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 1874246Notes

Reaction equation

HRID 1874246 reaction equation
[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]

Participants

7

Reactant 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

Product 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)butanamideYield 55%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

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).

Workup

  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

Sources & evidence

ORD record
ord-43838711813b460681d21a34bf1fdb63
Source dataset
uspto-grants-2012_11
Patent number
US08304403B2

Reaction notes

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