Ammonium formate → Methyl 2-amino-2-(4-fluorophenyl)acetate

HRID 2302301Notes

Reaction equation

HRID 2302301 reaction equation
Cl.[CH3:2][O:3][C:4](=[O:21])[CH:5]([NH:13]CC1C=CC=CC=1)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.C([O-])=O.[NH4+]>C(O)(C)C.[Pd]>[CH3:2][O:3][C:4](=[O:21])[CH:5]([NH2:13])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1

Participants

5

Reactant 2

HCID 2723923Ammonium formateHCID 693609224-Fluoro-alpha-[(phenylmethyl)amino]benzeneacetic acid methyl ester hydrochloride

Product 1

HCID 10943118Methyl 2-amino-2-(4-fluorophenyl)acetateYield 87%

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 3776IsopropanolSolvent

Conditions

Temperature
50 °C

Procedure

4-Fluoro-α-[(phenylmethyl)amino]benzeneacetic acid methyl ester hydrochloride (12.2 kg, 39.4 moles) was added to a slurry of 10% palladium-on-carbon (1.2 kg) in isopropanol (50 L). Ammonium formate (5.0 kg, 79.4 moles) was added and the batch was heated to 50° C. Progress of the reaction was monitored by HPLC. The batch was filtered through Hyflo Supercel and the filter cake was washed with isopropanol (25 L). The filtrate was evaporated to low volume and flushed with isopropyl acetate (50 L). The residue was dissolved in isopropyl acetate (30 L) and washed with 5% aqueous potassium phosphate (40 L), followed by saturated aqueous sodium chloride (10 L). The solution was evaporated under vacuum to give 5.79 kg (87% yield) of racemic α-amino-4-fluorobenzeneacetic acid methyl ester. HPLC Conditions—Column: Zorbax Rx-C8, 25 cm×4.6 mm; Column temperature: 40° C.; Mobile phase: acetonitrile:0.1% aqueous phosphoric acid (70:30 v/v); Flow rate: 1 mL/min; Detection: UV at 220 nm; Approximate retention times: α-amino-4-fluorobenzeneacetic acid methyl ester: 2.2 minutes; 4-fluoro-α-[(phenylmethyl)amino]benzeneacetic acid methyl ester 2.6 minutes. If unreacted 4-fluoro-α-[(phenylmethyl)amino]-benzeneacetic acid methyl ester (>2%) remains after 1 hour, a second charge of 10% palladium-on-carbon (300 g) slurried in isopropanol (2.0 L) can be made, followed by ammonium formate (1.0 kg). Heating then continues until the reaction is complete.

Workup

  1. filtrationThe batch was filtered through Hyflo Supercel
  2. washthe filter cake was washed with isopropanol (25 L)
  3. customThe filtrate was evaporated to low volume
  4. customflushed with isopropyl acetate (50 L)
  5. dissolutionThe residue was dissolved in isopropyl acetate (30 L)
  6. washwashed with 5% aqueous potassium phosphate (40 L)
  7. customThe solution was evaporated under vacuum

Sources & evidence

ORD record
ord-dcd0a9fbd6e541faac9c6a8d5580160c
Source dataset
uspto-grants-2002_08
Patent number
US06432953B1

Reaction notes

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