(3Z)-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylidene]-2,3-dihydro-1H-indol-2-one → Indol-2-one

HRID 380925Notes

Reaction equation

HRID 380925 reaction equation
F[C:2]1[C:3](I)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=C\C1NC=CC=1OC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[N:7]1[C:6](=[O:11])[CH:5]=[C:4]2[C:8]=1[CH:9]=[CH:10][CH:2]=[CH:3]2

Participants

6

Reactant 1

HCID 18363902(3Z)-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylidene]-2,3-dihydro-1H-indol-2-one2×

Product 1

HCID 17904787Indol-2-one

Reagents, catalysts & solvents 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolventHCID 8471TriethylamineSolvent

Procedure

Using Method C above, Ethyl-[(3R,4S,5R)-4-ethynyl-2,2,6-trimethyl-[1,3]-dioxan-5-yl]-carbamic acid tert-butyl ester (148.5 mg, 0.50 mmol) (Example 123C above) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (96 mg, 0.25 mmol) (Starting Material 6) using (Ph3P)4Pd (23.1 mg, 8 mol %) and CuI (5 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 5 h to give the coupling product (137.2 mg, 99.2% after flash column purification). This coupling product (125 mg) was then treated with 50% of trifluoroacetic acid/CH2Cl2 (5 mL) and 0.5 mL of water at r.t. for 1 h. The reaction mixture was concentrated to about 2 mL and diluted with AcOEt (50 mL) and then quenched with 2 N NaOH. The organic layer was washed with brine and dried with Na2SO4. After concentration, the crude product (113.6 mg) was triturated with AcOEt/hexanes and the precipitate was collected by filtration to offer (Z)-1,3-Dihydro-4-[(3R,4S,5R)-3,5-dihydroxy-4-ethylamino-1-hexynyl]-5-fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (LLLLL) as a brown-orange solid. (Yield 29.5 mg, 31.6%). The filtrate was then purified via flash column chromatography (5%-10% MeOH in CH2Cl2) to give (R)-(Z)-1,3-Dihydro-4-[(5-ethylamino-6-methyl)-6H-pyran-2-yl]-5-fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene)]-2H-indol-2-one (MMMMM). (Yield 33.6 mg, 37.6%).

Workup

  1. customthe coupling product (137.2 mg, 99.2% after flash column purification)
  2. additionThis coupling product (125 mg) was then treated with 50% of trifluoroacetic acid/CH2Cl2 (5 mL) and 0.5 mL of water at r.t. for 1 h
  3. concentrationThe reaction mixture was concentrated to about 2 mL
  4. additiondiluted with AcOEt (50 mL)
  5. customquenched with 2 N NaOH
  6. washThe organic layer was washed with brine
  7. dry with materialdried with Na2SO4
  8. concentrationAfter concentration
  9. customthe crude product (113.6 mg) was triturated with AcOEt/hexanes
  10. filtrationthe precipitate was collected by filtration
  11. customThe filtrate was then purified via flash column chromatography (5%-10% MeOH in CH2Cl2)

Sources & evidence

ORD record
ord-799f24d6a67b467b891b0166d7934410
Source dataset
uspto-grants-2001_10
Patent number
US06303793B1

Reaction notes

Loading…