Iodine → (2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)(tetrahydro-2H-pyran-4-yl)methanol

HRID 2075028Notes

Reaction equation

HRID 2075028 reaction equation
[Mg].II.Cl[CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[F:11][C:12]([F:45])([F:44])[C:13]1[CH:14]=[C:15]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:16][N:17]([CH2:24][C:25]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:26]=1[CH:27]=[O:28])[C:18]1[N:19]=[N:20][N:21]([CH3:23])[N:22]=1.C[Si](Cl)(C)C>C1COCC1.C[Mg]Br>[F:45][C:12]([F:11])([F:44])[C:13]1[CH:14]=[C:15]([CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=1)[CH2:16][N:17]([CH2:24][C:25]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:26]=1[CH:27]([CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[OH:28])[C:18]1[N:19]=[N:20][N:21]([CH3:23])[N:22]=1

Participants

8

Reactant 5

HCID 807IodineHCID 6397ChlorotrimethylsilaneHCID 1372022H-Pyran, 4-chlorotetrahydro-HCID 5462224MagnesiumHCID 589665242-{[(3,5-bis-trifluoromethyl-benzyl)(2-methyl-2H-tetrazol-5-yl)amino]-methyl}-4-trifluoromethyl-benzaldehyde

Product 1

HCID 58968611(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)(tetrahydro-2H-pyran-4-yl)methanolYield 52%

Reagents, catalysts & solvents 2

HCID 178418573HCID 178418573, compoundCatalystHCID 8028TetrahydrofuranSolvent4×

Conditions

Temperature
65 °C

Procedure

To a suspension of magnesium in THF was added iodine followed by 4-chlorotetrahydropyran in THF at 65° C. Small amount of methylmagnesium bromide (3 drops) was added to initiate the reaction. The mixture was stirred at 65° C. for 1.5 hours, cooled to room temperature. 2-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-benzaldehyde in THF was treated with trimethylsilyl chloride and stirred at room temperature for 1 hour. The Grignard was then added to the aldehyde in THF at 0° C. via syringe. The mixture was stirred at 0° C. for 1.5 hours, quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. Combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by chromatography over 25+S Biotage silica column (eluted with 0-50% ethyl acetate in hexanes) to afford the title compound as a pale yellow foam (91.6 mg, 52%). 1H NMR (400 MHz, CDCl3) δ ppm 1.07 (d, J=13.28 Hz, 1H) 1.27-1.37 (m, 1H) 1.40-1.52 (m, 1H) 1.77-1.89 (m, 2H) 2.51 (s, 1H) 3.19-3.34 (m, 2H) 3.86 (dd, J=11.14, 3.53 Hz, 1H) 3.99 (dd, J=11.62, 3.73 Hz, 1H) 4.18 (s, 3H) 4.68-4.83 (m, 4H) 4.88 (d, J=15.35 Hz, 1H) 7.34 (s, 1H) 7.55 (s, 2H) 7.64 (s, 2H) 7.77 (s, 1H). MS (ES+) Calc: 597.2, Found: 598.4 (M+1). The racemic alcohol mixture was separated by chiral chromatography using preparative HPLC (Column: Chiralcel OJ; Dimension: 5 cm×50 cm; Mobile phase: 95/5 heptane/ethanol with 0.1% DEA, Flow rate: 120 mL/minutes). The expected preparative retention times for the two enantiomers are 26 minutes (Enantiomer 1) and 36 minutes (Enantiomer 2). Enantiomer 1: MS Calc: 597.2, Found: 598.4; 100% ee. Enantiomer 2: MS Calc: 597.2, Found: 598.4; 100% ee

Workup

  1. customthe reaction
  2. temperaturecooled to room temperature
  3. stirringstirred at room temperature for 1 hour
  4. stirringThe mixture was stirred at 0° C. for 1.5 hours
  5. customquenched with saturated aqueous ammonium chloride
  6. extractionextracted with ethyl acetate
  7. washCombined organic layers were washed with brine
  8. dry with materialdried over sodium sulfate
  9. concentrationconcentrated in vacuo
  10. customThe residue was purified by chromatography over 25+S Biotage silica column (eluted with 0-50% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-ca2ec5b098ac4c77830dd581a6d90f67
Source dataset
uspto-grants-2011_04
Patent number
US07919506B2

Reaction notes

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