Lithium hydroxide, monohydrate → methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-4-phenyl-1-butenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate

HRID 1159576Notes

Reaction equation

HRID 1159576 reaction equation
[F:1][C:2]([F:18])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3](=[O:11])[CH2:4]P(=O)(OC)OC.O.[OH-].[Li+].[C:22]([O:25][C@@H:26]1[C@H:30]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[C@@H:29]([CH:41]=O)[C@H:28]([O:43][CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][O:45]2)[CH2:27]1)(=[O:24])[CH3:23]>COC(C)(C)C.O>[C:22]([O:25][C@@H:26]1[C@H:30]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[C@@H:29](/[CH:41]=[CH:4]/[C:3](=[O:11])[C:2]([F:1])([F:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@H:28]([O:43][CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][O:45]2)[CH2:27]1)(=[O:24])[CH3:23]

Participants

6

Reactant 3

HCID 168937Lithium hydroxide, monohydrateHCID 11729034methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyl-oxy)cyclopentyl]heptanateHCID 21949543HCID 21949543, compound

Product 1

HCID 59514701methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-4-phenyl-1-butenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanateYield 74.5%

Reagents, catalysts & solvents 2

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

Procedure

To a solution of dimethyl (3,3-difluoro-2-oxo-3-phenylpropyl)phosphonate (6) (0.262 g, 0.942 mmol) in t-butyl methyi ether (7 ml), lithium hydroxide monohydrate (38.2 mg, 0.910 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) (0.250 g, 0.627 mmol) in t-butyl methyl ether (3 ml) and water (0.3 ml) were added thereto, and the mixed solution was heat refluxed for approximately 48 hours After cooling to room temperature, the reaction mixture was added to water, and extracted twice with t-butyl methyl ether. The organic layers were combined, sequentially washed with water, saturated sodium bicarbonate water and saturated aqueous sodium chloride, and then dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Merck Art. 9385: 200 g; ethyl acetate:hexane=2:3). The fractions containing impurities were re-purified by silica gel column chromatography (Merck Art. 9385: 120 g; ethyl acetate:hexane=2:3), to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-4-phenyl-1-butenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (7) (0.257 g; 0.467 mmol; yield: 74.4%) as a colorless oil.

Workup

  1. temperaturethe mixed solution was heat
  2. temperaturerefluxed for approximately 48 hours
  3. temperatureAfter cooling to room temperature
  4. extractionextracted twice with t-butyl methyl ether
  5. washsequentially washed with water, saturated sodium bicarbonate water and saturated aqueous sodium chloride
  6. dry with materialdried with anhydrous magnesium sulfate
  7. concentrationAfter concentration under reduced pressure
  8. customthe residue was purified by silica gel column chromatography (Merck Art. 9385: 200 g; ethyl acetate:hexane=2:3)
  9. additionThe fractions containing impurities
  10. customwere re-purified by silica gel column chromatography (Merck Art. 9385: 120 g; ethyl acetate:hexane=2:3)

Sources & evidence

ORD record
ord-d0fae94304794300a10d89bd9b6621c9
Source dataset
uspto-grants-2010_10
Patent number
US07812182B2

Reaction notes

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