Acetic Acid → HCID 86635741, compound

HRID 1919814Notes

Reaction equation

HRID 1919814 reaction equation
FC(F)(F)C(O)=O.C1([C@H](N[C:17]2[C:18](=[O:42])[N:19]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=3)[C@@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH:29]4[CH2:31][CH2:30]4)[CH:23]=3)[CH:21]=2)C)C=CC=CC=1.C1(OC2C=C([C@@H]3N(C4C=CC(C(F)(F)F)=CC=4)C(=O)C(=O)C3)C=CC=2)CC1.[CH3:70][C:71]([NH2:83])([C:73]1[CH:74]=[N:75][C:76]([C:79]([F:82])([F:81])[F:80])=[CH:77][CH:78]=1)[CH3:72].C(O)(=O)C>C1(C)C=CC=CC=1.O>[CH3:72][C:71]([NH:83][C:17]1[C:18](=[O:42])[N:19]([C:32]2[CH:33]=[CH:34][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:36][CH:37]=2)[C@@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH:29]3[CH2:31][CH2:30]3)[CH:23]=2)[CH:21]=1)([C:73]1[CH:74]=[N:75][C:76]([C:79]([F:81])([F:82])[F:80])=[CH:77][CH:78]=1)[CH3:70]

Participants

8

Reactant 5

HCID 176Acetic AcidHCID 6422Trifluoroacetic acidHCID 545799022-[6-(Trifluoromethyl)pyridin-3-yl]propan-2-amineHCID 57951137HCID 57951137, compoundHCID 67500595HCID 67500595, compound

Product 1

HCID 86635741HCID 86635741, compound

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 1140TolueneSolvent2×

Procedure

Add trifluoroacetic acid (1.5 mL, 20 mmol) to a mixture of (R)-3-((R)-1-phenyl-ethylamino)-5-(3-cyclopropoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-1,5-dihydro-pyrrol-2-one (1.92 g, 4.01 mmol) in toluene (10 mL) and water (4 mL). Stir at ambient temperature for 60 min. Observe significant formation of (R)-5-(3-cyclopropoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-pyrrolidine-2,3-dione. LCMS, Ret. time=4.14 min., Method 3, MS (m/z): 376.0 (M+), 374.0 (M−1). Add a solution of 1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamine (1.2 g, 5.9 mmol) in toluene (10 mL) to the reaction solution. Then add acetic acid (1.9 mL, 33 mmol). Heat at 50° C. for 14 hours. Concentrate under reduced pressure. Purify the residue by silica gel chromatography (0-10% ethyl acetate-hexane) to obtain (R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamino]-5-(3-cyclopropoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-1,5-dihydro-pyrrol-2-one as a tan foam. LCMS, Ret. time=5.40 min., Method 3, MS (m/z): 562.0 (M+), 560.0 (M−1). Dissolve (R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamino]-5-(3-cyclopropoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-1,5-dihydro-pyrrol-2-one (1.09 g, 1.94 mmol) in acetic acid (20 mL) and add sodium cyanoborohydride (240 mg. 3.8 mmol). Stir 1 hour at ambient temperature. Concentrate under reduced pressure. Dissolve the residue in dichloromethane and wash with saturated sodium bicarbonate solution, dry over sodium sulfate, filter and concentrate under reduced pressure. Purify the residue by silica gel chromatography (0-15% ethyl acetate-hexane) to obtain (3R,5R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamino]-5-(3-cyclopropoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-pyrrolidin-2-one (645 mg, 59%) as a white foam. LCMS, Ret. time=5.04 min, Method 3 MS (m/z): 564.0 (M+1).

Workup

  1. temperatureHeat at 50° C. for 14 hours
  2. concentrationConcentrate under reduced pressure
  3. customPurify the residue by silica gel chromatography (0-10% ethyl acetate-hexane)

Sources & evidence

ORD record
ord-071b97b2cbec45959aa4a01b4690ddee
Source dataset
uspto-grants-2012_05
Patent number
US08168659B2

Reaction notes

Loading…