Tetrabutylammonium Fluoride → Mevidalen

HRID 1854564Notes

Reaction equation

HRID 1854564 reaction equation
[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][C@H:28]1[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][C:35]=2[CH2:38][CH2:39][C:40]([OH:43])([CH3:42])[CH3:41])[C@H:30]([CH3:44])[N:29]1[C:45](=[O:55])[CH2:46][C:47]1[C:52]([Cl:53])=[CH:51][CH:50]=[CH:49][C:48]=1[Cl:54])(C(C)(C)C)(C)C>O1CCCC1.CC(O)C>[Cl:54][C:48]1[CH:49]=[CH:50][CH:51]=[C:52]([Cl:53])[C:47]=1[CH2:46][C:45]([N:29]1[C@@H:28]([CH2:27][OH:26])[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][C:35]=2[CH2:38][CH2:39][C:40]([OH:43])([CH3:41])[CH3:42])[C@@H:30]1[CH3:44])=[O:55]

Participants

5

Reactant 2

HCID 2724141Tetrabutylammonium FluorideHCID 1234269101-[(1S,3R)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-(3-hydroxy-3-methylbutyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-(2,6-dichlorophenyl)ethanone

Product 1

HCID 86290953MevidalenYield 68.8%

Reagents, catalysts & solvents 2

HCID 3776IsopropanolSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
20 °C

Procedure

Add tetra-n-butylammonium fluoride (651.71 mL, 651.71 mmol, 1M in THF) to a solution of 1-[(1S,3R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-(3-hydroxy-3-methyl-butyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-2-(2,6-dichlorophenyl)ethanone (400 g, 566.71 mmol) in tetrahydrofuran (4 L) at 5° C. in an appropriate vessel. Heat the mixture to 20° C. and stir. After 3 hours, remove 3 L of tetrahydrofuran by concentrating under reduced pressure and dilute the residues with ethyl acetate (2.5 L). Wash the organics with saturated aqueous ammonium chloride (2 L), water (2 L) and brine (2×2 L). Dry the ethyl acetate solution over anhydrous sodium sulfate and concentrate under reduced pressure to give an oil. Dissolve this oil in 2-propanol (2.5 L) and concentrate under reduced pressure to give an oil. Purify by chiral SFC using AS-H column (50×250 mm, 5 micron particle size) eluting with 80% supercritical carbon dioxide and 20% of a 0.2% solution of diethylmethylamine in isopropyl alcohol at 280 g/min to give the title compound (182.8 g, 389.62 mmol). MS (m/z): 450.2 (M+1 (35C1)), 452.2 (M+1 (37Cl)). Optical rotation: [α]20D −39.4° (c=0.95, MeOH).

Workup

  1. customremove 3 L of tetrahydrofuran
  2. concentrationby concentrating under reduced pressure
  3. additiondilute the residues with ethyl acetate (2.5 L)
  4. washWash the organics with saturated aqueous ammonium chloride (2 L), water (2 L) and brine (2×2 L)
  5. dry with materialDry the ethyl acetate solution over anhydrous sodium sulfate
  6. concentrationconcentrate under reduced pressure
  7. customto give an oil
  8. concentrationconcentrate under reduced pressure
  9. customto give an oil
  10. customPurify by chiral SFC
  11. washeluting with 80% supercritical carbon dioxide and 20% of a 0.2% solution of diethylmethylamine in isopropyl alcohol at 280 g/min

Sources & evidence

ORD record
ord-b7ebeaee6b8b40f68ca77e7650d7757c
Source dataset
uspto-grants-2015_02
Patent number
US08962654B2

Reaction notes

Loading…