1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → (R)-3-(4-[3-(3,5-Bis(trifluoromethyl)phenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino]-2-hydroxypropionic acid ethyl ester

HRID 412431Notes

Reaction equation

HRID 412431 reaction equation
[F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:38])[N:15]([CH2:28][C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=2)[C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.ON1C2N=CC=CC=2N=N1.CCN=C=NCCCN(C)C.[CH2:62]([O:64][C:65](=[O:70])[C@H:66]([OH:69])[CH2:67][NH2:68])[CH3:63].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH2:62]([O:64][C:65](=[O:70])[C@H:66]([OH:69])[CH2:67][NH:68][C:33](=[O:34])[C:32]1[CH:31]=[CH:30][C:29]([CH2:28][N:15]([C:16]2[CH:17]=[CH:18][C:19]([CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)=[CH:20][CH:21]=2)[C:14]([NH:13][C:5]2[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:1])([F:39])[F:40])[CH:4]=2)=[O:38])=[CH:37][CH:36]=1)[CH3:63]

Participants

8

Reactant 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 81531DiisopropylethylamineHCID 181649HOAtHCID 223110784-[3-(3,5-Bis(trifluoromethyl)phenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoic acidHCID 54263093ethyl (2R)-3-amino-2-hydroxypropanoate

Product 1

HCID 86586059(R)-3-(4-[3-(3,5-Bis(trifluoromethyl)phenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino]-2-hydroxypropionic acid ethyl esterYield 101.9%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent2×

Procedure

4-[3-(3,5-Bis(trifluoromethyl)phenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoic acid (0.22 g, 0.39 mmol) was dissolved in DMF (3 mL) and 1-hydroxy-7-azabenzotriazole (0.06 g, 0.47 mmol) and EDAC (0.09 g, 1.2 mmol) were added. The mixture was stirred for 1.5 hour, and (R)-isoserine ethyl ester (0.10 g, 0.59 mmol) and diisopropylethylamine (0.10 mL, 0.59 mmol) in DMF (2 mL) were added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (25 mL). The aqueous phase was extracted with ethyl acetate (10 mL). The combined organic phases were washed with hydrochloric acid (0.2 N, 3×10 mL) and water:saturated sodium chloride (1:1), dried (magnesium sulphate) and concentrated in vacuo. The residue was purified by column chromatography (35 g silica gel) using ethyl acetate and n-heptane (6:4) as eluent to afford 0.27 g of (R)-3-{4-[3-(3,5-bis(trifluoromethyl)phenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid ethyl ester.

Workup

  1. stirringThe mixture was stirred at room temperature for 16 hours
  2. extractionextracted with ethyl acetate (25 mL)
  3. extractionThe aqueous phase was extracted with ethyl acetate (10 mL)
  4. washThe combined organic phases were washed with hydrochloric acid (0.2 N, 3×10 mL) and water
  5. dry with materialsaturated sodium chloride (1:1), dried (magnesium sulphate)
  6. concentrationconcentrated in vacuo
  7. customThe residue was purified by column chromatography (35 g silica gel)

Sources & evidence

ORD record
ord-7b8b7bb7c04d4619b1ae3906325fff34
Source dataset
uspto-grants-2003_05
Patent number
US06562807B2

Reaction notes

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