Tetrahydrofuran → HCID 86673650, compound

HRID 924326Notes

Reaction equation

HRID 924326 reaction equation
[C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17](OC)=[CH:16][CH:15]=3)[C:11](=[O:22])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.[Li+].[CH3:30][Si]([N-][Si](C)(C)C)(C)C.[C:39](Cl)(=[O:43])[CH:40]([CH3:42])[CH3:41].O1C[CH2:48][CH2:47][CH2:46]1>>[C:39]([C@@H:10]1[CH2:9][CH:8]([CH2:7][C:4]2[CH:5]=[CH:6][C:1]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:2][CH:3]=2)[N:12](/[CH:13]=[CH:14]/[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:30]=2)[C:11]1=[O:22])(=[O:43])[C:40]1[CH:42]=[CH:48][CH:47]=[CH:46][CH:41]=1

Participants

5

Reactant 4

HCID 8028Tetrahydrofuran2×HCID 62325Isobutyryl chlorideHCID 2733832Lithium HexamethyldisilazideHCID 53311905HCID 53311905, compound

Product 1

HCID 86673650HCID 86673650, compound

Procedure

(S)-5-Biphenyl-4-ylmethyl-1-((E)-styryl)-pyrrolidin-2-one (3a, R1=styryl) (2.0 g, 5.7 mmol) is dissolved in 15 mL of anhydrous tetrahydrofuran, cool to −10˜−15° C. by ice salt bath, add LiHMDS (14.2 mL, 14.2 mmol, 1 M in tetrahydrofuran) dropwise under nitrogen atmosphere, the result mixture is stirred at this temperature for 30 min, then add a solution of isobutyryl chloride (820 mg, 6.8 mmol) in 5 mL of anhydrous tetrahydrofuran dropwise, keep the temperature below −5° C., stir for 1 h, quench with saturated NH4Cl aqueous solution, add 50 mL of ethyl acetate, separate the aqueous phase, wash with saturated Na2CO3 aqueous solution and brine, dry over anhydrous Na2SO4, evaporate the solvent under vacuum to obtain (S)-5-Biphenyl-4-ylmethyl-3-isobutyryl-1-((E)-styryl)-pyrrolidin-2-one (4a, R1=styryl, R4=isopropyl), which is direct used in next step. The ratio of (3S,5S) to (3R,5S) is 70:30 as determined by HPLC. Spectroscopic data as Example 14, Method 1.

Workup

  1. temperaturecool to −10˜−15° C. by ice salt bath
  2. customthe temperature below −5° C.
  3. stirringstir for 1 h
  4. customquench with saturated NH4Cl aqueous solution
  5. additionadd 50 mL of ethyl acetate
  6. customseparate the aqueous phase
  7. washwash with saturated Na2CO3 aqueous solution and brine
  8. dry with materialdry over anhydrous Na2SO4
  9. customevaporate the solvent under vacuum

Sources & evidence

ORD record
ord-884e44240922425887d7127ee1721fba
Source dataset
uspto-grants-2016_03
Patent number
US09278908B2

Reaction notes

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