Lithium Hexamethyldisilazide → 3-cyano-N-(2,4-di methoxybenzyl)-4-fluoro-N-(5-fluoropyridin-2-yl)benzenesulfonamide

HRID 2178121Notes

Reaction equation

HRID 2178121 reaction equation
[CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:30]([C:32]1[CH:33]=[C:34]([S:39](Cl)(=[O:41])=[O:40])[CH:35]=[CH:36][C:37]=1[F:38])#[N:31]>C1COCC1>[C:30]([C:32]1[CH:33]=[C:34]([S:39]([N:6]([CH2:5][C:4]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:3]=2[O:2][CH3:1])[C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]=2)(=[O:41])=[O:40])[CH:35]=[CH:36][C:37]=1[F:38])#[N:31]

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 27789083-Cyano-4-fluorobenzenesulfonyl chlorideHCID 58042270N-(2,4-dimethoxybenzyl)-5-fluoropyridin-2-amine

Product 1

HCID 1176533623-cyano-N-(2,4-di methoxybenzyl)-4-fluoro-N-(5-fluoropyridin-2-yl)benzenesulfonamideYield 63%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To a −40° C. solution of N-(2,4-dimethoxybenzyl)-5-fluoropyridin-2-amine (Preparation 20, 2.32 g, 8.84 mmol) in THF (60 ml) was added LiHMDS (9.72 ml, 9.72 mmol, 1M in THF) keeping the temperature below −35° C. The reaction mixture was warmed to 0° C. for 40 minutes before re-cooling to −40° C. 3-Cyano-4-fluorobenzene-1-sulfonyl chloride (1.94 g, 8.84 mmol) was added to the reaction mixture as a solution in THF (10 mL) and the reaction mixture allowed to warm to room temperature for 18 hours. The reaction mixture was quenched with saturated ammonium chloride solution (100 mL) and extracted with EtOAc (2×100 mL). The organic layer was washed with saturated brine (100 mL), dried over MgSO4, filtered and the solvent removed under vacuum. The crude material was purified by silica gel column chromatography eluting with 20-40 EtOAc in heptane followed by reverse phase chromatography eluting with 0-100% MeCN in H2O to afford the title compound as a brown gum (2.48 g, 63%).

Workup

  1. customthe temperature below −35° C
  2. temperaturebefore re-cooling to −40° C
  3. temperatureto warm to room temperature for 18 hours
  4. customThe reaction mixture was quenched with saturated ammonium chloride solution (100 mL)
  5. extractionextracted with EtOAc (2×100 mL)
  6. washThe organic layer was washed with saturated brine (100 mL)
  7. dry with materialdried over MgSO4
  8. filtrationfiltered
  9. customthe solvent removed under vacuum
  10. customThe crude material was purified by silica gel column chromatography
  11. washeluting with 20-40 EtOAc in heptane
  12. washeluting with 0-100% MeCN in H2O

Sources & evidence

ORD record
ord-3920137cac4f4b8eb5c1093b3424eeaf
Source dataset
uspto-grants-2015_06
Patent number
US09067922B2

Reaction notes

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