Trimethylsilyl iodide → (3R,4S)-N-cyclopropyl-4-(4-(2-(2,6-dichloro-4-methylphenoxy)ethoxy)phenyl)-N-(3-(2-hydroxy-2-methylpropoxy)-5-(3-methoxypropyl)benzyl)piperidine-3-carboxamide

HRID 658262Notes

Reaction equation

HRID 658262 reaction equation
[CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([O:51][CH2:52][C:53]([OH:56])([CH3:55])[CH3:54])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.I[Si](C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([O:51][CH2:52][C:53]([OH:56])([CH3:54])[CH3:55])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][NH:9][CH2:8]2)=[O:6])[CH2:2][CH2:3]1

Participants

5

Reactant 3

HCID 85247Trimethylsilyl iodideHCID 2724141Tetrabutylammonium FluorideHCID 86639857tert-Butyl (3R,4S)-3-({cyclopropyl[3-(2-hydroxy-2-methylpropoxy)-5-(3-methoxypropyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)-ethoxy]phenyl}piperidine-1-carboxylate

Product 1

HCID 24953170(3R,4S)-N-cyclopropyl-4-(4-(2-(2,6-dichloro-4-methylphenoxy)ethoxy)phenyl)-N-(3-(2-hydroxy-2-methylpropoxy)-5-(3-methoxypropyl)benzyl)piperidine-3-carboxamide

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of tert-butyl (3R,4S)-3-({cyclopropyl[3-(2-hydroxy-2-methyl-propoxy)-5-(3-methoxypropyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1-carboxylate in acetonitrile (0.02 M) at 0° C. was added iodotrimethylsilane (2 eq.) and stirred for 10 min at 0° C. The reaction was quenched with saturated aqueous NaHCO3 solution and extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was dissolved in THF (0.2 M) and added tetrabutylammonium fluoride (2 eq.), and the reaction was stirred for 1 h at rt. The reaction mixture was concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 7% [2 M NH3 in MeOH] in DCM) to afford the title compound as a colorless oil. 1H NMR (acetone d-6): δ 7.30 (s, 2H), 7.20 (d, 2H), 6.85 (d, 2H), 6.65 (s, 1H), 6.55 (s, 1H), 6.38 (s, 1H), 4.30-4.45 (m, 6H), 3.50-3.80 (m, 4H), 3.00-3.48 (m, 8H), 2.70-2.90 (m, 2H), 2.55 (t, 2H), 2.30-2.40 (m, 4H), 1.70-1.85 (m, 4H), 1.30 (s, 6H), 0.4-0.9 (m, 4H). LRMS [M+H]=713.2

Workup

  1. customThe reaction was quenched with saturated aqueous NaHCO3 solution
  2. extractionextracted with EtOAc
  3. washThe combined organic extracts were washed with brine
  4. dry with materialdried over MgSO4
  5. concentrationconcentrated in vacuo
  6. dissolutionThe residue was dissolved in THF (0.2 M)
  7. stirringthe reaction was stirred for 1 h at rt
  8. concentrationThe reaction mixture was concentrated in vacuo
  9. customThe crude product was purified by flash column chromatography (SiO2, 7% [2 M NH3 in MeOH] in DCM)

Sources & evidence

ORD record
ord-6e4413bc0f2a401396a90aff444c35cb
Source dataset
uspto-grants-2011_12
Patent number
US08076359B2

Reaction notes

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