tert-Butyl 4-formylpiperidine-1-carboxylate → tert-butyl 4-((2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)(hydroxy)methyl)piperidine-1-carboxylate

HRID 2075046Notes

Reaction equation

HRID 2075046 reaction equation
[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1Br)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.C([Mg]Cl)(C)C.[Li+].[Cl-].[CH:42]([CH:44]1[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]1)=[O:43]>C1COCC1>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:42]([OH:43])[CH:44]1[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:55])([CH3:54])[CH3:56])=[O:51])[CH2:46][CH2:45]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1

Participants

5

Reactant 3

HCID 1514430tert-Butyl 4-formylpiperidine-1-carboxylateHCID 58966468(3,5-bis-trifluoromethyl-benzyl)-(2-bromo-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)amineHCID 178461733HCID 178461733, compound

Product 1

HCID 58968740tert-butyl 4-((2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)(hydroxy)methyl)piperidine-1-carboxylateYield 44%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of (3,5-bis-trifluoromethyl-benzyl)-(2-bromo-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amine (115 mg, 0.21 mmol) in THF (0.5 mL) at 0° C. was added i-PrMgCl/LiCl (0.3 mL, 0.39 mmol). The mixture was stirred 0° C. for 3 hours and tert-butyl 4-formylpiperidine-1-carboxylate (70.7 mg, 0.33 mmol) in THF (0.1 mL) was added. The mixture was stirred at 0° C. to room temperature for 3 hours and quenched with saturated aqueous ammonium chloride. The mixture was 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 (62.2 mg, 44%). 1H NMR (400 MHz, CDCl3) δ ppm 1.12-1.19 (m, 1H) 1.20-1.32 (m, 1H) 1.43 (s, 9H) 1.69-1.78 (m, 1H) 1.89 (dd, J=13.07, 1.87 Hz, 1H) 2.46-2.67 (m, 2H) 3.99-4.15 (m, 2H) 4.18 (s, 3H) 4.66-4.73 (m, 2H) 4.68-4.83 (m, 4H) 4.87 (d, J=15.77 Hz, 1H) 7.33 (s, 1H) 7.55 (s, 2H) 7.64 (s, 2H) 7.77 (s, 1H). MS (ES+) Calc: 696.2, Found: 697.6 (M+1)

Workup

  1. stirringThe mixture was stirred at 0° C. to room temperature for 3 hours
  2. customquenched with saturated aqueous ammonium chloride
  3. extractionThe mixture was extracted with ethyl acetate
  4. washCombined organic layers were washed with brine
  5. dry with materialdried over sodium sulfate
  6. concentrationconcentrated in vacuo
  7. 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-259734118b32422b9ea04634ea7bed60
Source dataset
uspto-grants-2011_04
Patent number
US07919506B2

Reaction notes

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