Реакция #1340613

Уравнение реакции

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

Выход 93.0%

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

Выход 93.0%

Растворители

ethyl acetate

tetrahydrofuran

Условия реакции

Обработка

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

Методика

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%).

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