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

HRID 541497Notes

Reaction equation

HRID 541497 reaction equation
[CH3:1][O:2][C:3](=[O:24])[C@H:4]([OH:23])[CH2:5][N:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1)[NH:7]C(OC(C)(C)C)=O.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([F:35])=[C:30](B(O)O)[CH:31]=1.[C:36]([O-])([O-])=O.[K+].[K+].O.Cl.O1CCOCC1>CCOCC.[Pd].CCO>[CH2:1]([O:2][C:3](=[O:24])[C@H:4]([OH:23])[CH2:5][N:6]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:28]2[CH:27]=[C:26]([Cl:25])[CH:31]=[CH:30][C:29]=2[F:35])=[CH:20][CH:21]=1)[NH2:7])[CH3:36]

Participants

10

Reactant 6

HCID 313Hydrochloric AcidHCID 962WaterHCID 11430Potassium CarbonateHCID 312751,4-DioxaneHCID 3718925(5-Chloro-2-fluoro-phenyl)boronic acidHCID 67972599HCID 67972599, compound

Product 1

HCID 67972425(R)-3-[N-(5'-Chloro-2'-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic Acid Ethyl EsterYield 15.3%

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 702EthanolSolvent3×HCID 3283Diethyl EtherSolvent

Conditions

Temperature
90 °C

Procedure

(R)-3-[N-(4-Bromobenzyl)-N′-t-butoxycarbonylhydrazino]-2-hydroxypropionic acid methyl ester (1.0 g, 2.5 mmol), 5-chloro-2-fluorophenylboronic acid (865 mg, 5.0 mmol), and K2CO3 (857 mg, 6.2 mmol), were combined in EtOH (30 mL, 500 mmol) and water (8 mL, 400 mmol), followed by the addition of SilicaCat® DPP-Pd (0.28 mmol/g loading; 886 mg, 248 μmol). The mixture was heated at 90° C. until the reaction was complete (2 hours). The precipitate was filtered off, and the filtrate was concentrated and purified by reverse phase chromatography (30-95% MeCN in water with 0.5% TFA). The clean fractions were collected, lyophilized, and combined with 4 M HCl in dioxane (8 mL, 30 mmol) and EtOH (10 mL, 200 mmol). The resulting mixture was stirred at room temperature until the reaction was complete (7 hours). The mixture was concentrated to yield an oil, which was stirred in ether with few drops of EtOH overnight. The precipitate was filtered off and rinsed with ether to yield the title compound (140 mg).

Workup

  1. custom(2 hours)
  2. filtrationThe precipitate was filtered off
  3. concentrationthe filtrate was concentrated
  4. custompurified by reverse phase chromatography (30-95% MeCN in water with 0.5% TFA)
  5. customThe clean fractions were collected
  6. custom(7 hours)
  7. concentrationThe mixture was concentrated
  8. customto yield an oil, which
  9. filtrationThe precipitate was filtered off
  10. washrinsed with ether

Sources & evidence

ORD record
ord-d76382975b4f400293c84b9b50efda38
Source dataset
uspto-grants-2014_10
Patent number
US08871792B2

Reaction notes

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