(3Z)-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylidene]-2,3-dihydro-1H-indol-2-one → Rac-(z)-1,3-dihydro-5-fluoro-4-[3-(2-hydroxy-propylamino)-1-propynyl]-3-[(3-methoxy-1h-pyrrol-2-yl)methylene]-2h-indol-2-one hydrochloride salt

HRID 380926Notes

Reaction equation

HRID 380926 reaction equation
C([N:8]([CH2:13][C:14]#[CH:15])[CH2:9][CH:10]([OH:12])[CH3:11])(OC(C)(C)C)=O.[F:16][C:17]1[C:18](I)=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])/[C:20]/2=[CH:27]\[C:28]1[NH:29][CH:30]=[CH:31][C:32]=1[O:33][CH3:34].FC(F)(F)C(O)=O.C(Cl)[Cl:44]>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.C(Cl)Cl.O>[ClH:44].[F:16][C:17]1[C:18]([C:15]#[C:14][CH2:13][NH:8][CH2:9][CH:10]([OH:12])[CH3:11])=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])/[C:20]/2=[CH:27]\[C:28]1[NH:29][CH:30]=[CH:31][C:32]=1[O:33][CH3:34]

Participants

10

Reactant 3

HCID 18363902(3Z)-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylidene]-2,3-dihydro-1H-indol-2-one2×HCID 18366127N-Boc-1-prop-2-ynylamino-propan-2-olHCID 21863450Trifluoroacetic acid methylene chloride

Product 1

HCID 69950350Rac-(z)-1,3-dihydro-5-fluoro-4-[3-(2-hydroxy-propylamino)-1-propynyl]-3-[(3-methoxy-1h-pyrrol-2-yl)methylene]-2h-indol-2-one hydrochloride salt

Reagents, catalysts & solvents 6

HCID 962WaterCatalystHCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8471TriethylamineSolvent

Conditions

Temperature
0 °C

Procedure

Using Method C above, N-Boc-1-prop-2-ynylamino-propan-2-ol (0.14 g, 0.65 mmol) (Example 125A above) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (0.1 g, 0.26 mmol) (Starting Material 6) using (Ph3P)4Pd (30.0 mg) and CuI (5.0 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 5 h. To the resulting compound in CH2Cl2 (6 mL) was added a 1:1 mixture of trifluoroacetic acid/CH2Cl2 (6 mL) and 3 drops of water at 0° C. and the mixture was stirred at 0° C. for 2 h. The mixture was then quenched with conc. NH4OH (6 mL) and diluted with EtOAc. The organic layer was washed with brine and dried with MgSO4. The resulting product was purified via flash column chromatography (10% MeOH in CH2Cl2). To the free base in methanol (3 mL) was added 4N HCl in dioxane (0.04 mL). Evaporation of solvent to dryness gave rac-(Z)-1,3-Dihydro-5-fluoro-4-[3-(2-hydroxy-propylamino)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one hydrochloride salt. (Yield 39 mg, 35%).

Workup

  1. customThe mixture was then quenched with conc. NH4OH (6 mL)
  2. additiondiluted with EtOAc
  3. washThe organic layer was washed with brine
  4. dry with materialdried with MgSO4
  5. customThe resulting product was purified via flash column chromatography (10% MeOH in CH2Cl2)
  6. additionTo the free base in methanol (3 mL) was added 4N HCl in dioxane (0.04 mL)
  7. customEvaporation of solvent to dryness

Sources & evidence

ORD record
ord-cd6dbefc658148268257491a61ecb09d
Source dataset
uspto-grants-2001_10
Patent number
US06303793B1

Reaction notes

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