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

HRID 883722Notes

Reaction equation

HRID 883722 reaction equation
COP([CH2:7][C:8](=[O:16])[C:9]([F:15])([F:14])[CH2:10][CH2:11][CH2:12][CH3:13])(=O)OC.O.[OH-].[Li+].[C:20]([O:23][C@@H:24]1[C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C@@H:27]([CH:39]=O)[C@H:26]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:25]1)(=[O:22])[CH3:21]>COC(C)(C)C.O>[C:20]([O:23][C@@H:24]1[C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C@@H:27](/[CH:39]=[CH:7]/[C:8](=[O:16])[C:9]([F:14])([F:15])[CH2:10][CH2:11][CH2:12][CH3:13])[C@H:26]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:25]1)(=[O:22])[CH3:21]

Participants

6

Reactant 3

HCID 168937Lithium hydroxide, monohydrateHCID 11118722Dimethyl (3,3-difluoro-2-oxoheptyl)phosphonateHCID 11729034methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyl-oxy)cyclopentyl]heptanate

Product 1

HCID 59514691methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanateYield 89.3%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 15413tert-Butyl methyl etherSolvent2×

Procedure

To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1) (69.65 g, 269.8 mmol) in t-butyl methyl ether (1046 ml), lithium hydroxide monohydrate (10.69 g, 254.8 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) (59.72 g, 149.9 mmol) in t-butyl methyl ether (233 ml) and water (20.2 ml) were added thereto, and the mixed solution was heat refluxed for approximately 41 hours (internal temperature: approximately 54° C.). After cooling to room temperature, water (351 ml) was added to the solution and the mixture was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with ethyl acetate (234 ml). The organic layers were combined, washed sequentially with 3% aqueous sodium chloride (351 ml) and saturated aqueous sodium chloride (351 ml), and dried with anhydrous magnesium sulfate (55 g). After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 2280; ethyl acetate:hexane =1:4). The fractions containing impurities were re-purified by silica gel column chromatography (Fuji Silysia BW-300: 582 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) (71.02 g; 133.8 mmol; yield: 89.3%) as a pale yellow oil.

Workup

  1. temperaturethe mixed solution was heat
  2. temperaturerefluxed for approximately 41 hours (internal temperature: approximately 54° 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 (234 ml)
  7. washwashed sequentially with 3% aqueous sodium chloride (351 ml) and saturated aqueous sodium chloride (351 ml)
  8. dry with materialdried with anhydrous magnesium sulfate (55 g)
  9. concentrationAfter concentration under reduced pressure
  10. customthe residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 2280; ethyl acetate:hexane =1:4)
  11. additionThe fractions containing impurities
  12. customwere re-purified by silica gel column chromatography (Fuji Silysia BW-300: 582 g; ethyl acetate:hexane =1:4)

Sources & evidence

ORD record
ord-ebe31e18f7ab46959ac169870794545b
Source dataset
uspto-grants-2012_08
Patent number
US08236969B2

Reaction notes

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