4-Methylmorpholine → (r)-4,4,4-Trifluoro-n-(1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2,-tetrafluoroethoxy) phenyl)-2-phenylethyl)butanamide

HRID 238824ノート

反応式

HRID 238824 の反応式
[F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](O)=[O:6].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[F:43][C:44]1[CH:49]=[CH:48][C:47]([C@:50]([C:59]2[CH:64]=[C:63]([O:65][C:66]([F:71])([F:70])[CH:67]([F:69])[F:68])[CH:62]=[C:61]([F:72])[CH:60]=2)([NH2:58])[CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[CH:46][C:45]=1[O:73][CH:74]([CH3:76])[CH3:75].CN1CCOCC1>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([NH:58][C@:50]([C:47]1[CH:48]=[CH:49][C:44]([F:43])=[C:45]([O:73][CH:74]([CH3:76])[CH3:75])[CH:46]=1)([C:59]1[CH:64]=[C:63]([O:65][C:66]([F:71])([F:70])[CH:67]([F:69])[F:68])[CH:62]=[C:61]([F:72])[CH:60]=1)[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:6]

参加物

7

反応物 4

HCID 79724-MethylmorpholineHCID 2724699PyBOPHCID 27770854,4,4-Trifluorobutanoic acidHCID 59458471(R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamine

生成物 1

HCID 59458413(r)-4,4,4-Trifluoro-n-(1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2,-tetrafluoroethoxy) phenyl)-2-phenylethyl)butanamide収率 55%

試薬・触媒・溶媒 2

HCID 6344Dichloromethane溶媒HCID 8857Ethyl Acetate溶媒

実験手順

To a solution of 4,4,4-trifluorobutyric acid (13 mg, 0.09 mmol) in DCM (0.8 mL) was added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (52 mg, 0.1 mmol), (R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamine (40 mg, 0.08 mmol), followed by NMM (28 μl, 0.25 mmol). The reaction mixture was stirred at room temperature for 16 h, then another 16 h at 60° C. The reaction mixture was diluted with EtOAc (10 mL) and the organic layer was washed with H2O, dried over MgSO4, filtered and concentrated. The residue was purified by preparative HPLC Phenomenex Luna C18 column, 30×50 mm eluting with 10-90% ACN/H2O over 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm; 40-100% ACN (90% in water, 0.1% TFA) gradient over 10 min with flow rate 40 mL/min and UV detection at 220 nm. (R)-4,4,4-trifluoro-N-(1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2,-tetrafluoroethoxy)phenyl)-2-phenylethyl)butanamide (Example 312) was isolated as a lyophillate (27 mg, 55% yield). LCMS: RT=2.15 min [M+H] 608.2 (2 min 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); HPLC: RT=3.79 min, Purity 100% (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% ACN/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm); 1H NMR (400 MHz, CDCl3) δ ppm 1.18 (d, J=6.05 Hz, 3H), 1.24 (d, J=6.05 Hz, 3H), 2.34-2.48 (m, 2H), 2.51-2.61 (m, 2H), 3.79 (d, J=13.19 Hz, 1H), 3.98 (d, J=13.19 Hz, 1H), 4.29-4.39 (m, 1H), 6.12-6.44 (m, 1H), 6.67-6.82 (m, 4H), 6.91-7.07 (m, 4H), 7.10-7.19 (m, 3H), 8.29 (s, 1H).

後処理

  1. customanother 16 h
  2. customat 60° C
  3. washthe organic layer was washed with H2O
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue was purified by preparative HPLC Phenomenex Luna C18 column, 30×50 mm
  8. washeluting with 10-90% ACN/H2O over 10 minutes
  9. additioncontaining 0.1% TFA
  10. wait40-100% ACN (90% in water, 0.1% TFA) gradient over 10 min with flow rate 40 mL/min and UV detection at 220 nm

出典と根拠

ORDレコード
ord-0ab07cef6bda4dca90b1a5c42953f68f
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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