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 1874246노트

반응식

HRID 1874246 반응식
[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]

참가 물질

7

반응물 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

생성물 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)butanamide수율 55%

시약·촉매·용매 2

HCID 6344Dichloromethane용매HCID 8857Ethyl Acetate용매

실험 절차

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).

후처리

  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

출처 및 근거

ORD 기록
ord-43838711813b460681d21a34bf1fdb63
출처 데이터셋
uspto-grants-2012_11
특허 번호
US08304403B2

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