Formaldehyde → HCID 67998522, compound

HRID 932222Notes

Reaction equation

HRID 932222 reaction equation
C(NC(C)C)(C)C.[Li]CCCC.[Si:13]([O:30][CH2:31][C@@H:32]([N:36]1[C@H:41]([C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=2)[C@@H:40]([C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([Cl:55])[CH:50]=2)[CH2:39][C@@:38]([CH2:57][C:58]([O:60][CH3:61])=[O:59])([CH3:56])[C:37]1=[O:62])[CH:33]1[CH2:35][CH2:34]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Li+].CC([N-]C(C)C)C.[CH2:71]=[O:72]>C1COCC1.N#N>[Si:13]([O:30][CH2:31][C@@H:32]([N:36]1[C@H:41]([C:42]2[CH:43]=[CH:44][C:45]([Cl:48])=[CH:46][CH:47]=2)[C@@H:40]([C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([Cl:55])[CH:50]=2)[CH2:39][C@@:38]([C@@H:57]([CH2:71][OH:72])[C:58]([O:60][CH3:61])=[O:59])([CH3:56])[C:37]1=[O:62])[CH:33]1[CH2:34][CH2:35]1)([C:26]([CH3:27])([CH3:29])[CH3:28])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1

Participants

8

Reactant 5

HCID 712Formaldehyde3×HCID 7912DiisopropylamineHCID 2724682Lithium diisopropylamideHCID 67999455HCID 67999455, compoundHCID 178418339Butyllithium

Product 1

HCID 67998522HCID 67998522, compound

Reagents, catalysts & solvents 2

HCID 947NitrogenSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-15 °C

Procedure

To a solution of diisopropylamine (249 μL, 1.75 mmol) in THF (1.2 mL) was added 1.6 M n-BuLi in hexanes (984 μL, 1.57 mmol) slowly at −15° C. After 30 minutes, a solution of methyl 2-((3R,5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetate (255 mg, 0.35 mmol; Example 263, Step B) in THF (1.2 mL) was added dropwise to the LDA solution and the resulting solution was stirred at −15° C. for 30 min (the solution turned bright yellow). Then, formaldehyde in N2 stream was carried over the reaction surface for 5 min (formaldehyde was generated by cracking para-formaldehyde (105 mg, 3.50 mmol) with heat gun) at −15° C. After being stirred at −15° C. for 30 min, the reaction was allowed to warm to rt and stirred for 4 h. The reaction was quenched (ice cold sat. NH4Cl), extracted (2×EtOAc) and washed (brine×3). The combined organic layers were dried (Na2SO4) and concentrated under the reduced pressure. Purification of the residue by chromatography on silica gel (24 g SiO2, 20% and 50% EtOAc/Hex) provided the title compound as a colorless film.

Workup

  1. stirringAfter being stirred at −15° C. for 30 min
  2. temperatureto warm to rt
  3. stirringstirred for 4 h
  4. customThe reaction was quenched (ice cold sat. NH4Cl)
  5. extractionextracted (2×EtOAc)
  6. washwashed (brine×3)
  7. dry with materialThe combined organic layers were dried (Na2SO4)
  8. concentrationconcentrated under the reduced pressure
  9. customPurification of the residue by chromatography on silica gel (24 g SiO2, 20% and 50% EtOAc/Hex)

Sources & evidence

ORD record
ord-89e890d053ea44fb8dcf63fb17ae24fc
Source dataset
uspto-grants-2016_03
Patent number
US09296736B2

Reaction notes

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