Hydrochloric Acid → 3-{[{[5'-Isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}(methoxycarbonyl)amino]methyl}-5-(trifluoromethyl)benzoic acid

HRID 217518

Reaction equation

HRID 217518 reaction equation
[CH3:1][O:2][C:3](=[O:40])[N:4]([CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([CH:38]=[O:39])[CH:29]=1)[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1[C:16]1[CH:21]=[C:20]([CH:22]([CH3:24])[CH3:23])[CH:19]=[CH:18][C:17]=1[O:25][CH3:26].CC(=CC)C.[O-:46]Cl=O.[Na+].Cl>C1COCC1.O.CCOC(C)=O.C(O)(C)(C)C>[CH:22]([C:20]1[CH:19]=[CH:18][C:17]([O:25][CH3:26])=[C:16]([C:7]2[CH:8]=[CH:9][C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][C:6]=2[CH2:5][N:4]([CH2:27][C:28]2[CH:29]=[C:30]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=2)[C:38]([OH:46])=[O:39])[C:3]([O:2][CH3:1])=[O:40])[CH:21]=1)([CH3:24])[CH3:23]

Participants

9

Reactant 4

HCID 313Hydrochloric AcidHCID 105532-Methyl-2-buteneHCID 11497822Methyl[3-formyl-5-(trifluoromethyl)benzyl]{[5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamateHCID 23668197Sodium Chlorite

Product 1

HCID 115560893-{[{[5'-Isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}(methoxycarbonyl)amino]methyl}-5-(trifluoromethyl)benzoic acid

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 6386tert-ButanolSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of methyl[3-formyl-5-(trifluoromethyl)benzyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (37.0 mg, 0.065 mmol) (Example 40) in THF (123 μL) was added t-butanol (360 μL), 2-methyl 2-butene (123 μL), and a solution of NaClO2 (12.9 mg, 0.014 mmol) and NaH2PO4 (19.7 mg, 0.014 mmol) in H2O (152 μL). The reaction was stirred vigorously for two hours at room temperature, diluted with EtOAc (30 mL), and poured into 1N HCl (10 mL). The aqueous layer was extracted with EtOAc (3×20 mL) and the combined organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 0.1% acetic acid in 8% MeOH/CH2Cl2 afforded 3-{[{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}(methoxycarbonyl)amino]methyl}-5-(trifluoromethyl)benzoic acid. Rf=0.35 (10% MeOH/CH2Cl2). LCMS=584.3 (M+1)+. 1H NMR (C6D6, 500 MHz, 70° C.) δ 8.28 (broad singlet, 1H), 8.04 (broad singlet, 1H), 7.68 (broad singlet, 1H), 7.37-7.34 (m, 2H), 7.07-7.05 (m, 2H), 6.87 (s, 1H), 6.62 (d, J=8.0 Hz, 1H), 4.43 (broad singlet, 2H), 4.41 (broad singlet, 2H), 3.40 (s, 3H), 3.29 (s, 3H), 2.75 (m, 1H), 1.17 (d, J=6.5 Hz, 6H).

Workup

  1. extractionThe aqueous layer was extracted with EtOAc (3×20 mL)
  2. washthe combined organic extracts were washed with brine (10 mL)
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customPurification by flash chromatography with 0.1% acetic acid in 8% MeOH/CH2Cl2

Sources & evidence

ORD record
ord-b353a02f2a33410882200fff9db7c514
Source dataset
uspto-grants-2012_06
Patent number
US08193365B2

Linked notes

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