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 1925583Notes

Reaction equation

HRID 1925583 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)benzoate

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 solution 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), in acetonitrile (2 mL) was added to a mixture of phenylmethyl 3-(4-amino-6-methyl-1H-indazol-1-yl)benzoate (357 mg, 1.0 mmol) and ytterbium(III) triflate (124 mg, 0.2 mmol). The mixture was stirred and heated to 85° C. under nitrogen in a greenhouse apparatus for 18 hours when the temperature was raised to 100° C. and the mixture heated under vigorous reflux 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 cyclohexane to 1:1 cyclohexane:ethyl acetate gradient over 40 minutes to give the title compound as a white solid (424 mg).

Workup

  1. temperaturewas raised to 100° C.
  2. temperaturethe mixture heated
  3. temperatureunder vigorous reflux for a further ˜21 hours
  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 cyclohexane to 1:1 cyclohexane

Sources & evidence

ORD record
ord-d818e78e7b5e4cc8a2cce9376b7a7150
Source dataset
uspto-grants-2012_05
Patent number
US08178573B2

Reaction notes

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