tert-Butanol → tert-butyl 4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenylcarbamate

HRID 83909Notes

Reaction equation

HRID 83909 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:33]([F:34])=[CH:32][C:28](C(O)=O)=[CH:27][C:26]=3[F:35])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:36][CH3:37].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:45])=CC=1.CC[N:57]([CH:61](C)C)C(C)C.[C:64]([OH:68])([CH3:67])([CH3:66])[CH3:65]>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[C:14]([S:23][CH2:24][C:25]3[C:33]([F:34])=[CH:32][C:28]([NH:57][C:61](=[O:45])[O:68][C:64]([CH3:67])([CH3:66])[CH3:65])=[CH:27][C:26]=3[F:35])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:36][CH3:37]

Participants

7

Reactant 4

HCID 6386tert-ButanolHCID 81531DiisopropylethylamineHCID 199401P,P-Diphenylphosphinic azideHCID 667403914-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorobenzoic acid

Product 1

HCID 66741002tert-butyl 4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenylcarbamateYield 74%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorobenzoic acid (88 g, 0.16 mmol) in toluene (590 mL) and tert-butanol (200 mL) were added DPPA (49 g, 0.178 mol) and DIPEA (272 g, 0.21 mol) at 0° C. The reaction mixture was warmed to room temperature, stirred 30 min and heated at 80° C. overnight. After cooling, the reaction mixture was diluted with EtOAc (800 mL) and washed with 10% citric acid (1.5 L), satd NaHCO3 (1.5 L) and brine (1.5 L), dried over MgSO4, filtered and concentrated under reduced pressure to give a residue. The resulting residue was purified by column chromatography (Hex/EtOAc=3:1 to 2:1, v/v) to afford tert-butyl 4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenylcarbamate (75 g, 74%) as a light-pink foam. 1H NMR (400 MHz, CDCl3): δ 7.22 (s, 1H), 7.14-7.16 (d, 1H), 6.88-6.92 (d, 2H), 6.85 (s, 1H), 6.75-6.80 (t, 2H), 6.48-6.53 (m, 2H), 6.33-6.37 (m, 2H), 3.99 (s, 2H), 3.76 (s, 3H), 1.52 (s, 9H), 1.49 (s, 6H).

Workup

  1. temperatureheated at 80° C. overnight
  2. temperatureAfter cooling
  3. washwashed with 10% citric acid (1.5 L), satd NaHCO3 (1.5 L) and brine (1.5 L)
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customto give a residue
  8. customThe resulting residue was purified by column chromatography (Hex/EtOAc=3:1 to 2:1

Sources & evidence

ORD record
ord-36fc1ec0c38840f688c8f6413b629324
Source dataset
uspto-grants-2014_09
Patent number
US08846739B2

Reaction notes

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