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

HRID 1069786Notes

Reaction equation

HRID 1069786 reaction equation
C([N:8]([CH2:13][C:14]#[CH:15])[CH2:9][CH:10]([OH:12])[CH3:11])(OC(C)(C)C)=O.[C:16]([C:19]1[CH:20]=[C:21](/[CH:24]=[C:25]2\[C:26](=[O:36])[NH:27][C:28]3[C:33]\2=[C:32](I)[C:31]([F:35])=[CH:30][CH:29]=3)[NH:22][CH:23]=1)(=[O:18])[CH3:17].FC(F)(F)C(O)=O.C(Cl)[Cl:45]>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.CN(C=O)C.CCN(CC)CC.C(Cl)Cl.O>[ClH:45].[C:16]([C:19]1[CH:20]=[C:21](/[CH:24]=[C:25]2\[C:26](=[O:36])[NH:27][C:28]3[C:33]\2=[C:32]([C:15]#[C:14][CH2:13][NH:8][CH2:9][CH:10]([OH:12])[CH3:11])[C:31]([F:35])=[CH:30][CH:29]=3)[NH:22][CH:23]=1)(=[O:18])[CH3:17]

Participants

9

Reactant 3

HCID 18366029(Z)-3-[(4-Acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-oneHCID 18366127N-Boc-1-prop-2-ynylamino-propan-2-olHCID 21863450Trifluoroacetic acid methylene chloride

Product 1

HCID 69948052Rac-(z)-3-[(4-acetyl-1h-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-[3-(2-hydroxy-propylamino)-1-propynyl]-2h-indol-2-one hydrochloride salt

Reagents, catalysts & solvents 5

HCID 962WaterCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8471TriethylamineSolvent

Conditions

Temperature
0 °C

Procedure

Using Method C above, N-Boc-1-prop-2-ynylamino-propan-2-ol (0.13 g, 0.63 mmol) (Example 125A above) was coupled with (Z)-3-[(4-acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (0.1 g, 0.25 mmol) (Example 90B) using (Ph3P)4Pd (30.0 mg) and Cul (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 MgSQ4. The resulting product was purified via flash column chromatography (10% MeOH in CH2Cl2). To the free base in methanol (2 mL) was added 4N HCl in dioxane (0.06 mL). Evaporation of solvent to dryness gave rac-(Z)-3-[(4-Acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-[3-(2-hydroxy-propylamino)-1-propynyl]-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. customdried with MgSQ4
  5. customThe resulting product was purified via flash column chromatography (10% MeOH in CH2Cl2)
  6. additionTo the free base in methanol (2 mL) was added 4N HCl in dioxane (0.06 mL)
  7. customEvaporation of solvent to dryness

Sources & evidence

ORD record
ord-051dd2373e684bf8a5f31205670d8c2c
Source dataset
uspto-grants-2001_06
Patent number
US06252086B1

Reaction notes

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