Ammonium Chloride → 4-([3-(tert-butyldimethylsilanyloxy)phenyl]{3-[N-(3-fluorophenyl)-N-methyl-carbamoyl]phenyl}hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester

HRID 445032Notes

Reaction equation

HRID 445032 reaction equation
C([Li])CCC.[F:6][C:7]1[CH:8]=[C:9]([N:13]([CH3:23])[C:14](=[O:22])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=2)[CH:10]=[CH:11][CH:12]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH:34]([C:37](=[O:52])[C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH:39]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].[NH4+].[Cl-]>C1COCC1.O>[C:24]([O:28][C:29]([N:31]1[CH2:32][CH2:33][CH:34]([C:37]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:46])[CH3:47])[CH:39]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:14](=[O:22])[N:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([F:6])[CH:8]=3)[CH3:23])[CH:16]=2)[OH:52])[CH2:35][CH2:36]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]

Participants

7

Reactant 4

HCID 25517Ammonium ChlorideHCID 61985917N-(3-fluorophenyl)-3-iodo-N-methylbenzamideHCID 697908934-[3-(Tert-butyl-dimethyl-silanyloxy)benzoyl]-piperidine-1-carboxylic acid tert-butyl esterHCID 178418339Butyllithium

Product 1

HCID 697908904-([3-(tert-butyldimethylsilanyloxy)phenyl]{3-[N-(3-fluorophenyl)-N-methyl-carbamoyl]phenyl}hydroxymethyl)piperidine-1-carboxylic acid tert-butyl esterYield 42%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

n-Butyllithium (1.61 mL of 1.92 M solution; 3.10 mmol) was added to a mixture of N-(3-fluorophenyl)-3-iodo-N-methylbenzamide (1.0 g; 2.82 mmol) and 4-[3-(tert-butyl-dimethyl-silanyloxy)benzoyl]-piperidine-1-carboxylic acid tert-butyl ester (1.182 g; 2.82 mmol) in THF (150 mL) at −78° C. under nitrogen in one portion. The reaction was stirred under nitrogen overnight while the temperature warmed to room temperature. Saturated NH4Cl solution (25 mL) was added to the reaction mixture, followed by the addition of 25 mL of water. The mixture was extracted by ether (300 mL×2). The ether layer was washed by water (200 mL×2) and brine (200 mL×1), dried by Na2SO4 and concentrated to give 2.03 g of crude product, which was purified by silica gel column chromatography eluted with 30% EtOAc in pentane to give 4-([3-(tert-butyldimethylsilanyloxy)phenyl]{3-[N-(3-fluorophenyl)-N-methylcarbamoyl]phenyl}hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (763 mg; 42%). 1H NMR (600 MHz, DMSO-d6) δ 7.34 (bs, 1H), 7.29 (s, 1H), 7.23-7.16 (m, 3H), 7.09 (m, 2H), 6.94 (m, 2H), 6.85 (m, 2H), 6.60 (d, 1H, J=7.0 Hz), 5.25 (s, 1H), 3.88 (m, 2H), 3.35 (s, 3H), 2.60 (bs, 2H), 2.34 (m, 1H), 1.37 (s, 9H), 1.36 (m, 2H), 1.16 (m, 2H), 0.91 (s, 9H), 0.12 (s, 6H).

Workup

  1. extractionThe mixture was extracted by ether (300 mL×2)
  2. washThe ether layer was washed by water (200 mL×2) and brine (200 mL×1)
  3. dry with materialdried by Na2SO4
  4. concentrationconcentrated
  5. customto give 2.03 g of crude product, which
  6. customwas purified by silica gel column chromatography
  7. washeluted with 30% EtOAc in pentane

Sources & evidence

ORD record
ord-41c26aa7480d4cf2b0f809c3317a2af1
Source dataset
uspto-grants-2013_07
Patent number
US08476280B2

Reaction notes

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