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

HRID 541522Notes

Reaction equation

HRID 541522 reaction equation
[C:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3]Cl.[Na+].[I-].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([F:42])=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:36][C@@H:37]([OH:41])[C:38]([OH:40])=[O:39])[NH:26][C:27]([C:29]3[O:33][N:32]=[C:31]([O:34][CH3:35])[CH:30]=3)=[O:28])=[CH:20][CH:19]=2)[CH:17]=1.CCN(C(C)C)C(C)C>CC(C)=O.C(O)(=O)C>[CH2:6]([O:5][C:1]([O:2][CH2:3][O:40][C:38](=[O:39])[C@H:37]([OH:41])[CH2:36][N:25]([CH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:16]2[CH:17]=[C:12]([Cl:11])[CH:13]=[CH:14][C:15]=2[F:42])=[CH:23][CH:22]=1)[NH:26][C:27]([C:29]1[O:33][N:32]=[C:31]([O:34][CH3:35])[CH:30]=1)=[O:28])=[O:8])[CH3:7]

Participants

7

Reactant 4

HCID 5238Sodium IodideHCID 81531DiisopropylethylamineHCID 5325479Chloromethyl Ethyl CarbonateHCID 67972936(R)-3-[N-(5'-Chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic Acid

Product 1

HCID 86705100(R)-3-[N-(5'-Chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic Acid Ethoxycarbonyloxymethyl EsterYield 23.8%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 180AcetoneSolvent2×

Conditions

Temperature
65 °C

Procedure

A mixture of chloromethyl ethyl carbonate (17.9 mg, 129 μmol) and NaI (19.4 mg, 129 μmol) in acetone (0.7 mL, 10 mmol) was heated at 65° C. for 1 hour. The mixture was then cooled to room temperature and a mixture of (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid (20.0 mg) and DIPEA (15.0 μL, 0.1 mmol) in acetone (0.3 mL) was added. The resulting mixture was stirred at room temperature for 1 hour then concentrated. The residue was dissolved in AcOH (2.0 mL), filtered, and purified by reverse phase preparative HPLC. The desired fractions were combined and freeze dried to yield a white solid. The solid was dissolved in acetic acid (1.5 mL), filtered and purified by reverse phase preparative HPLC to yield the title compound (5.8 mg, purity 94%). MS m/z [M+H]+ calc'd for C25H25ClFN3O9, 566.13. found 566.

Workup

  1. temperatureThe mixture was then cooled to room temperature
  2. additionwas added
  3. concentrationthen concentrated
  4. dissolutionThe residue was dissolved in AcOH (2.0 mL)
  5. filtrationfiltered
  6. custompurified by reverse phase preparative HPLC
  7. customfreeze dried
  8. customto yield a white solid
  9. filtrationfiltered
  10. custompurified by reverse phase preparative HPLC

Sources & evidence

ORD record
ord-0224c1ab8d8a4303a60a753dea98bfde
Source dataset
uspto-grants-2014_10
Patent number
US08871792B2

Reaction notes

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