Dimethylformamide → (R)-3-[N-(5'-Chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(5-oxo-1-phenyl-4,5-dihydro-1H-[1,2,4]triazole-3-carbonyl)-hydrazino]-2-hydroxypropionic Acid Ethyl Ester

HRID 541529Notes

Reaction equation

HRID 541529 reaction equation
[O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[NH:3]1.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.[CH2:46]([O:48][C:49](=[O:70])[C@H:50]([OH:69])[CH2:51][N:52]([CH2:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[C:65]([Cl:67])[CH:64]=[CH:63][C:62]=2[F:68])=[CH:57][CH:56]=1)[NH2:53])[CH3:47].CCN(C(C)C)C(C)C>CCOC(C)=O.CC(O)=O>[CH2:46]([O:48][C:49](=[O:70])[C@H:50]([OH:69])[CH2:51][N:52]([CH2:54][C:55]1[CH:56]=[CH:57][C:58]([C:61]2[CH:66]=[C:65]([Cl:67])[CH:64]=[CH:63][C:62]=2[F:68])=[CH:59][CH:60]=1)[NH:53][C:13]([C:4]1[NH:3][C:2](=[O:1])[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=1)=[O:15])[CH3:47]

Participants

8

Reactant 5

HCID 6228DimethylformamideHCID 81531DiisopropylethylamineHCID 42624899O-(6-Chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphateHCID 67972425(R)-3-[N-(5'-Chloro-2'-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic Acid Ethyl EsterHCID 1354826545-Oxo-1-phenyl-4,5-dihydro-1H-[1,2,4]triazole-3-carboxylic Acid

Product 1

HCID 136344434(R)-3-[N-(5'-Chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(5-oxo-1-phenyl-4,5-dihydro-1H-[1,2,4]triazole-3-carbonyl)-hydrazino]-2-hydroxypropionic Acid Ethyl EsterYield 1.4%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 8857Ethyl AcetateSolvent

Procedure

5-Oxo-1-phenyl-4,5-dihydro-1H-[1,2,4]triazole-3-carboxylic acid (89.5 mg, 436 μmol) was combined with HCTU (244 mg, 589 μmol) in DMF (1.0 mL, 13 mmol) and stirred for 10 minutes. (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid ethyl ester (80.0 mg, 0.2 mmol) and DIPEA (0.1 mL, 0.7 mmol) were added, and the resulting mixture was stirred overnight. The mixture was diluted with EtOAc (10.0 mL) and washed with water (3.0 mL), saturated aqueous NaHCO3 (2×3.0 mL), and saturated aqueous NaCl (3.0 mL), then dried over Na2SO4, filtered and concentrated to give a yellowish solid. A portion (20 mg) of the solid was dissolved in AcOH (1.5 mL), filtered and purified by reverse phase preparative HPLC to yield the title compound (1.6 mg, purity 100%). MS m/z [M+H]+ calc'd for C27H23ClFN3O3, 554.15. found 554.4.

Workup

  1. stirringthe resulting mixture was stirred overnight
  2. washwashed with water (3.0 mL), saturated aqueous NaHCO3 (2×3.0 mL), and saturated aqueous NaCl (3.0 mL)
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customto give a yellowish solid
  7. filtrationfiltered
  8. custompurified by reverse phase preparative HPLC

Sources & evidence

ORD record
ord-eda5161ad355419588da54556f8d3cc2
Source dataset
uspto-grants-2014_10
Patent number
US08871792B2

Reaction notes

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