Ytterbium triflate → phenylmethyl 3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)benzoate

HRID 418787Notes

Reaction equation

HRID 418787 reaction equation
[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[NH2:21][C:22]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]2[C:23]=1[CH:24]=[N:25][N:26]2[C:32]1[CH:33]=[C:34]([CH:45]=[CH:46][CH:47]=1)[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36].[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][NH:21][C:22]2[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]3[C:23]=2[CH:24]=[N:25][N:26]3[C:32]2[CH:33]=[C:34]([CH:45]=[CH:46][CH:47]=2)[C:35]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36])[CH:7]=1

Participants

5

Reactant 3

HCID 2733225Ytterbium triflateHCID 160992392-[2-(5-Fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxiraneHCID 59010011phenylmethyl 3-(4-amino-6-methyl-1H-indazol-1-yl)benzoate2×

Product 1

HCID 59010008phenylmethyl 3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)benzoateYield 65.3%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
85 °C

Procedure

A mixture of racemic 2-{2-[5-fluoro-2-(methyloxy)phenyl]-2-methylpropyl}-2-(trifluoromethyl)oxirane (which may be prepared according to WO 04/063163, 350 mg, 1.2 mmol), phenylmethyl 3-(4-amino-6-methyl-1H-indazol-1-yl)benzoate (Intermediate 29, 357 mg, 1.0 mmol) and ytterbium(III) triflate (124 mg, 0.2 mmol) in acetonitrile (2 mL) was heated at 85° C. for 18 hours when the temperature was raised to reflux temperature and heating continued for a further 21 hours. The mixture was cooled to room temperature and partitioned between dichloromethane (50 mL) and aqueous sodium bicarbonate (50 mL). The aqueous layer was extracted again with dichloromethane (50 mL) and the combined organic extracts were dried over anhydrous sodium sulphate and evaporated. The residue was purified by silica gel chromatography using the Flashmaster II (50 g cartridge) eluting with a 1:1 cyclohexane:ethyl acetate gradient over 40 minutes to give the title compound as a white solid (424 mg).

Workup

  1. temperaturewas raised
  2. temperatureto reflux temperature
  3. temperatureheating
  4. temperatureThe mixture was cooled to room temperature
  5. custompartitioned between dichloromethane (50 mL) and aqueous sodium bicarbonate (50 mL)
  6. extractionThe aqueous layer was extracted again with dichloromethane (50 mL)
  7. dry with materialthe combined organic extracts were dried over anhydrous sodium sulphate
  8. customevaporated
  9. customThe residue was purified by silica gel chromatography
  10. washeluting with a 1:1 cyclohexane

Sources & evidence

ORD record
ord-253c8fb6331e4889a03e7e453e83f73a
Source dataset
uspto-grants-2012_01
Patent number
US08093281B2

Reaction notes

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