Hydrochloric Acid → (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 Isobutyl Ester

HRID 541530Notes

Reaction equation

HRID 541530 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.C([O:48][C:49](=O)[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])C.CCN(C(C)C)C(C)C.[CH2:80]([OH:84])[CH:81]([CH3:83])[CH3:82].Cl.O1CCOCC1>CCOC(C)=O>[CH2:80]([O:84][C:49](=[O:48])[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)[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])[CH:81]([CH3:83])[CH3:82]

Participants

10

Reactant 8

HCID 313Hydrochloric AcidHCID 6228DimethylformamideHCID 6560IsobutanolHCID 312751,4-DioxaneHCID 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 136344435(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 Isobutyl EsterYield 1.4%

Reagents, catalysts & solvents 1

HCID 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 treated with isobutyl alcohol (170 μL, 1.8 mmol) and 4.0 M HCl in 1,4-dioxane (36.0 μL, 144 μmol) at room temperature overnight. The mixture was concentrated, and the residue 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 C29H29ClFN3O3, 582.18. found 582.4.

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. concentrationThe mixture was concentrated
  8. dissolutionthe residue was dissolved in AcOH (1.5 mL)
  9. filtrationfiltered
  10. custompurified by reverse phase preparative HPLC

Sources & evidence

ORD record
ord-2f91fca2e96b4b068b1c946347ef2923
Source dataset
uspto-grants-2014_10
Patent number
US08871792B2

Reaction notes

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