Methyl iodide → (5R,6S)-1-((S)-1-(tert-Butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one

HRID 1048445Notes

Reaction equation

HRID 1048445 reaction equation
[Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][CH2:25][C:24]1=[O:43])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:44]I>>[Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][CH:25]([CH3:44])[C:24]1=[O:43])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1

Participants

3

Reactant 2

HCID 6328Methyl iodideHCID 67999011(5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one

Product 1

HCID 67999856(5R,6S)-1-((S)-1-(tert-Butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one

Conditions

Temperature
-78 °C

Procedure

To a −78° C. solution of 98.2 g (156 mmol) of (5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 185, Step C) and 10.0 mL (160 mmol) of methyl iodide in dry, degassed THF (400 mL) was added 200 mL (200 mmol) of a degassed 1 M solution of lithium bis(trimethylsilyl)amide in THF slowly over 20 min. The orange solution was stirred at −78° C. for 1.5 h and then warmed to 0° C. and stirred for an additional 1.5 h. The reaction was quenched with saturated aqueous ammonium chloride, and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by chromatography on silica gel (Biotage® Snap™ column; Biotage, LLC, Charlotte, N.C.), 5-55% EtOAc/hexanes, gradient elution) provided the title compound as a light yellow foam.

Workup

  1. customdegassed THF (400 mL)
  2. additionwas added 200 mL (200 mmol) of a degassed 1 M solution of lithium bis(trimethylsilyl)amide in THF slowly over 20 min
  3. temperaturewarmed to 0° C.
  4. stirringstirred for an additional 1.5 h
  5. customThe reaction was quenched with saturated aqueous ammonium chloride
  6. extractionextracted with EtOAc (3×)
  7. dry with materialThe combined organic layers were dried over Na2SO4
  8. filtrationfiltered
  9. concentrationthe filtrate was concentrated
  10. customPurification of the residue by chromatography
  11. washon silica gel (Biotage® Snap™ column; Biotage, LLC, Charlotte, N.C.), 5-55% EtOAc/hexanes, gradient elution)

Sources & evidence

ORD record
ord-84de3344133947988b7d9b70824d7d4d
Source dataset
uspto-grants-2013_10
Patent number
US08569341B2

Reaction notes

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