Ethanol → (R)-3-[N'-(5-Acetyl-2H-pyrazole-3-carbonyl)-N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid

HRID 541537Notes

Reaction equation

HRID 541537 reaction equation
[C:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[NH:6][N:5]=1)(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.CCN(C(C)C)C(C)C.C([O:53][C:54](=[O:75])[C@H:55]([OH:74])[CH2:56][N:57]([CH2:59][C:60]1[CH:65]=[CH:64][C:63]([C:66]2[CH:71]=[C:70]([Cl:72])[CH:69]=[CH:68][C:67]=2[F:73])=[CH:62][CH:61]=1)[NH2:58])C.CCO.[Li+].[OH-].O>>[C:1]([C:4]1[CH:8]=[C:7]([C:9]([NH:58][N:57]([CH2:56][C@@H:55]([OH:74])[C:54]([OH:75])=[O:53])[CH2:59][C:60]2[CH:61]=[CH:62][C:63]([C:66]3[CH:71]=[C:70]([Cl:72])[CH:69]=[CH:68][C:67]=3[F:73])=[CH:64][CH:65]=2)=[O:11])[NH:6][N:5]=1)(=[O:3])[CH3:2]

Participants

9

Reactant 8

HCID 702EthanolHCID 962WaterHCID 3939Lithium HydroxideHCID 6228DimethylformamideHCID 81531DiisopropylethylamineHCID 167673463-acetyl-1H-pyrazole-5-carboxylic acidHCID 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 Ester

Product 1

HCID 86705116(R)-3-[N'-(5-Acetyl-2H-pyrazole-3-carbonyl)-N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acidYield 57.9%

Procedure

3-Acetyl-1H-pyrazole-5-carboxylic acid (69.3 mg, 450 μmol) and HCTU (186 mg, 450 μmol) were combined in DMF (1.9 mL, 24.5 mmol), and stirred at room temperature. After 15 minutes, DIPEA (214 μL, 1.2 mmol) and (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid ethyl ester (150 mg, 0.4 mmol) were added. The mixture was stirred for 30 minutes at room temperature, then evaporated under reduced pressure. The residue was dissolved in EtOH (1.4 mL, 24.5 mmol). A solution of 1.0 M LiOH in water (2.0 mL, 2.0 mmol) was added, and the resulting mixture was stirred at 40° C. for 3 hours. The solvent was removed under pressure and the residue was purified by preparative HPLC to yield the title compound (110 mg, purity 100%) as a TFA salt. MS m/z [M+H]+ calc'd for C22H20ClFN4O5, 475.11. found 475.1.

Workup

  1. stirringThe mixture was stirred for 30 minutes at room temperature
  2. customevaporated under reduced pressure
  3. stirringthe resulting mixture was stirred at 40° C. for 3 hours
  4. customThe solvent was removed under pressure
  5. customthe residue was purified by preparative HPLC

Sources & evidence

ORD record
ord-438e7917a90845209f83569ae4e39fbf
Source dataset
uspto-grants-2014_10
Patent number
US08871792B2

Reaction notes

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