Reaction #1340613

Reaction equation

citric acid

potassium ethyl malonate

magnesium chloride

triethylamine

1,1′-carbonyldiimidazole

4-[(3S,4S)-3-(tert-butoxycarbonyl)amino-4-methylpyrrolidin-1-yl]-2,5-difluoro-3-methylbenzoic acid

→

title compound

Yield 93.0%

Ethyl 3-[((3S,4S)-3-(tert-butoxycarbonyl)amino-4-methylpyrrolidin-1-yl)-2,5-difluoro-3-methylphenyl]-3-oxopropionate

Yield 93.0%

Solvents

ethyl acetate

tetrahydrofuran

Conditions

Workup

1. 1
   workup.ADDITIONThe reaction mixture was added dropwise to the solution
2. 2
   Temperatureunder cooling with ice
3. 3
   workup.STIRRINGby stirring at an external temperature of 50° C. for 16 hours
4. 4
   TemperatureUnder cooling with ice
5. 5
   Extractionthe resultant mixture was extracted with ethyl acetate (200 mL×2)
6. 6
   Washwashed by saturated sodium hydrogencarbonate (100 mL) and saturated brine (100 mL)
7. 7
   Dryingdried over anhydrous sodium sulfate
8. 8
   FiltrationAfter filtration
9. 9
   Concentrationthe filtrate was concentrated under reduced pressure
10. 10
    Otherthe obtained residue was purified through silica gel column chromatography (n-hexane:ethyl acetate=4:1)

Procedure

1,1′-carbonyldiimidazole (1.46 g, 9.00 mmol) was added to a solution of 4-[(3S,4S)-3-(tert-butoxycarbonyl)amino-4-methylpyrrolidin-1-yl]-2,5-difluoro-3-methylbenzoic acid (2.20 g, 6.30 mmol) in tetrahydrofuran (30 mL), and the mixture was stirred at room temperature for 3 hours. Separately, a magnesium salt was prepared potassium ethyl malonate (3.40 g, 20.0 mmol), magnesium chloride (2.38 g, 25.0 mmol), and triethylamine (4.18 mL, 30.0 mmol), and the salt was dissolved in ethyl acetate (40 mL). The reaction mixture was added dropwise to the solution under cooling with ice, followed by stirring at an external temperature of 50° C. for 16 hours. Under cooling with ice, a 10% aqueous citric acid solution was added thereto, and the resultant mixture was extracted with ethyl acetate (200 mL×2), washed by saturated sodium hydrogencarbonate (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified through silica gel column chromatography (n-hexane:ethyl acetate=4:1), to thereby yield the title compound (2.58 g, 93.0%).

Source