Sodium Iodide → Butyric acid (R)-3-[N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionyloxymethyl Ester

HRID 541521Notes

Reaction equation

HRID 541521 reaction equation
[C:1]([O:6][CH2:7]Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[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>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([F:42])=[C:16]([C:18]2[CH:19]=[CH:20][C:21]([CH2:24][N:25]([CH2:36][C@@H:37]([OH:41])[C:38]([O:40][CH2:7][O:6][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[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:22][CH:23]=2)[CH:17]=1

Participants

7

Reactant 4

HCID 5238Sodium IodideHCID 81531DiisopropylethylamineHCID 2725008Chloromethyl butanoateHCID 67972936(R)-3-[N-(5'-Chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic Acid

Product 1

HCID 86705099Butyric acid (R)-3-[N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionyloxymethyl EsterYield 26.7%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 180AcetoneSolvent2×

Conditions

Temperature
65 °C

Procedure

A mixture of chloromethyl butyrate (16.2 μL, 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 mL, 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 (6.5 mg, purity 100%). MS m/z [M+H]+ calc'd for C26H27ClFN3O8, 564.15. found. 564.

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-3fca85e3727b40fd9c479850b42643c4
Source dataset
uspto-grants-2014_10
Patent number
US08871792B2

Reaction notes

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