Acetone → (R)-3-[N-(5'-Chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic Acid 2-Methoxy-Ethyl Ester

HRID 541520Notes

Reaction equation

HRID 541520 reaction equation
Br[CH2:2][CH2:3][O:4][CH3:5].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([F:37])=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]([CH2:31][C@@H:32]([OH:36])[C:33]([OH:35])=[O:34])[NH:21][C:22]([C:24]3[O:28][N:27]=[C:26]([O:29][CH3:30])[CH:25]=3)=[O:23])=[CH:15][CH:14]=2)[CH:12]=1.CCN(C(C)C)C(C)C.CC(C)=O.[Na+].[I-]>>[CH3:5][O:4][CH2:3][CH2:2][O:35][C:33](=[O:34])[C@H:32]([OH:36])[CH2:31][N:20]([CH2:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]2[CH:12]=[C:7]([Cl:6])[CH:8]=[CH:9][C:10]=2[F:37])=[CH:18][CH:17]=1)[NH:21][C:22]([C:24]1[O:28][N:27]=[C:26]([O:29][CH3:30])[CH:25]=1)=[O:23]

Participants

6

Reactant 5

HCID 180AcetoneHCID 5238Sodium Iodide3×HCID 809722-Bromoethyl methyl ether3×HCID 81531Diisopropylethylamine3×HCID 67972936(R)-3-[N-(5'-Chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic Acid

Product 1

HCID 86705098(R)-3-[N-(5'-Chloro-2'-fluorobiphenyl-4-ylmethyl)-N'-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic Acid 2-Methoxy-Ethyl EsterYield 11.6%

Conditions

Temperature
60 °C

Procedure

1-Bromo-2-methoxyethane (12.2 μL, 129 μmol) was added to a mixture of (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid (20.0 mg, 43 μmol) and DIPEA (45.1 μL, 259 μmol) in acetone (1.0 mL, 14 mmol). The resulting mixture was heated at 60° C. for 4 hours. NaI (19.4 mg, 129 μmol) was added and the reaction was monitored for 2 hours. Additional 1-bromo-2-methoxyethane (3 eq.), DIEA (4 eq.), and NaI (3 eq.) were added and the heating continued overnight. Additional 1-bromo-2-methoxyethane (3 eq.), NaI (3 eq.), and DIEA (3 eq.) were added and heating continued overnight. The mixture was then concentrated, and the residue was dissolved in AcOH (1.5 mL), filtered and purified by reverse phase preparative HPLC to yield the title compound (2.6 mg, purity 99%). MS m/z [M+H]+ calc'd for C24H25ClFN3O7, 522.14. found 522.4.

Workup

  1. waitthe heating continued overnight
  2. temperatureheating continued overnight
  3. concentrationThe mixture was then concentrated
  4. dissolutionthe residue was dissolved in AcOH (1.5 mL)
  5. filtrationfiltered
  6. custompurified by reverse phase preparative HPLC

Sources & evidence

ORD record
ord-fe9109bee3c1427abef5b59d9ed2cbf5
Source dataset
uspto-grants-2014_10
Patent number
US08871792B2

Reaction notes

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