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(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-hydroxy-pyrrolidin-3-yl)ethynyl]-3-[(3-methoxy-1h-pyrrol-2-yl)methylene]-2h-indol-2-one hydrochloride salt

HRID 1069765
Notes
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Reaction equation

HRID 1069765 reaction equation
C([N:8]1[CH2:12][CH2:11][C:10]([OH:15])([C:13]#[CH:14])[CH2:9]1)(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.CN(C=O)C.CCN(CC)CC.C(Cl)Cl.O>[ClH:44].[F:16][C:17]1[C:18]([C:14]#[C:13][C:10]2([OH:15])[CH2:11][CH2:12][NH:8][CH2:9]2)=[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]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

9

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 18366064Tert-butyl 3-ethynyl-3-hydroxypyrrolidine-1-carboxylateHCID 21863450Trifluoroacetic acid methylene chloride

Product 1

HCID 18366147Rac-(z)-1,3-dihydro-5-fluoro-4-[(3-hydroxy-pyrrolidin-3-yl)ethynyl]-3-[(3-methoxy-1h-pyrrol-2-yl)methylene]-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, rac-N-boc-3-hydroxy-3-ethynyl-pyrrolidine (70.7 mg, 0.33 mmol) (see Example 97B) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (0.10 g, 0.26 mmol) (Starting Material 6) using (Ph3P)4Pd (31 mg) and Cul (6.0 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 1 day. To the resulting compound in CH2Cl2 (5 mL) was added a 1:1 mixture of trifluoroacetic acid/CH2Cl2 (5 mL) and 2 drops of water at 0° C. and the mixture was stirred at 0° C. for 1.5 h. The mixture was then quenched with conc. NH4OH (5 mL) and diluted with EtOAc. The organic layer was washed with brine and dried with MgSO4. The product was purified via flash column chromatography (10% MeOH in CH2Cl2). To free base in methanol (3 mL) was added 4N HCl in dioxane (0.03 mL).

Workup

  1. customThe mixture was then quenched with conc. NH4OH (5 mL)
  2. additiondiluted with EtOAc
  3. washThe organic layer was washed with brine
  4. dry with materialdried with MgSO4
  5. customThe product was purified via flash column chromatography (10% MeOH in CH2Cl2)
  6. additionTo free base in methanol (3 mL) was added 4N HCl in dioxane (0.03 mL)

Sources & evidence

ORD record
ord-2265931a87504e91ac67ad6b9e8db5c1
Source dataset
uspto-grants-2001_06
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US06252086B1

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes