Methanol → (R)-3-[N-(5'-Chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic Acid

HRID 541516Notes

Reaction equation

HRID 541516 reaction equation
[CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[O:5][N:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.C([O:42][C:43](=[O:64])[C@H:44]([OH:63])[CH2:45][N:46]([CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[C:59]([Cl:61])[CH:58]=[CH:57][C:56]=2[F:62])=[CH:51][CH:50]=1)[NH2:47])C.CCN(C(C)C)C(C)C.CO.O>>[Cl:61][C:59]1[CH:58]=[CH:57][C:56]([F:62])=[C:55]([C:52]2[CH:53]=[CH:54][C:49]([CH2:48][N:46]([CH2:45][C@@H:44]([OH:63])[C:43]([OH:64])=[O:42])[NH:47][C:8]([C:6]3[O:5][N:4]=[C:3]([O:2][CH3:1])[CH:7]=3)=[O:10])=[CH:50][CH:51]=2)[CH:60]=1

Participants

8

Reactant 7

HCID 887MethanolHCID 962WaterHCID 6228DimethylformamideHCID 81531DiisopropylethylamineHCID 3277173-Methoxy-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 67972936(R)-3-[N-(5'-Chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic AcidYield 62.5%

Procedure

To a mixture of 3-methoxy-isoxazole-5-carboxylic acid (140 mg, 1.0 mmol) and HATU (373 mg, 1.0 mmol) in DMF (5.0 mL, 64 mmol) was added (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid ethyl ester (300.0 mg, 1.0 mmol) and DIPEA (0.3 mL, 1.6 mmol). The resulting mixture was stirred at room temperature overnight until the reaction was complete. The mixture was partitioned between EtOAc (10.0 mL) and water (3.0 mL). The organic layer was washed with water (2×3.0 mL), saturated aqueous NaCl (3.0 mL), dried over Na2SO4, filtered and concentrated to yield a yellowish oil. The oil was purified by flash chromatography (2×4 g stacker column, 0-100% EtOAc/hexanes). The desired fractions were combined and concentrated to yield a light yellowish oil. The oily residue was then treated with a mixture of MeOH (5.0 mL, 120 mmol) and water (1.0 mL, 56 mmol). LiOH monohydrate (68.6 mg, 1.6 mmol) was added. After stirring at room temperature for 30 minutes, the mixture was concentrated. The residue was treated with EtOAc (10.0 mL) and acidified with 1N HCl until pH˜3. The organic layer was washed with saturated aqueous NaCl (2×3.0 mL), dried over Na2SO4, filtered and concentrated to yield the title compound as a white foam (289.7 mg). MS m/z [M+H]+ calc'd for C21H19ClFN3O6, 464.09. found 464.0.

Workup

  1. customThe mixture was partitioned between EtOAc (10.0 mL) and water (3.0 mL)
  2. washThe organic layer was washed with water (2×3.0 mL), saturated aqueous NaCl (3.0 mL)
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customto yield a yellowish oil
  7. customThe oil was purified by flash chromatography (2×4 g stacker column, 0-100% EtOAc/hexanes)
  8. concentrationconcentrated
  9. customto yield a light yellowish oil
  10. stirringAfter stirring at room temperature for 30 minutes
  11. concentrationthe mixture was concentrated
  12. additionThe residue was treated with EtOAc (10.0 mL)
  13. washThe organic layer was washed with saturated aqueous NaCl (2×3.0 mL)
  14. dry with materialdried over Na2SO4
  15. filtrationfiltered
  16. concentrationconcentrated

Sources & evidence

ORD record
ord-676d607a76684ed28c429944c526c4e9
Source dataset
uspto-grants-2014_10
Patent number
US08871792B2

Reaction notes

Loading…