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Phosphoric Acid → HCID 57671322, compound

HRID 1013827
Notes
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Reaction equation

HRID 1013827 reaction equation
[OH:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1.CN(C)CC.C[Si](Cl)(C)C.Br[CH2:20][C:21]1[C:26]([Cl:27])=[CH:25][C:24]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][C:22]=1[Cl:35].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].P(=O)(O)(O)O>C1COCC1.O.C(OCC)(=O)C>[Cl:27][C:26]1[CH:25]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH:23]=[C:22]([Cl:35])[C:21]=1[CH2:20][C@@H:5]1[CH2:4][C@@H:3]([CH2:2][OH:1])[O:7][C:6]1=[O:8]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

10

Reactant 6

HCID 1004Phosphoric AcidHCID 6397ChlorotrimethylsilaneHCID 11723DimethylethylamineHCID 2733813(S)-(+)-gamma-Hydroxymethyl-gamma-butyrolactoneHCID 2733832Lithium hexamethyldisilazaneHCID 57671317HCID 57671317, compound

Product 1

HCID 57671322
HCID 57671322, compound
Yield 79%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent3×HCID 8857Ethyl AcetateSolvent

Procedure

Dissolve commercially available (S)-5-hydroxymethyl-dihydro-furan-2-one (33.0 g, 284 mmoles) in 450 mL of THF, and then add 31.2 g (427 mmoles) of dimethylethylamine along with 50 mL of THF (rinse). Place the mixture under nitrogen and cool in an ice/water bath. Add trimethylsilyl chloride 39.8 mL (313 mmoles) while maintaining the temperature below 13° C. Filter the mixture and rinse the cake with THF (2×100 mL). Cool the solution of TMS (trimethylsilyl) protected lactone to −78° C. and add 4-bromomethyl-3,5-dichloro-4′-fluoro-biphenyl (71.2 g, 213 mmoles). Add a 1 M solution of lithium hexamethyldisilazide in THF (264 mL, 264 mmoles) over 1 h at −65 to −78° C. After stirring for 1 h, add a 600 mL solution of 120 mL of conc. phosphoric acid in water. After stirring for 10 min at room temperature, add 1 L of ethyl acetate and stir the mixture for 10 min. The layers separate. Wash the organic layer with water (2×500 mL). Evaporate the solvent down to a solution of approximately 250 mL and add an additional 250 mL of EtOAc. Evaporate the solvent until a solution of approximately 300-350 mL remains. Heat the mixture to reflux and add 494 mL of heptane. Allow the slurry to cool to room temperature, collect the solids by filtration, and rinse with heptane (2×100 mL). Dry the solid under vacuum to afford 62.1 g (59%) of the titled compound. MS (m/z): 369 (M+1, 35Cl), 371 (M+1, 37Cl).

Workup

  1. temperaturecool in an ice/water bath
  2. filtrationFilter the mixture
  3. washrinse the cake with THF (2×100 mL)
  4. temperatureCool the solution of TMS (trimethylsilyl)
  5. customto −78° C.
  6. stirringAfter stirring for 10 min at room temperature
  7. stirringstir the mixture for 10 min
  8. customThe layers separate
  9. washWash the organic layer with water (2×500 mL)
  10. customEvaporate the solvent down to a solution of approximately 250 mL
  11. additionadd an additional 250 mL of EtOAc
  12. customEvaporate the solvent until a solution of approximately 300-350 mL
  13. temperatureHeat the mixture
  14. temperatureto reflux
  15. additionadd 494 mL of heptane
  16. customcollect the solids
  17. filtrationby filtration
  18. washrinse with heptane (2×100 mL)
  19. customDry the solid under vacuum

Sources & evidence

ORD record
ord-cae31a63bb1b44d491e897c5d28345f4
Source dataset
uspto-grants-2011_07
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07981918B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes