Acetic Acid → HCID 57951120, compound

HRID 1919813Notes

Reaction equation

HRID 1919813 reaction equation
[F:1][C:2]([F:7])([F:6])[C:3](O)=[O:4].C1([C@H](NC2C(=O)N(C3C=CC(C(F)(F)F)=CC=3)[C@@H](C3C=CC=C(OCC(F)(F)F)C=3)C=2)C)C=CC=CC=1.FC(F)(F)CO[C:49]1[CH:50]=[C:51]([C@@H:55]2[N:59]([C:60]3[CH:65]=[CH:64][C:63]([C:66]([F:69])([F:68])[F:67])=[CH:62][CH:61]=3)[C:58](=[O:70])[C:57](=O)[CH2:56]2)[CH:52]=[CH:53][CH:54]=1.C(O)(=O)C.[CH3:78][C:79]([NH2:91])([C:81]1[CH:82]=[N:83][C:84]([C:87]([F:90])([F:89])[F:88])=[CH:85][CH:86]=1)[CH3:80].CC(NC1C(=O)N(C2C=CC(C(F)(F)F)=CC=2)[C@@H](C2C=CC=C(OCC(F)(F)F)C=2)C=1)(C1C=NC(C(F)(F)F)=CC=1)C.C([BH3-])#N.[Na+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[CH3:80][C:79]([NH:91][C@@H:57]1[CH2:56][C@H:55]([C:51]2[CH:50]=[CH:49][CH:54]=[C:53]([O:4][CH2:3][C:2]([F:7])([F:6])[F:1])[CH:52]=2)[N:59]([C:60]2[CH:61]=[CH:62][C:63]([C:66]([F:69])([F:68])[F:67])=[CH:64][CH:65]=2)[C:58]1=[O:70])([C:81]1[CH:82]=[N:83][C:84]([C:87]([F:89])([F:90])[F:88])=[CH:85][CH:86]=1)[CH3:78]

Participants

11

Reactant 7

HCID 176Acetic AcidHCID 6422Trifluoroacetic acidHCID 5003444Sodium cyanoborohydrideHCID 545799022-[6-(Trifluoromethyl)pyridin-3-yl]propan-2-amineHCID 57951179HCID 57951179, compoundHCID 87423678HCID 87423678, compoundHCID 87423882HCID 87423882, compound2×

Product 1

HCID 57951120HCID 57951120, compoundYield 42%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 1140TolueneSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

Add trifluoroacetic acid (3.5 mL, 46.1 mmol) dropwise to a biphasic mixture of (R)-3-((R)-1-phenyl-ethylamino)-5-[3-(2,2,2-trifluoro-ethoxy)-phenyl]-1-(4-trifluoromethyl-phenyl)-1,5-dihydro-pyrrol-2-one (4.8 g, 9.22 mmol) in toluene (24 mL) and water (9.6 mL). Stir at ambient temperature for 60 min. Observe significant formation of (R)-5-[3-(2,2,2-trifluoro-ethoxy)-phenyl]-1-(4-trifluoromethyl-phenyl)-pyrrolidine-2,3-dione (LC MS 77%, Ret. time=4.08 min., Method 3, MS (m/z): 416 (M−1). Separate the aqueous layer and wash the toluene layer with water, pH 7 buffer and saturated sodium chloride solution. Add acetic acid (4.23 mL, 73.8 mmol) and 1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamine (3.77 g, 18.4 mmol) to the toluene solution containing (R)-5-[3-(2,2,2-trifluoro-ethoxy)-phenyl]-1-(4-trifluoromethyl-phenyl)-pyrrolidine-2,3-dione. Heat to 55° C. for 18 hours. Observe significant formation of (R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamino]-5-[3-(2,2,2-trifluoro-ethoxy)-phenyl]-1-(4-trifluoromethyl-phenyl)-1,5-dihydro-pyrrol-2-one (LC MS 100%, Ret. time=5.26 min., Method 3, MS (m/z): 604 (M+1). Dilute reaction mixture with ethyl acetate and wash with water and saturated sodium chloride solution, dry over sodium sulfate, filter and concentrate to dryness. Dissolve the crude (R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamino]-5-[3-(2,2,2-trifluoro-ethoxy)-phenyl]-1-(4-trifluoromethyl-phenyl)-1,5-dihydro-pyrrol-2-one in acetic acid (46 mL) and add sodium cyanoborohydride (1.16 g. 18.4 mmol). Stir 15 min. at ambient temperature. Concentrate under reduced pressure. Dissolve the residue in ethyl acetate and wash with saturated sodium bicarbonate solution and saturated sodium chloride solution, dry over sodium sulfate, filter and concentrate under reduced pressure. Purify the residue by silica gel chromatography (5-50% ethyl acetate-hexane) and purify again by silica gel chromatography (0-1% methanol-dichloromethane) to obtain (3R,5R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamino]-5-[3-(2,2,2-trifluoro-ethoxy)-phenyl]-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one (2.36 g, 42%) as a clear colorless oil. MS (m/z): 606 (M+1).

Workup

  1. customSeparate the aqueous layer
  2. washwash the toluene layer with water, pH 7 buffer
  3. temperatureHeat to 55° C. for 18 hours
  4. additionDilute
  5. washwash with water and saturated sodium chloride solution
  6. dry with materialdry over sodium sulfate
  7. filtrationfilter
  8. concentrationconcentrate to dryness
  9. dissolutionDissolve the crude (R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamino]-5-[3-(2,2,2-trifluoro-ethoxy)-phenyl]-1-(4-trifluoromethyl-phenyl)-1,5-dihydro-pyrrol-2-one in acetic acid (46 mL)
  10. stirringStir 15 min. at ambient temperature
  11. concentrationConcentrate under reduced pressure
  12. dissolutionDissolve the residue in ethyl acetate
  13. washwash with saturated sodium bicarbonate solution and saturated sodium chloride solution
  14. dry with materialdry over sodium sulfate
  15. filtrationfilter
  16. concentrationconcentrate under reduced pressure
  17. customPurify the residue by silica gel chromatography (5-50% ethyl acetate-hexane)
  18. custompurify again by silica gel chromatography (0-1% methanol-dichloromethane)

Sources & evidence

ORD record
ord-232b5d1dbd8e43e38f263996ce32cedb
Source dataset
uspto-grants-2012_05
Patent number
US08168659B2

Reaction notes

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