Chlorotrimethylsilane → HCID 57672058, compound

HRID 1692115Notes

Reaction equation

HRID 1692115 reaction equation
[OH:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1.CN(C)CC.[Si](Cl)(C)(C)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:30][C:31]1[C:36]([Cl:37])=[CH:35][C:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([N:46]3[CH2:51][CH2:50][CH:49]([C:52]([F:55])([F:54])[F:53])[CH2:48][CH2:47]3)=[O:45])=[CH:40][CH:39]=2)=[CH:33][C:32]=1[Cl:56]>C1COCC1.CCOC(C)=O.CCCCCCC>[Cl:56][C:32]1[CH:33]=[C:34]([C:38]2[CH:39]=[CH:40][C:41]([C:44]([N:46]3[CH2:51][CH2:50][CH:49]([C:52]([F:55])([F:54])[F:53])[CH2:48][CH2:47]3)=[O:45])=[CH:42][CH:43]=2)[CH:35]=[C:36]([Cl:37])[C:31]=1[CH2:30][C@@H:5]1[CH2:4][C@@H:3]([CH2:2][OH:1])[O:7][C:6]1=[O:8]

Participants

8

Reactant 5

HCID 6397ChlorotrimethylsilaneHCID 11723DimethylethylamineHCID 2733813(S)-(+)-gamma-Hydroxymethyl-gamma-butyrolactoneHCID 2733832Lithium Hexamethyldisilazide2×HCID 57672064(4'-Bromomethyl-3',5'-dichloro-biphenyl-4-yl)-(4-trifluoromethyl-piperidin-1-yl)-methanone3×

Product 1

HCID 57672058HCID 57672058, compoundYield 60%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 21899848Ethylacetate heptaneSolvent2×

Conditions

Temperature
-10 °C

Procedure

Dissolve (S)-5-Hydroxymethyl-dihydro-furan-2-one (1.21 g, 1 eq.) in THF (16 mL) and cool to −10° C. To this add dimethylethylamine (1.8 mL, 1.5 eq.) followed by the dropwise addition of TMS-Cl (1.46 mL, 1.1 eq.) Allow the reaction to stir for 1.5 hours at −10° C. Gas Chromatography confirms complete consumption of the (S)-5-Hydroxymethyl-dihydro-furan-2-one. Filter the mixture and wash with additional THF (25 mL). Cool the solution to −78° C. To this add LiHMDS (10 mL, 1.23 eq. to (4′-Bromomethyl-3′,5′-dichloro-biphenyl-4-yl)-(4-trifluoromethyl-piperidin-1-yl)-methanone) dropwise and allow to stir at −78° C. for 30 minutes. Add (4′-Bromomethyl-3′,5′-dichloro-biphenyl-4-yl)-(4-trifluoromethyl-piperidin-1-yl)-methanone (4 g, 0.76 eq. to (S)-5-Hydroxymethyl-dihydro-furan-2-one) and keep the reaction at −78° C. After 1 hour, TLC (50% EtOAc/Heptane) shows approximately 50% (4′-Bromomethyl-3′,5′-dichloro-biphenyl-4-yl)-(4-trifluoromethyl-piperidin-1-yl)-methanone. At the end of the day, add LiHMDS (3 mL) and allow to warm to room temperature overnight. TLC (50% EtOAc/Heptane) still shows a small amount of (4′-Bromomethyl-3′,5′-dichloro-biphenyl-4-yl)-(4-trifluoromethyl-piperidin-1-yl)-methanone. Quench the reaction with phosphoric acid:water (1:3) (50 mL) and allow to stir at room temperature for 1 hour. Extract the aqueous layer with EtOAc (3×100 mL). Combine the organic layers, dry and concentrate. Pass the crude oil through a silica gel plug (EtOAc) to give the titled compound (2.57 g, 60% yield).

Workup

  1. customthe reaction
  2. customconsumption of the (S)-5-Hydroxymethyl-dihydro-furan-2-one
  3. filtrationFilter the mixture
  4. washwash with additional THF (25 mL)
  5. temperatureCool the solution to −78° C
  6. stirringto stir at −78° C. for 30 minutes
  7. customthe reaction at −78° C
  8. waitAfter 1 hour
  9. temperatureto warm to room temperature overnight
  10. customQuench
  11. customthe reaction with phosphoric acid:water (1:3) (50 mL)
  12. stirringto stir at room temperature for 1 hour
  13. extractionExtract the aqueous layer with EtOAc (3×100 mL)
  14. customCombine the organic layers, dry
  15. concentrationconcentrate

Sources & evidence

ORD record
ord-5f05a8ea2cd0469eb796bccb8e6f973c
Source dataset
uspto-grants-2012_04
Patent number
US08153807B2

Reaction notes

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