反応 #1340613

反応方程式

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

収率 93.0%

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

収率 93.0%

溶媒

ethyl acetate

tetrahydrofuran

反応条件

後処理

1. 1
   workup.ADDITIONThe reaction mixture was added dropwise to the solution
2. 2
   温度under cooling with ice
3. 3
   workup.STIRRINGby stirring at an external temperature of 50° C. for 16 hours
4. 4
   温度Under cooling with ice
5. 5
   抽出the resultant mixture was extracted with ethyl acetate (200 mL×2)
6. 6
   洗浄washed by saturated sodium hydrogencarbonate (100 mL) and saturated brine (100 mL)
7. 7
   乾燥dried over anhydrous sodium sulfate
8. 8
   ろ過After filtration
9. 9
   濃縮the filtrate was concentrated under reduced pressure
10. 10
    その他the obtained residue was purified through silica gel column chromatography (n-hexane:ethyl acetate=4:1)

実験手順

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%).

出典