Trichloroacetonitrile → 7-{1-[4-(7-Methyl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-isoquinolin-3-yl}-4,7-diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester

HRID 2368462

Reaktionsgleichung

Reaktionsgleichung von HRID 2368462
[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][N:13]([C:16]2[N:17]=[C:18]([C:26]3[C:27](=[O:44])[N:28](CO)[C:29](=[O:41])[C:30]=3[C:31]3[C:39]4[C:34](=[C:35]([CH3:40])[CH:36]=[CH:37][CH:38]=4)[NH:33][CH:32]=3)[C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:12][C:9]21[CH2:11][CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CCN2C(=NCCC2)CC1.ClC(Cl)(Cl)C#N.C(OP(=O)(O)OC(C)(C)C)(C)(C)C>C(#N)C.CCOC(C)=O.C1CCCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][N:13]([C:16]2[N:17]=[C:18]([C:26]3[C:27](=[O:44])[NH:28][C:29](=[O:41])[C:30]=3[C:31]3[C:39]4[C:34](=[C:35]([CH3:40])[CH:36]=[CH:37][CH:38]=4)[NH:33][CH:32]=3)[C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:12][C:9]21[CH2:11][CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Komponenten

7

Edukt 4

HCID 11011TrichloroacetonitrileHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 429756Phosphoric acid, bis(1,1-dimethylethyl) esterHCID 710146367-{1-[1-hydroxymethyl-4-(7-methyl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-isoquinolin-3-yl}-4,7-diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester

Produkt 1

HCID 710147157-{1-[4-(7-Methyl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-isoquinolin-3-yl}-4,7-diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 6342AcetonitrileLösungsmittelHCID 21867204Cyclohexane ethylacetateLösungsmittel2×

Versuchsvorschrift

To a solution of 7-{1-[1-hydroxymethyl-4-(7-methyl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-isoquinolin-3-yl}-4,7-diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester (7.30 g, 12.30 mmol) in acetonitrile (60 mL) was added dropwise a solution of DBU (0.374 g, 0.371 mL, 2.46 mmol) in trichloroacetonitrile (17.8 g, 12.3 mL, 123 mmol) at r.t. under argon. The reaction mixture was stirred for 5 h at r.t. until TLC (SiO2, EtOAc/cyclohexane 6:4) indicated complete conversion. The reaction mixture was evaporated to dryness at reduced pressure and the residue was suspended in acetonitrile (60 mL). Phosphoric acid di-tert-butyl ester (3.36 g, 15.99 mmol) was added and the reaction mixture was stirred for approximately 3.5 h at r.t. under argon until TLC (SiO2, EtOAc/cyclohexane 6:4) indicated that the reaction was complete. The reaction mixture was concentrated at reduced pressure and the residue was partitioned between EtOAc and water. The layers were separated and the organic phase was washed with water (5 times). The organic phase was dried over Na2SO4 and concentrated at reduced pressure to afford a red solid. The crude product was purified by FCC (Biotage SP4™ system, SiO2, cyclohexane/EtOAc 20:80) to yield the title compound as a red solid. 1H-NMR (400 MHz, DMSO-d6): 12.03 (s, 1H), 8.08 (d, 1H), 7.70-7.65 (m, 2H), 7.47 (t, 1H), 7.11 (s, 1H), 7.11-7.07 (m, 1H), 6.77 (d, 1H), 6.44 (t, 1H), 5.97 (d, 1H), 5.39 (d, 1H), 3.49-3.08 (m, 6H), 2.39 (s, 3H), 1.45 (s, 18H), 1.41 (s, 9H), 0.87-0.56 (m, 4H). 31P-NMR (162 MHz, DMSO-d6): −12.1. LCMS: [M+1]+=786.4, Rt(1)=2.53 min., Rt(2)=1.62 min.

Aufarbeitung

  1. customThe reaction mixture was evaporated to dryness at reduced pressure
  2. concentrationThe reaction mixture was concentrated at reduced pressure
  3. customthe residue was partitioned between EtOAc and water
  4. customThe layers were separated
  5. washthe organic phase was washed with water (5 times)
  6. dry with materialThe organic phase was dried over Na2SO4
  7. concentrationconcentrated at reduced pressure
  8. customto afford a red solid
  9. customThe crude product was purified by FCC (Biotage SP4™ system, SiO2, cyclohexane/EtOAc 20:80)

Quellen und Nachweise

ORD-Eintrag
ord-d86b5886a0654a74a59b6362b98f3d0b
Quelldatensatz
uspto-grants-2014_04
Patentnummer
US08703782B2

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