction notes

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