Acetic Acid → HCID 24809626, compound

HRID 1672526Notes

Reaction equation

C(O)(=O)C.CC(N)(C1C=NC(C(F)(F)F)=CC=1)C.FC(F)(F)OC1C=C([C@@H]2N(C3C=CC(C(F)(F)F)=CC=3)C(=O)C(=O)C2)C=CC=1.[CH3:47][C:48]([NH:60][C:61]1[C:62](=[O:87])[N:63]([C:77]2[CH:82]=[CH:81][C:80]([C:83]([F:86])([F:85])[F:84])=[CH:79][CH:78]=2)[C@@H:64]([C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([O:72][C:73]([F:76])([F:75])[F:74])[CH:67]=2)[CH:65]=1)([C:50]1[CH:51]=[N:52][C:53]([C:56]([F:59])([F:58])[F:57])=[CH:54][CH:55]=1)[CH3:49].C([BH3-])#N.[Na+]>C1(C)C=CC=CC=1>[CH3:49][C:48]([NH:60][C@@H:61]1[CH2:65][C@H:64]([C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([O:72][C:73]([F:74])([F:75])[F:76])[CH:67]=2)[N:63]([C:77]2[CH:78]=[CH:79][C:80]([C:83]([F:84])([F:86])[F:85])=[CH:81][CH:82]=2)[C:62]1=[O:87])([C:50]1[CH:51]=[N:52][C:53]([C:56]([F:57])([F:58])[F:59])=[CH:54][CH:55]=1)[CH3:47].[CH3:49][C:48]([NH:60][C@H:61]1[CH2:65][C@H:64]([C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([O:72][C:73]([F:74])([F:75])[F:76])[CH:67]=2)[N:63]([C:77]2[CH:78]=[CH:79][C:80]([C:83]([F:84])([F:86])[F:85])=[CH:81][CH:82]=2)[C:62]1=[O:87])([C:50]1[CH:51]=[N:52][C:53]([C:56]([F:57])([F:58])[F:59])=[CH:54][CH:55]=1)[CH3:47]

Participants

Conditions

Temperature: 55 °C

Procedure

Separate the aqueous layer and wash the toluene layer with water, pH 7 buffer and saturated sodium chloride solution. Add acetic acid (26.2 mL, 456 mmol) and 1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamine (23.3 g, 114 mmol) to the toluene solution containing (R)-5-[3-trifluoromethoxy-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-trifluoromethoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-1,5-dihydro-pyrrol-2-one (LC MS 100%, Ret. time=5.59 minutes, Method D, MS (m/z): 590 (M+1). Concentrate under reduced pressure. Dissolve the crude (R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamino]-5-(3-trifluoromethoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-1,5-dihydro-pyrrol-2-one in acetic acid (285 mL) and add sodium cyanoborohydride (7.2 g. 114 mmol). Stir 1.75 hours at ambient temperature and concentrate under reduced pressure. Dissolve the residue in ethyl acetate and wash with saturated sodium bicarbonate solution, water and saturated sodium chloride solution. Dry the solution over sodium sulfate, filter and concentrate under reduced pressure. Purify the residue by silica gel chromatography (10-30% ethyl acetate-hexane) to obtain (3R,5R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamino]-1-(4-trifluoromethyl-phenyl)-5-(3-trifluoromethoxy-phenyl)-pyrrolidin-2-one (18.0 g, 53%) as a yellow oil and (3S,5R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamino]-1-(4-trifluoromethyl-phenyl)-5-(3-trifluoromethoxy-phenyl)-pyrrolidin-2-one (0.92 g, 2.7%) as an oil.

Workup

customSeparate the aqueous layer
washwash the toluene layer with water, pH 7 buffer
concentrationConcentrate under reduced pressure
dissolutionDissolve the crude (R)-3-[1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamino]-5-(3-trifluoromethoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-1,5-dihydro-pyrrol-2-one in acetic acid (285 mL)
concentrationconcentrate under reduced pressure
dissolutionDissolve the residue in ethyl acetate
washwash with saturated sodium bicarbonate solution, water and saturated sodium chloride solution
dry with materialDry the solution over sodium sulfate
filtrationfilter
concentrationconcentrate under reduced pressure
customPurify the residue by silica gel chromatography (10-30% ethyl acetate-hexane)

Sources & evidence

ORD record: ord-bf76c10824b845389705044fcc0b3710
Source dataset: uspto-grants-2011_08
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07998985B2

Reaction notes

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