Acetone → (R)-3-{N-(5'-Chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino}-2-phosphonooxypropionic Acid

HRID 541514Notes

Reaction equation

HRID 541514 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:37])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:31][C@@H:32]([OH:36])[C:33]([OH:35])=[O:34])[NH:16][C:17]([C:19]3[O:23][N:22]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[F:30])[CH:20]=3)=[O:18])=[CH:10][CH:9]=2)[CH:7]=1.CCO.Cl.O1CCOCC1.N1C=CC=CC=1.[P:54](Cl)(Cl)(Cl)=[O:55].CC(C)=O.[Li+].[OH-:64].[OH2:65]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:37])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:31][C@@H:32]([O:36][P:54]([OH:55])([OH:65])=[O:64])[C:33]([OH:35])=[O:34])[NH:16][C:17]([C:19]3[O:23][N:22]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[F:30])[CH:20]=3)=[O:18])=[CH:10][CH:9]=2)[CH:7]=1

Participants

10

Reactant 9

HCID 180AcetoneHCID 313Hydrochloric AcidHCID 702Ethanol2×HCID 962WaterHCID 1049PyridineHCID 3939Lithium HydroxideHCID 24813Phosphorus oxychlorideHCID 312751,4-DioxaneHCID 67973214(R)-3-{N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino}-2-hydroxypropionic acid

Product 1

HCID 86705093(R)-3-{N-(5'-Chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino}-2-phosphonooxypropionic Acid

Procedure

(R)-3-{N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino}-2-hydroxy-propionic acid (12.0 mg, 22.7 μmol) in EtOH (80 μL, 1.4 mmol) was combined with a solution of 4.0 M HCl in 1,4-dioxane (227 μL, 909 mmol), and the resulting mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the residue was dissolved in pyridine (20 μL, 250 mmol). The resulting solution was added to a solution of phosphoryl chloride (19 μL, 0.2 mmol) in acetone (67 μL, 0.9 mmol) and stirred at room temperature for 10 minutes. The solvent was removed in vacuo and the residue was dissolved in EtOH (80 μL, 1.4 mmol). A solution of 1.0 M LiOH in water (1.4 mL, 1.4 mmol) was then added until the pH reached-12. The mixture was stirred for 1 hour and the solvent was removed in vacuo. The residue was purified by preparative HPLC to yield the title compound (5 mg). MS m/z [M+H]+ calc'd for C26H21ClF2N3O8P, 608.07. found 608.0.

Workup

  1. customThe solvent was removed in vacuo
  2. stirringstirred at room temperature for 10 minutes
  3. customThe solvent was removed in vacuo
  4. stirringThe mixture was stirred for 1 hour
  5. customthe solvent was removed in vacuo
  6. customThe residue was purified by preparative HPLC

Sources & evidence

ORD record
ord-4de83de65f234a87a46306f65e68a62a
Source dataset
uspto-grants-2014_10
Patent number
US08871792B2

Reaction notes

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