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

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.

1. temperaturethe mixture was heat
2. temperaturerefluxed for approximately 49 hours (internal temperature: approximately 53° C.)
3. temperatureAfter cooling to room temperature
4. stirringthe mixture was stirred
5. customseparated into two layers
6. extractionThe aqueous layer was extracted twice with ethyl acetate (200 ml)
7. washwashed twice with saturated aqueous sodium chloride (300 ml)
8. dry with materialdried with anhydrous magnesium sulfate (50 g)
9. concentrationAfter concentration under reduced pressure
10. customthe residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 1805 g; ethyl acetate:hexane =1:4)
11. additionThe fractions containing impurities
12. customwere re-purified by silica gel column chromatography (Fuji Silysia BW-300: 580 g; ethyl acetate:hexane =1:4)

ORD-Eintrag

ord-b86d7f0a37354f8fbdd888443bdb957c

Quelldatensatz

uspto-grants-2012_08

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08236969B2