Thionyl Chloride → (R)-4,4,4-trifluoro-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2,2-dimethylbutanamide

HRID 1712740Notes

Reaction equation

HRID 1712740 reaction equation
[F:1][C:2]([F:11])([F:10])[CH2:3][C:4]([CH3:9])([CH3:8])[C:5](O)=[O:6].O=S(Cl)Cl.[F:16][C:17]1[CH:18]=[C:19]([C@@:30]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)([NH2:38])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:20]=[C:21]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:22]=1>ClCCCl>[F:1][C:2]([F:11])([F:10])[CH2:3][C:4]([CH3:9])([CH3:8])[C:5]([NH:38][C@@:30]([C:19]1[CH:20]=[C:21]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:22]=[C:17]([F:16])[CH:18]=1)([C:39]1[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=1)[CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:6]

Participants

5

Reactant 3

HCID 24386Thionyl ChlorideHCID 100579374,4,4-Trifluoro-2,2-dimethylbutanoic acidHCID 59458485(R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine

Product 1

HCID 23582865(R)-4,4,4-trifluoro-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2,2-dimethylbutanamideYield 24%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

To a solution of 4,4,4-trifluoro-2,2-dimethylbutanoic acid (30 mg, 0.176 mmol) in DCE (1 mL) was added SOCl2 (21 mg, 0.176 mmol) and the resulting mixture was refluxed for 2 h. After cooling to room temperature, TEA was added (82 uL, 0.59 mmol), followed by the addition of (R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine, prepared as described in Procedure 3, 4, 5 and 6, (25 mg, 0.059 mmol). The reaction mixture was heated to reflux overnight, concentrated and the residue was purified by preparative HPLC (Axia column, 30×100 mm, 40 mL/min, 40-100% ACN/H2O/0.1% TFA over 12 min) to give (R)-4,4,4-trifluoro-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2,2-dimethylbutanamide (Example 266) as a brownish oil (8 mg, 24% yield). LCMS: RT=2.13 min [M+H] 578.3 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); 1H NMR (400 MHz, CDCl3) ppm 1.28 (s, 6H), 2.21-2.51 (m, 2H), 3.77 (ABqt, J=13 Hz, 2H), 5.83 (t, J=53 Hz, 1H), 6.37 (s, 1H), 6.65-6.74 (m, 2H), 6.75-6.95 (m, 3H), 6.94-7.09 (m, 4H), 7.09-7.31 (m, 3H).

Workup

  1. temperaturethe resulting mixture was refluxed for 2 h
  2. additionTEA was added (82 uL, 0.59 mmol)
  3. customprepared
  4. temperatureThe reaction mixture was heated
  5. temperatureto reflux overnight
  6. concentrationconcentrated
  7. customthe residue was purified by preparative HPLC (Axia column, 30×100 mm, 40 mL/min, 40-100% ACN/H2O/0.1% TFA over 12 min)

Sources & evidence

ORD record
ord-572037318a874f1bb5876307b1b2d61f
Source dataset
uspto-grants-2010_09
Patent number
US07790770B2

Reaction notes

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