275387-85-4 → (Z)-4-[(3R,4R)-3-Amino-4-hydroxy-1-pentynyl]-1,3-dihydro-5-fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one

HRID 1069756Notes

Reaction equation

HRID 1069756 reaction equation
C([N:8]1[C@H:12]([C:13]#[CH:14])[C@@H:11]([CH3:15])[O:10]C1(C)C)(OC(C)(C)C)=O.[F:18][C:19]1[C:20](I)=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])/[C:22]/2=[CH:29]\[C:30]1[NH:31][CH:32]=[CH:33][C:34]=1[O:35][CH3:36].FC(F)(F)C(O)=O.C(Cl)Cl>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>[NH2:8][C@@H:12]([C@H:11]([OH:10])[CH3:15])[C:13]#[C:14][C:20]1[C:19]([F:18])=[CH:27][CH:26]=[C:25]2[C:21]=1/[C:22](=[CH:29]/[C:30]1[NH:31][CH:32]=[CH:33][C:34]=1[O:35][CH3:36])/[C:23](=[O:28])[NH:24]2

Participants

9

Reactant 3

HCID 12970128275387-85-4HCID 18363902(3Z)-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylidene]-2,3-dihydro-1H-indol-2-one2×HCID 21863450Trifluoroacetic acid methylene chloride

Product 1

HCID 23645079(Z)-4-[(3R,4R)-3-Amino-4-hydroxy-1-pentynyl]-1,3-dihydro-5-fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one

Reagents, catalysts & solvents 5

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

Conditions

Temperature
0 °C

Procedure

Using Method C above, (4R,5R)-N-Boc-2,2,5-trimethyl-4-ethynyl-oxazolidine (0.18 g, 0.65 mmol) (Example 102B) 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 mg) and Cul (6 mg) as catalyst in DMF (6 mL) and Et3N (6 mL) as solvent at 85° C. for 1 day. 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 1.5 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. (Z)-4-[(3R,4R)-3-Amino-4-hydroxy-1-pentynyl]-1,3-dihydro-5-fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was purified via flash column chromatography (10% MeOH in CH2Cl2). (Yield 44 mg, 48%).

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. custom(Z)-4-[(3R,4R)-3-Amino-4-hydroxy-1-pentynyl]-1,3-dihydro-5-fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was purified via flash column chromatography (10% MeOH in CH2Cl2)

Sources & evidence

ORD record
ord-2e1b26884ecc40c1bc430d1b11a82cd5
Source dataset
uspto-grants-2001_06
Patent number
US06252086B1

Reaction notes

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