Chlorodifluoromethane → 4-[4'-[(Difluoromethyl)thio][1,1'-biphenyl]-4-yl]-2-(2,6-difluorophenyl)-4,5-dihydrooxazole

HRID 1872024Notes

Reaction equation

HRID 1872024 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([S:26][Si](C(C)C)(C(C)C)C(C)C)=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[N:13]=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].[OH-].[K+].Cl[CH:58]([F:60])[F:59]>C1COCC1.O>[F:59][CH:58]([F:60])[S:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]2[CH:16]=[CH:15][C:14]([CH:12]3[CH2:11][O:10][C:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[N:13]3)=[CH:19][CH:18]=2)=[CH:21][CH:22]=1

Participants

7

Reactant 4

HCID 6372ChlorodifluoromethaneHCID 14797Potassium HydroxideHCID 2724141Tetrabutylammonium FluorideHCID 186900462-(2,6-Difluorophenyl)-4,5-dihydro-4-[4'-[[tris(1-methylethyl)silyl]thio][1,1'-biphenyl]-4-yl]oxazole

Product 1

HCID 154525844-[4'-[(Difluoromethyl)thio][1,1'-biphenyl]-4-yl]-2-(2,6-difluorophenyl)-4,5-dihydrooxazole

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 10.9 g of the title compound of Step B in 20 mL of THF was added 23 mL of a commercial 1.0 M solution of n-Bu4NF in THF (containing 5% water) at 15 to 20° C. (water bath cooling) under a nitrogen atmosphere. After 5 minutes, 5.9 g of freshly-ground KOH was added, and then excess Freon® 22 (chlorodifluoromethane) was added through a subsurface tube at a rate sufficient to maintain a slight overpressure. After 20 to 30 minutes, the gas addition was stopped, and the reaction mixture was poured into ice-cold aqueous NH4Cl and extracted with ethyl acetate. The organic phase was washed with water and saturated aqueous NaCl, dried over MgSO4, and concentrated under vacuum. The residue was adsorbed onto silica gel, applied to a column of silica gel and eluted with hexanes/ethyl acetate (4:1 to 3:1 v:v) to obtain an oil. The oil crystallized upon trituration with ether and hexane to produce a white solid that was dried to provide 6.2 g of the title compound of Step C, a compound of this invention, melting at 72-76° C. 1H NMR (CDCl3, 300 MHz) δ 4.3-4.4 (m,1H), 4.8 (m,1H), 5.5 (m,1H), 6.85 (m,1H), 7.0 (m, 2H), 7.4-7.7 (m,9H).

Workup

  1. temperatureto maintain a slight overpressure
  2. waitAfter 20 to 30 minutes
  3. additionthe gas addition
  4. additionthe reaction mixture was poured into ice-cold aqueous NH4Cl
  5. extractionextracted with ethyl acetate
  6. washThe organic phase was washed with water and saturated aqueous NaCl
  7. dry with materialdried over MgSO4
  8. concentrationconcentrated under vacuum
  9. washeluted with hexanes/ethyl acetate (4:1 to 3:1 v:v)
  10. customto obtain an oil
  11. customThe oil crystallized upon trituration with ether and hexane
  12. customto produce a white solid
  13. customthat was dried

Sources & evidence

ORD record
ord-774ab66f371b495889922a5b677ab577
Source dataset
uspto-grants-2000_08
Patent number
US06107319

Reaction notes

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