Hydrochloric Acid → (R)-3-{N-(5'-Chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino}-2-hydroxypropionic Acid Isobutyl Ester

HRID 541507Notes

Reaction equation

HRID 541507 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:12]=[C:11]([C:13]([OH:15])=O)[O:10][N:9]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CC(N(C)C)=O.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>>[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:11]1[O:10][N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:12]=1)=[O:15])[CH:81]([CH3:83])[CH3:82]

Participants

9

Reactant 8

HCID 313Hydrochloric AcidHCID 6560IsobutanolHCID 312751,4-DioxaneHCID 31374DimethylacetamideHCID 81531DiisopropylethylamineHCID 31602553-(2-Fluorophenyl)-1,2-oxazole-5-carboxylic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 67972425(R)-3-[N-(5'-Chloro-2'-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic Acid Ethyl Ester

Product 1

HCID 117669046(R)-3-{N-(5'-Chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino}-2-hydroxypropionic Acid Isobutyl EsterYield 3.9%

Procedure

3-(2-fluorophenyl)isoxazole-5-carboxylic acid (15.4 mg, 74 μmol) and HATU (33.9 mg, 89 μmol) were stirred in DMA (0.5 mL, 5 mmol) for 10 minutes. (R)-3-[N-(5′-Chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid ethyl ester (27.3 mg, 74 μmol) and DIPEA (38.9 μL, 223 μmol) were added, and the resulting mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under reduced pressure, and the residue was dissolved EtOAc (20 mL) and washed with water (2×2 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The product was then mixed with isobutyl alcohol (0.5 mL, 5 mmol) and 4.0 M HCl in 1,4-dioxane (93 μL, 372 mmol), and stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was dissolved in 50% AcOH-water (1.5 ml), filtered, and purified by reverse phase preparative HPLC to yield the title compound (1.7 mg, purity 100%) as a TFA salt. MS m/z [M+H]+ calc'd for C30H28ClF2N3O5, 584.17. found 584.4.

Workup

  1. concentrationThe mixture was then concentrated under reduced pressure
  2. dissolutionthe residue was dissolved EtOAc (20 mL)
  3. washwashed with water (2×2 mL)
  4. dry with materialThe organic layer was dried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. stirringstirred at room temperature overnight
  8. concentrationThe mixture was concentrated under reduced pressure
  9. dissolutionthe residue was dissolved in 50% AcOH-water (1.5 ml)
  10. filtrationfiltered
  11. custompurified by reverse phase preparative HPLC

Sources & evidence

ORD record
ord-b990589324fe414a891b9573cb81a4c7
Source dataset
uspto-grants-2014_10
Patent number
US08871792B2

Reaction notes

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