Tetrahydrofuran → 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide

HRID 1619633Notes

Reaction equation

HRID 1619633 reaction equation
[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[N:10][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1CCCC1.[Cl:33][C:34]1[C:35]([F:45])=[CH:36][C:37]([F:44])=[C:38]([S:40](Cl)(=[O:42])=[O:41])[CH:39]=1.[Cl-].[NH4+]>CC1CCCO1.O>[Cl:33][C:34]1[C:35]([F:45])=[CH:36][C:37]([F:44])=[C:38]([S:40]([N:6]([CH2:5][C:4]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=2[O:2][CH3:1])[C:7]2[S:8][CH:9]=[N:10][N:11]=2)(=[O:42])=[O:41])[CH:39]=1

Participants

8

Reactant 5

HCID 8028TetrahydrofuranHCID 25517Ammonium ChlorideHCID 2733832Lithium HexamethyldisilazideHCID 27735275-Chloro-2,4-difluorobenzenesulphonyl chlorideHCID 58042278N-(2,4-dimethoxybenzyl)-1,3,4-thiadiazol-2-amine

Product 1

HCID 580422535-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamideYield 58.5%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 73012-MethyltetrahydrofuranSolvent2×

Conditions

Temperature
15 °C

Procedure

N-(2,4-Dimethoxybenzyl)-1,3,4-thiadiazol-2-amine (Preparation 14, 203.4 g, 0.809 mol) was dissolved in 2-methyltetrahydrofuran (1.63 L) and the yellow suspension cooled to between −38° C. and −45° C. A 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (890 mL, 0.890 mol) was added slowly over 15 minutes keeping the temperature between −38° C. and −45° C. to give an orange suspension. This orange suspension was stirred at −38° C. to −45° C. for 45 minutes and then a solution of 5-chloro-2,4-difluorobenzenesulfonyl chloride, (200 g, 0.809 mol) in 2-methyltetrahydrofuran (407 mL) added slowly over 20 minutes keeping the temperature between −38° C. and −45° C. The mixture was warmed to 15° C. over 1 hour. The reaction was quenched with a solution of ammonium chloride (203.4 g, 3.80 mol) in water (1.02 L) and stirred vigorously for 5 minutes. The layers were separated and the organic layer washed with water (813.6 mL) and concentrated in vacuo to give an orange solid which was triturated with isopropyl acetate (1.22 L) to afford the title compound as a yellow-orange solid (218.6 g).

Workup

  1. temperaturethe yellow suspension cooled to between −38° C. and −45° C
  2. customthe temperature between −38° C. and −45° C.
  3. customto give an orange suspension
  4. customthe temperature between −38° C. and −45° C
  5. stirringstirred vigorously for 5 minutes
  6. customThe layers were separated
  7. washthe organic layer washed with water (813.6 mL)
  8. concentrationconcentrated in vacuo
  9. customto give an orange solid which
  10. customwas triturated with isopropyl acetate (1.22 L)

Sources & evidence

ORD record
ord-265a742a59294c16b0de68f6e220ff7d
Source dataset
uspto-grants-2014_07
Patent number
US08772293B2

Reaction notes

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