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 238774ノート

反応式

HRID 238774 の反応式
[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]

参加物

5

反応物 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

生成物 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-dimethylbutanamide収率 24%

試薬・触媒・溶媒 1

HCID 111,2-Dichloroethane溶媒

実験手順

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).

後処理

  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)

出典と根拠

ORDレコード
ord-60aba85699f94647ba22f24d1f552394
出典データセット
uspto-grants-2014_02
特許番号
US08642576B2

反応ノート

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