Lithium hydroxide, monohydrate → methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-(6S)-4,4-difluoro-6-methyl-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate

HRID 593322Notes

Reaction equation

HRID 593322 reaction equation
[F:1][C:2]([F:17])([CH2:12][C@@H:13]([CH3:16])[CH2:14][CH3:15])[C:3](=[O:11])[CH2:4]P(=O)(OC)OC.O.[OH-].[Li+].[C:21]([O:24][C@@H:25]1[C@H:29]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[C@@H:28]([CH:40]=O)[C@H:27]([O:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][O:44]2)[CH2:26]1)(=[O:23])[CH3:22]>COC(C)(C)C.O>[C:21]([O:24][C@@H:25]1[C@H:29]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[C@@H:28](/[CH:40]=[CH:4]/[C:3](=[O:11])[C:2]([F:1])([F:17])[CH2:12][C@@H:13]([CH3:16])[CH2:14][CH3:15])[C@H:27]([O:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][O:44]2)[CH2:26]1)(=[O:23])[CH3:22]

Participants

6

Reactant 3

HCID 168937Lithium hydroxide, monohydrateHCID 11729034methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyl-oxy)cyclopentyl]heptanateHCID 54522042dimethyl ((5S)-3,3-difluoro-5-methyl-2-oxoheptyl)phosphonate

Product 1

HCID 59514700methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-(6S)-4,4-difluoro-6-methyl-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanateYield 85.8%

Reagents, catalysts & solvents 2

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

Procedure

To a solution of dimethyl ((5S)-3,3-difluoro-5-methyl-2-oxoheptyl)phosphonate (A) (74.7 g, 274 mmol) in t-butyl methyl ether (1120 ml), lithium hydroxide monohydrate (11.5 g, 273 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-tetrahydropyranyl-oxy)cyclopentyl]heptanate (B) (64.02 g, 160.6=1) in t-butyl methyl ether (278 ml) and water (21.7 ml) were added thereto, and the mixed solution was heat refluxed for approximately 31 hours (internal temperature: approximately 53° 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 twice with 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: 2110 g; ethyl acetate:hexane=1:4 to 1:2). The fractions containing impurities were re-purified by silica gel column chromatography (Fuji Silysia BW-300: 850 g; ethyl acetate:hexane=1:4 to 1:2) to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-(6S)-4,4-difluoro-6-methyl-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (C) (75.03 g; 137.8 mmol; yield: 85.8%) as a pale yellow oil.

Workup

  1. temperaturethe mixed solution was heat
  2. temperaturerefluxed for approximately 31 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 (234 ml)
  7. washwashed twice with 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: 2110 g; ethyl acetate:hexane=1:4 to 1:2)
  11. additionThe fractions containing impurities
  12. customwere re-purified by silica gel column chromatography (Fuji Silysia BW-300: 850 g; ethyl acetate:hexane=1:4 to 1:2)

Sources & evidence

ORD record
ord-8a0b7636643b4e098a6ef446fd436712
Source dataset
uspto-grants-2016_01
Patent number
US09242950B2

Reaction notes

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