Phosgene → {2'-[3-(3,5-Dichloro-benzyl)-1-ethyl-ureidomethyl]-6-methoxy-4'-trifluoromethyl-biphenyl-3-yl}-acetic acid ethyl ester

HRID 1810403Notes

Reaction equation

HRID 1810403 reaction equation
[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].C(N(C(C)C)CC)(C)C.[C:38](Cl)(Cl)=[O:39].[Cl:42][C:43]1[CH:44]=[C:45]([CH:48]=[C:49]([Cl:51])[CH:50]=1)[CH2:46][NH2:47].C(N(CC)CC)C>C(Cl)Cl.O>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:26][CH3:27])[C:38]([NH:47][CH2:46][C:45]2[CH:44]=[C:43]([Cl:42])[CH:50]=[C:49]([Cl:51])[CH:48]=2)=[O:39])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]

Participants

8

Reactant 5

HCID 6371PhosgeneHCID 8471Triethylamine3×HCID 81531DiisopropylethylamineHCID 457602Benzenemethanamine, 3,5-dichloro-HCID 66604101(2'-Ethylaminomethyl-6-methoxy-4'-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester

Product 1

HCID 66604207{2'-[3-(3,5-Dichloro-benzyl)-1-ethyl-ureidomethyl]-6-methoxy-4'-trifluoromethyl-biphenyl-3-yl}-acetic acid ethyl ester

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent2×

Procedure

To a solution of (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (0.170 g, 0.43 mmol) in CH2Cl2 (2 mL) at 0° C. was added diisopropylethylamine (0.19 mL, 1.08 mmol), followed by phosgene (20% in toluene; 0.34 mL, 0.64 mmol), and the mixture was stirred for 1.5 hours. 3,5-Dichlorobenzylamine (0.091 g, 0.52 mmol) was added, followed by triethylamine (0.12 mL, 0.86 mmol), and the reaction was warmed to room temperature and stirred for 45 minutes. Analytical LCMS indicated that some starting material was still present, so additional triethylamine (0.12 mL, 0.86 mmol) was added, and the reaction was stirred for 1.5 hours. Analytical LCMS showed that starting material still remained, so another portion of triethylamine (0.25 mL, 17.9 mmol) was added, and the reaction was stirred overnight at room temperature. The mixture was worked up with CH2Cl2 and H2O, and the aqueous layer was extracted twice with CH2Cl2. The combined organic layers were dried and concentrated, and the residue was purified by silica gel chromatography (0-50% EtOAc in hexanes) to give the title compound.

Workup

  1. stirringstirred for 45 minutes
  2. stirringthe reaction was stirred for 1.5 hours
  3. stirringthe reaction was stirred overnight at room temperature
  4. extractionthe aqueous layer was extracted twice with CH2Cl2
  5. customThe combined organic layers were dried
  6. concentrationconcentrated
  7. customthe residue was purified by silica gel chromatography (0-50% EtOAc in hexanes)

Sources & evidence

ORD record
ord-ced05928de6c4f8e8f00c3b898e1cd92
Source dataset
uspto-grants-2013_01
Patent number
US08362044B2

Reaction notes

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