Trifluoroacetic acid → HCID 86650657, compound

HRID 1969447Notes

Reaction equation

HRID 1969447 reaction equation
[F:1][C:2]([F:7])([F:6])[C:3](O)=O.FC(F)(F)C1C=CC(N2[C@@H](C3C=CC=C(OC)C=3)C=C(N[C@@H](C3C=CC=CC=3)C)C2=O)=CC=1.COC1C=C([C@@H]2N(C3C=CC(C(F)(F)F)=CC=3)C(=O)C(=O)C2)C=CC=1.CC(N)(C1C=CC=C(C(F)(F)F)N=1)C.[CH3:80][C:81]([NH:93][C:94]1[C:95](=[O:117])[N:96]([C:107]2[CH:112]=[CH:111][C:110]([C:113]([F:116])([F:115])[F:114])=[CH:109][CH:108]=2)[C@@H:97]([C:99]2[CH:104]=[CH:103][CH:102]=[C:101]([O:105][CH3:106])[CH:100]=2)[CH:98]=1)([C:83]1[CH:88]=[CH:87][CH:86]=C(C(F)(F)F)[N:84]=1)[CH3:82].C([BH3-])#N.[Na+]>CC(O)=O.O.C1(C)C=CC=CC=1>[CH3:82][C:81]([NH:93][C@@H:94]1[CH2:98][C@H:97]([C:99]2[CH:104]=[CH:103][CH:102]=[C:101]([O:105][CH3:106])[CH:100]=2)[N:96]([C:107]2[CH:108]=[CH:109][C:110]([C:113]([F:115])([F:116])[F:114])=[CH:111][CH:112]=2)[C:95]1=[O:117])([C:83]1[CH:88]=[CH:87][CH:86]=[C:3]([C:2]([F:7])([F:6])[F:1])[N:84]=1)[CH3:80]

Participants

10

Reactant 6

HCID 6422Trifluoroacetic acidHCID 5003444Sodium cyanoborohydrideHCID 573469902-[6-(Trifluoromethyl)pyridin-2-yl]propan-2-amineHCID 66909185HCID 66909185, compound2×HCID 66936814HCID 66936814, compoundHCID 86650658HCID 86650658, compound2×

Product 1

HCID 86650657HCID 86650657, compoundYield 45%

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolvent3×HCID 962WaterSolventHCID 1140TolueneSolvent2×

Procedure

Add trifluoroacetic acid (5.5 mL, 72.9 mmol) to a mixture of 1-(4-trifluoromethyl-phenyl)-3-((R)-1-phenyl-ethylamino)-5(R)-(3-methoxy-phenyl)-1,5-dihydro-pyrrol-2-one (6.6 g, 14.6 mmol) in HOAc (81 mL) and water (3.7 mL). Stir at ambient temperature for 3 hours. Observe significant formation of (R)-5-(3-methoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-pyrrolidine-2,3-dione (LC-MS ESI m/z: 350.2 (M+H)+, Tr=3.71 min., method 1). Dilute the reaction mixture with toluene (100 mL) and wash the organic with water and pH 7 buffer. Filter through sodium sulfate and add HOAc (6.7 mL, 116.8 mmol) and 1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamine (3.6 g, 17.5 mmol) to this toluene solution containing (R)-5-(3-methoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-pyrrolidine-2,3-dione. Heat to 50° C. for 18 hours. Concentrate reaction mixture to give a purple oil. Observe significant formation of 3-[1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino]-1-(4-trifluoromethyl-phenyl)-5(R)-(3-methoxy-phenyl)-1,5-dihydro-pyrrol-2-one (LC-MS ESI m/z: 536.2 (M+H)+, Tr=5.31 min., method 1). Dissolve the crude 3-[1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino]-1-(4-trifluoromethyl-phenyl)-5(R)-(3-methoxy-phenyl)-1,5-dihydro-pyrrol-2-one in HOAc (73 mL) and add sodium cyanoborohydride (2.8 g. 43.8 mmol). Stir 3 hours at ambient temperature. Concentrate under reduced pressure. Partition the residue between dichloromethane and 1N sodium hydroxide solution. Extract the aqueous with dichloromethane. Dry the organic over sodium sulfate, filter and concentrate under reduced pressure. Purify the residue by silica gel chromatography (25% EtOAc-hexane) to obtain (3R,5R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-2-yl)-ethylamino]-5-(3-methoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one (3.55 g, 45%) as a brown oil. LC-MS ESI m/z: 538.2 (M+H)+, Tr=3.35 min., method 1.

Workup

  1. washwash the organic with water and pH 7 buffer
  2. filtrationFilter through sodium sulfate
  3. temperatureHeat to 50° C. for 18 hours
  4. concentrationConcentrate
  5. customreaction mixture
  6. customto give a purple oil
  7. stirringStir 3 hours at ambient temperature
  8. concentrationConcentrate under reduced pressure
  9. customPartition the residue between dichloromethane and 1N sodium hydroxide solution
  10. extractionExtract the aqueous with dichloromethane
  11. dry with materialDry the organic over sodium sulfate
  12. filtrationfilter
  13. concentrationconcentrate under reduced pressure
  14. customPurify the residue by silica gel chromatography (25% EtOAc-hexane)

Sources & evidence

ORD record
ord-1062d9eab2a44d938e49d2943b5eb480
Source dataset
uspto-grants-2013_04
Patent number
US08426448B2

Reaction notes

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