Diisopropylethylamine → HCID 11626906, compound

HRID 1994481Notes

Reaction equation

HRID 1994481 reaction equation
[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:31][CH3:32])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][NH:21][CH2:22][C@@H:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH2:24])[CH:9]=1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:43](Cl)([O:45]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:31][CH3:32])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:19])[F:17])=[CH:12][C:11]=2[CH2:20][N:21]2[CH2:22][C@@H:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:24][C:43]2=[O:45])[CH:9]=1)([CH3:3])[CH3:2]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 94429TriphosgeneHCID 516892Sodium BicarbonateHCID 68591310HCID 68591310, compound

Product 1

HCID 11626906HCID 11626906, compound

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A solution of (1R)—N2-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1-phenylethane-1,2-diamine (96.0 mg, 0.22 mmol) in CH2Cl2 (15 mL) was cooled to 0° C. and DIPEA (230 μL, 1.32 mmol) was added followed by triphosgene (32.6 mg, 0.11 mmol). After 45 minutes, the reaction was poured into saturated NaHCO3 (25 mL). The mixture was extracted with EtOAc (75 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography with 10 to 60% EtOAc/hexanes afforded (4R)-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl)}4-phenylimidazolidin-2-one. The minor enantiomer was removed by chiral HPLC using an AD chiral column and 15% IPA/heptanes to afford enantiomerically pure product. Rf=0.16 (40% EtOAc/hexanes). LCMS=469.3 (M+1)+. 1H NMR (CDCl3, 500 MHz) (atropisomers present in 1:1 ratio, doubling of some peaks observed) δ 7.65 (m, 1H), 7.54 (d, J=7.7 Hz, 1H), 7.21-7.36 (m, 7H), 6.87-6.94 (m, 2H), 4.65-4.77 (m, 2H), 4.10-4.49 (m, 2H), 3.71 & 3.72 (2 singlets, 3H), 3.49-3.53 (m, 1H), 2.94-2.97 (m, 1H), 2.87 (m, 1H), 1.19-1.24 (m, 6H).

Workup

  1. extractionThe mixture was extracted with EtOAc (75 mL)
  2. washThe organic layer was washed with brine
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customPurification of the residue by flash chromatography with 10 to 60% EtOAc/hexanes
  7. customafforded (4R)-1-{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl)}4-phenylimidazolidin-2-one
  8. customThe minor enantiomer was removed by chiral HPLC
  9. customto afford enantiomerically pure product

Sources & evidence

ORD record
ord-f86c13a5a3504681b223f014802082da
Source dataset
uspto-grants-2010_01
Patent number
US07652049B2

Reaction notes

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