Tetrahydrofuran → 2-(2a-Methyl-4-oxo-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-yl)-N-(2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[c]pyridine-6,3'-pyrrolo[2,3-b]pyridin]-3-yl)acetamide

HRID 1696418Notes

Reaction equation

HRID 1696418 reaction equation
[CH3:1][C:2]12[CH2:13][N:12]([CH2:14][C:15]([O-])=[O:16])[C:10]3[C:11]1=[C:6]([CH:7]=[CH:8][CH:9]=3)[NH:5][C:4](=[O:18])[CH2:3]2.[Li+].[N+](C1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][C:26](=O)[NH:27]2)([O-])=O.C1C[N:36]([C:38](Cl)=[N+:39]2CCCC2)[CH2:35][CH2:34]1.F[P-](F)(F)(F)(F)F.C([N:55](CC)C(C)C)(C)C.[CH2:61]1[CH2:65][O:64][CH2:63][CH2:62]1>>[CH3:1][C:2]12[CH2:13][N:12]([CH2:14][C:15]([NH:55][C:28]3[N:27]=[CH:26][C:25]4[CH2:24][C:61]5([CH2:31][C:30]=4[CH:29]=3)[C:62]3[C:38](=[N:36][CH:35]=[CH:34][CH:63]=3)[NH:39][C:65]5=[O:64])=[O:16])[C:10]3[C:11]1=[C:6]([CH:7]=[CH:8][CH:9]=3)[NH:5][C:4](=[O:18])[CH2:3]2

Participants

6

Reactant 5

HCID 8028TetrahydrofuranHCID 81531DiisopropylethylamineHCID 27366521-(Chloro-1-pyrrolidinylmethylene)pyrrolidinium HexafluorophosphateHCID 216778744-Nitro-1,3-dihydro-2H-indol-2-oneHCID 66636493Lithium (2a-methyl-4-oxo-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2h)-yl)acetate

Product 1

HCID 251276752-(2a-Methyl-4-oxo-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-yl)-N-(2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[c]pyridine-6,3'-pyrrolo[2,3-b]pyridin]-3-yl)acetamide

Procedure

A mixture of lithium (2a-methyl-4-oxo-2a,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-1(2H)-yl)acetate, enantiomer A (58 mg, 0.23 mmol, described in Intermediate 44), (±)-3-amino-5,7-dihydrospiro[cyclopenta[c]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1H)-one (71 mg, 0.28 mmol, described in Intermediate 3), N,N,N′,N′-bis(tetramethylene)chloroformamidinium hexafluorophosphate (153 mg, 0.46 mmol), and N,N-diisopropylethylamine (0.20 mL, 1.15 mmol) in THF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (3×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.

Workup

  1. customThe reaction mixture is purified directly by HPLC
  2. washeluting with a gradient of H2O
  3. additionThe pure, product-containing fractions
  4. extractionThe resulting mixture is extracted with EtOAc (3×20 mL)
  5. washthe combined organic extracts are washed with brine
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-bb98a86876b245cdb1ca409791cd3be1
Source dataset
uspto-grants-2012_04
Patent number
US08163752B2

Reaction notes

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