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

HRID 239377Notes

Reaction equation

HRID 239377 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].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:34][C:35]1[N:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N:36]=1>C1COCC1>[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 76.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
1.5 °C

Procedure

Methyl 3-{[(2,6-difluorophenyl)sulfonyl]amino}-2-fluorobenzoate (490 g, 1 equiv.), prepared generally in accordance with Step A, above, was dissolved in THF (2.45 L, 5 vols) and stirred and cooled to 0-3° C. 1M lithium bis(trimethylsilyl)amide in THF (5.25 L, 3.7 equiv.) solution was charged to the reaction mixture followed addition of 2-chloro-4-methylpyrimidine (238 g, 1.3 equiv.) in THF (2.45 L, 5 vols). The reaction was then stirred for 1 hr. The reaction was quenched with 4.5M HCl (3.92 L, 8 vols). The aqueous layer (bottom layer) was removed and discarded. The organic layer was concentrated under reduced pressure to ˜2 L. IPAC (isopropyl acetate) (2.45 L) was added to the reaction mixture which was then concentrated to ˜2 L. IPAC (0.5 L) and MTBE (2.45 L) was added and stirred overnight under N2. The solids were filtered. The solids and mother filtrate added back together and stirred for several hours. The solids were filtered and washed with MTBE (˜5 vol). The solids were placed in vacuum oven at 50° C. overnight. The solids were dried in vacuum oven at 30° C. over weekend to obtain N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (479 g, 72%).

Workup

  1. stirringThe reaction was then stirred for 1 hr
  2. customThe reaction was quenched with 4.5M HCl (3.92 L, 8 vols)
  3. customThe aqueous layer (bottom layer) was removed
  4. concentrationThe organic layer was concentrated under reduced pressure to ˜2 L
  5. additionIPAC (isopropyl acetate) (2.45 L) was added to the reaction mixture which
  6. concentrationwas then concentrated to ˜2 L
  7. additionIPAC (0.5 L) and MTBE (2.45 L) was added
  8. stirringstirred overnight under N2
  9. filtrationThe solids were filtered
  10. additionThe solids and mother filtrate added back together
  11. stirringstirred for several hours
  12. filtrationThe solids were filtered
  13. washwashed with MTBE (˜5 vol)
  14. customThe solids were dried in vacuum oven at 30° C. over weekend

Sources & evidence

ORD record
ord-ea02d00c0b294c9b81042581cbfffe63
Source dataset
uspto-grants-2014_02
Patent number
US08642759B2

Reaction notes

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