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

HRID 541513Notes

Reaction equation

HRID 541513 reaction equation
[C:1](=[O:9])([O:5][CH:6]([CH3:8])[CH3:7])[O:2][CH2:3]Cl.[Na+].[I-].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([F:48])=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][N:26]([CH2:42][C@@H:43]([OH:47])[C:44]([OH:46])=[O:45])[NH:27][C:28]([C:30]3[O:34][N:33]=[C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[F:41])[CH:31]=3)=[O:29])=[CH:21][CH:20]=2)[CH:18]=1.CCN(CC)CC>CC(C)=O>[CH:6]([O:5][C:1]([O:2][CH2:3][O:46][C:44](=[O:45])[C@H:43]([OH:47])[CH2:42][N:26]([CH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[CH:18]=[C:13]([Cl:12])[CH:14]=[CH:15][C:16]=2[F:48])=[CH:20][CH:21]=1)[NH:27][C:28]([C:30]1[O:34][N:33]=[C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[F:41])[CH:31]=1)=[O:29])=[O:9])([CH3:8])[CH3:7]

Participants

6

Reactant 4

HCID 5238Sodium IodideHCID 8471TriethylamineHCID 14787051Chloromethyl isopropyl carbonateHCID 67973214(R)-3-{N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino}-2-hydroxypropionic acid

Product 1

HCID 86705092(R)-3-{N-(5'-Chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino}-2-hydroxypropionic Acid Isopropoxycarbonyloxymethyl EsterYield 7.4%

Reagents, catalysts & solvents 1

HCID 180AcetoneSolvent2×

Conditions

Temperature
60 °C

Procedure

Chloromethyl isopropyl carbonate (17.3 mg, 114 μmol) and NaI 17.0 mg, 114 μmol) were combined in acetone (1.0 mL, 14 mmol) and heated at 60° C. for 1 hour. The mixture was then cooled to room temperature. A mixture of (R)-3-{N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino}-2-hydroxypropionic acid (20.0 mg, 38 μmol) dissolved in acetone (1.0 mL) and treated with Et3N (10.6 μL, 76 μmol) was added and the resulting mixture was stirred at room temperature for 5 hours. The mixture was concentrated and the residue was dissolved in AcOH (2.0 mL), filtered and purified by reverse phase preparative HPLC. The product was freeze dried and purified by reverse phase preparative HPLC to yield the title compound (1.8 mg, purity 100%). MS m/z [M+H]+ calc'd for C31H28ClF2N3O8, 644.15. found 644.1.

Workup

  1. temperatureThe mixture was then cooled to room temperature
  2. additionwas added
  3. concentrationThe mixture was concentrated
  4. dissolutionthe residue was dissolved in AcOH (2.0 mL)
  5. filtrationfiltered
  6. custompurified by reverse phase preparative HPLC
  7. customdried
  8. custompurified by reverse phase preparative HPLC

Sources & evidence

ORD record
ord-476d623d819e434891baf300001b46c2
Source dataset
uspto-grants-2014_10
Patent number
US08871792B2

Reaction notes

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