tert-Butyl mercaptan → (3S,5R,6S)-3-Allyl-1-((S)-2-(tert-butylthio)-1-cyclopropylethyl)-6-(4-chloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methylpiperidin-2-one

HRID 1846979Notes

Reaction equation

HRID 1846979 reaction equation
[CH3:1][C:2]([SH:5])([CH3:4])[CH3:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CC1C=CC(S([O-])(=O)=O)=CC=1.[CH2:27]([C@@:30]1([CH3:57])[CH2:35][C@H:34]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[C@@H:33]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([F:50])[CH:44]=2)[N+:32]2[C@@H:51]([CH:54]3[CH2:56][CH2:55]3)[CH2:52][O:53][C:31]1=2)[CH:28]=[CH2:29]>O1CCCC1>[CH2:27]([C@@:30]1([CH3:57])[CH2:35][C@H:34]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[C@@H:33]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([F:50])[CH:44]=2)[N:32]([C@@H:51]([CH:54]2[CH2:55][CH2:56]2)[CH2:52][S:5][C:2]([CH3:4])([CH3:3])[CH3:1])[C:31]1=[O:53])[CH:28]=[CH2:29]

Participants

5

Reactant 3

HCID 6387tert-Butyl mercaptanHCID 2733832Lithium HexamethyldisilazideHCID 86731827(3S,5S,6R,8S)-8-Allyl-5-(4-chloro-3-fluorophenyl)-6-(3-chlorophenyl)-3-cyclopropyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium 4-methylbenzenesulfonate

Product 1

HCID 90354368(3S,5R,6S)-3-Allyl-1-((S)-2-(tert-butylthio)-1-cyclopropylethyl)-6-(4-chloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methylpiperidin-2-one

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
60 °C

Procedure

2-Methyl-2-propanethiol (15.25 mL, 135 mmol, dried over activated 4 Å molecular sieves) was added to a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.0 M, 135 mL, 135 mmol) at room temperature under argon in a 500 mL round-bottomed flask. The reaction mixture was heated to 60° C. After 30 minutes, a solution of (3S,5S,6R,8S)-8-allyl-5-(4-chloro-3-fluorophenyl)-6-(3-chlorophenyl)-3-cyclopropyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-60 ]pyridin-4-ium 4-methylbenzenesulfonate (78 g, 123 mmol, Example 4, Step H) in anhydrous tetrahydrofuran (100 mL) was added via cannula. The reaction mixture was heated at 60° C. for 3 hours and then cooled to room temperature. The reaction mixture was quenched with water and extracted thrice with ethyl acetate. The organics were pooled, washed with brine, dried over magnesium sulfate, filtered and concentrated under a vacuum to provide a yellow foam. Purification by flash column chromatography (1.5 kg SiO2 column, gradient elution with 5% to 30% ethyl acetate in hexanes provided the title compound as an off-white foam.

Workup

  1. temperatureThe reaction mixture was heated at 60° C. for 3 hours
  2. temperaturecooled to room temperature
  3. customThe reaction mixture was quenched with water
  4. extractionextracted thrice with ethyl acetate
  5. washwashed with brine
  6. dry with materialdried over magnesium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated under a vacuum
  9. customto provide a yellow foam
  10. customPurification by flash column chromatography (
  11. wash1.5 kg SiO2 column, gradient elution with 5% to 30% ethyl acetate in hexanes

Sources & evidence

ORD record
ord-de719052a75a43288cce2f91b4981a53
Source dataset
uspto-grants-2015_02
Patent number
US08952036B2

Reaction notes

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