Реакция #970889

Уравнение реакции

methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate

dimethyl(3,3-difluoro-2-oxoheptyl)phosphonate

lithium hydroxide monohydrate

→

methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate

Выход 90.1%

Растворители

water

t-butyl methyl ether

water

t-butyl methyl ether

Условия реакции

Обработка

1. 1
   Температураthe mixture was heat
2. 2
   Температураrefluxed for approximately 49 hours (internal temperature: approximately 53° C.)
3. 3
   ТемператураAfter cooling to room temperature
4. 4
   workup.STIRRINGthe mixture was stirred
5. 5
   Другоеseparated into two layers
6. 6
   ЭкстракцияThe aqueous layer was extracted twice with ethyl acetate (200 ml)
7. 7
   Промывкаwashed twice with saturated aqueous sodium chloride (300 ml)
8. 8
   Сушкаdried with anhydrous magnesium sulfate (50 g)
9. 9
   КонцентрированиеAfter concentration under reduced pressure
10. 10
    Другоеthe residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 1805 g; ethyl acetate:hexane =1:4)
11. 11
    workup.ADDITIONThe fractions containing impurities
12. 12
    Другоеwere re-purified by silica gel column chromatography (Fuji Silysia BW-300: 580 g; ethyl acetate:hexane =1:4)

Методика

To a solution of dimethyl(3,3-difluoro-2-oxoheptyl)phosphonate (1) (50.50 g, 195.6 mmol) in t-butyl methyl ether (750 ml), lithium hydroxide monohydrate (7.94 g, 189 mmol) was added and the mixture was stirred for one hour at room temperature. A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (2) (52.00 g, 130.5 mmol) in t-butyl methyl ether (150 ml) and water (27 ml) were added thereto, and the mixture was heat refluxed for approximately 49 hours (internal temperature: approximately 53° C.). After cooling to room temperature, water (300 ml) was added and the mixture was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with ethyl acetate (200 ml). The organic layers were combined, washed twice with saturated aqueous sodium chloride (300 ml), and dried with anhydrous magnesium sulfate (50 g). After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 1805 g; ethyl acetate:hexane =1:4). The fractions containing impurities were re-purified by silica gel column chromatography (Fuji Silysia BW-300: 580 g; ethyl acetate:hexane =1:4), to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (3) (62.38 g; 117.6 mmol; yield: 90.1%) as a pale yellow oil.

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