Diisopropylamine → 2-(2,4-difluorophenoxy)-3-hydroxy-3-[4-nitro-2-(2-trimethylsilanyl-ethoxymethyl)-2H-pyrazol-3-yl]propionic acid methyl ester

HRID 230174Notes

Reaction equation

HRID 230174 reaction equation
C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:26])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25].[N+:27]([C:30]1[CH:34]=[N:33][N:32]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:31]=1[CH:43]=[O:44])([O-:29])=[O:28]>C(OCC)C.[Cl-].[NH4+].C(OCC)(=O)C.O>[CH3:13][O:14][C:15](=[O:26])[CH:16]([O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25])[CH:43]([OH:44])[C:31]1[N:32]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:41])([CH3:40])[CH3:42])[N:33]=[CH:34][C:30]=1[N+:27]([O-:29])=[O:28]

Participants

9

Reactant 4

HCID 7912DiisopropylamineHCID 23434554Methyl 2-(2,4-difluorophenoxy)acetateHCID 863462134-Nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbaldehydeHCID 178418339Butyllithium

Product 1

HCID 598129592-(2,4-difluorophenoxy)-3-hydroxy-3-[4-nitro-2-(2-trimethylsilanyl-ethoxymethyl)-2H-pyrazol-3-yl]propionic acid methyl ester

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 3283Diethyl EtherSolvent3×HCID 8857Ethyl AcetateSolventHCID 25517Ammonium ChlorideSolvent

Procedure

To a −78° C. solution of diisopropylamine (0.3 mL, 2.1 eq) in diethyl ether (3 mL) was added a 2.5 M solution of n-butyllithium in hexanes (Aldrich) (0.84 mL, 2.1 eq). The resulting mixture was stirred for 15 minutes. To this mixture was added a solution of (2,4-difluorophenoxy)acetic acid methyl ester (425 mg, 2.1 eq) in diethyl ether (2 mL) via a syringe, and the resulting mixture was stirred at −78° C. for 30 minutes, after which a solution of 4-nitro-2-(2-trimethylsilanyl-ethoxymethyl)-2H-pyrazole-3-carbaldehyde (271 mg, 1 mmol) in diethyl ether (2 mL) was added. The resulting mixture was stirred for 2 hours. The −78° C. reaction mixture was diluted with a saturated aqueous ammonium chloride solution, then diluted with ethyl acetate (150 mL) and water (25 mL). The organic layer was separated, washed with brine (1×50 mL), dried over magnesium sulfate, filtered and concentrated to give the crude product as an oil (709 mg). Purification of the crude product by Preparative Thin Layer Chromatography eluting with 25% ethyl acetate in hexanes gave the title compound as a diastereomeric mixture (257 mg, thick colorless oil). M+=473.

Workup

  1. stirringthe resulting mixture was stirred at −78° C. for 30 minutes
  2. stirringThe resulting mixture was stirred for 2 hours
  3. customThe −78° C. reaction mixture
  4. customThe organic layer was separated
  5. washwashed with brine (1×50 mL)
  6. dry with materialdried over magnesium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customto give the crude product as an oil (709 mg)
  10. customPurification of the crude product by Preparative Thin Layer Chromatography
  11. washeluting with 25% ethyl acetate in hexanes

Sources & evidence

ORD record
ord-acb2a34aee7b4ae0b2c924d855815aad
Source dataset
uspto-grants-2009_07
Patent number
US07566708B2

Reaction notes

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