2-((S)-6-((R)-7-Fluoro-4-(4-(2-methoxy-2-oxoethoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetic acid → 2-((S)-6-((R)-7-Fluoro-4-(4-((1-hydroxycyclopropyl)methoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetic acid

HRID 237721Notes

Reaction equation

HRID 237721 reaction equation
[CH2:1]([Mg]Cl)[CH3:2].[F:5][C:6]1[CH:7]=[CH:8][C:9]([C:29]2[C:34]([CH3:35])=[CH:33][C:32]([O:36][CH2:37][C:38](OC)=[O:39])=[CH:31][C:30]=2[CH3:42])=[C:10]2[C:14]=1[C@H:13]([O:15][C:16]1[CH:28]=[CH:27][C:19]3[C@H:20]([CH2:23][C:24]([OH:26])=[O:25])[CH2:21][O:22][C:18]=3[CH:17]=1)[CH2:12][CH2:11]2>O1CCCC1.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[F:5][C:6]1[CH:7]=[CH:8][C:9]([C:29]2[C:34]([CH3:35])=[CH:33][C:32]([O:36][CH2:37][C:38]3([OH:39])[CH2:2][CH2:1]3)=[CH:31][C:30]=2[CH3:42])=[C:10]2[C:14]=1[C@H:13]([O:15][C:16]1[CH:28]=[CH:27][C:19]3[C@H:20]([CH2:23][C:24]([OH:26])=[O:25])[CH2:21][O:22][C:18]=3[CH:17]=1)[CH2:12][CH2:11]2

Participants

5

Reactant 2

HCID 866971262-((S)-6-((R)-7-Fluoro-4-(4-(2-methoxy-2-oxoethoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetic acidHCID 178461633HCID 178461633, compound2×

Product 1

HCID 866973902-((S)-6-((R)-7-Fluoro-4-(4-((1-hydroxycyclopropyl)methoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetic acid

Reagents, catalysts & solvents 2

HCID 178460666HCID 178460666, compoundCatalystHCID 8028TetrahydrofuranSolvent3×

Procedure

Ethylmagnesium chloride (380 μL of a 1 M solution in tetrahydrofurane) is added dropwise under argon to a solution of 2-((S)-6-((R)-7-fluoro-4-(4-(2-methoxy-2-oxoethoxy)-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetic acid in tetrahydrofurane (4 mL). The mixture is stirred at room temperature for 30 minutes. Ti(OiPr)4 (120 μL) is added dropwise and after stirring for 30 minutes ethylmagnesium chloride (1.15 mL of a 1 M solution in tetrahydrofurane) is added dropwise. The mixture is stirred for 2 hours, partitioned between ethylacetate and saturated aqueous NH4Cl solution and stirred vigorously for 30 minutes. After filtering over celite the phases are separated, the aqueous phase is extracted with diethylether and the combined organic phases are washed with brine and dried (MgSO4). The solvents are evaporated and the residue is purified by HPLC on reversed phase. Yield: 38 mg; LC (method 8): tR=0.38 min; Mass spectrum (ESI+): m/z=519 [M+H]+.

Workup

  1. additionis added dropwise
  2. stirringThe mixture is stirred for 2 hours
  3. custompartitioned between ethylacetate and saturated aqueous NH4Cl solution
  4. stirringstirred vigorously for 30 minutes
  5. filtrationAfter filtering over celite the phases
  6. customare separated
  7. extractionthe aqueous phase is extracted with diethylether
  8. washthe combined organic phases are washed with brine
  9. dry with materialdried (MgSO4)
  10. customThe solvents are evaporated
  11. customthe residue is purified by HPLC on reversed phase

Sources & evidence

ORD record
ord-9acf33e5de334fcba07f987653a015a7
Source dataset
uspto-grants-2014_02
Patent number
US08642585B2

Reaction notes

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