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 1874197Notes

Reaction equation

HRID 1874197 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-8e4b10013f4f4f02bbb89298abe8492c
Source dataset
uspto-grants-2012_11
Patent number
US08304403B2

Reaction notes

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