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

HRID 541512Notes

Reaction equation

HRID 541512 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:47])=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:41][C@@H:42]([OH:46])[C:43]([OH:45])=[O:44])[NH:26][C:27]([C:29]3[O:33][N:32]=[C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[F:40])[CH:30]=3)=[O:28])=[CH:20][CH:19]=2)[CH:17]=1.CCN(CC)CC>CC(C)=O.CC(O)=O>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([F:47])=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:41][C@@H:42]([OH:46])[C:43]([O:45][CH2:7][O:6][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[O:44])[NH:26][C:27]([C:29]3[O:33][N:32]=[C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[F:40])[CH:30]=3)=[O:28])=[CH:20][CH:19]=2)[CH:17]=1

Participants

7

Reactant 4

HCID 5238Sodium IodideHCID 8471TriethylamineHCID 2725008Chloromethyl butanoateHCID 67973214(R)-3-{N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino}-2-hydroxypropionic acid

Product 1

HCID 117669061Butyric acid (R)-3-[N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-[3-(2-fluorophenyl)isoxazole-5-carbonyl]hydrazino]-2-hydroxypropionyloxymethyl EsterYield 30.3%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 180AcetoneSolvent2×

Conditions

Temperature
65 °C

Procedure

Chloromethyl butyrate (11.4 μL, 0.1 mmol) and NaI (13.6 mg, 0.1 mmol) were combined in acetone (0.7 mL, 10 mmol) and heated at 65° 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 (16.0 mg, 30 μmol) dissolved in acetone (0.2 mL) and treated with Et3N (8.5 μL, 61 μmol) was added and the resulting mixture was stirred at room temperature for 25 minutes. The mixture was concentrated and 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 yellowish solid. This solid was dissolved in AcOH (1.5 mL), filtered, and purified by reverse phase preparative HPLC. The desired fractions were combined and freeze dried to yield the title compound (5.7 mg, purity 100%) as a TFA salt white solid. MS m/z [M+H]+ calc'd for C31H28ClF2N3O2, 628.16. found 628.

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. customfreeze dried
  8. customto yield a yellowish solid
  9. filtrationfiltered
  10. custompurified by reverse phase preparative HPLC
  11. customfreeze dried

Sources & evidence

ORD record
ord-f134f361c6834453b3906bbc32323f3e
Source dataset
uspto-grants-2014_10
Patent number
US08871792B2

Reaction notes

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