1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → Ethyl (9aS)-4-{4-[(2,3-dihydro-1H-indol-1-ylamino)carbonyl]phenyl}-2-(4-fluorobenzyl)-5-oxo-7,8,9,9a-tetrahydro-5H-pyrido[2,3-a]pyrrolizine-3-carboxylate

HRID 458473Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 458473
[CH2:1]([O:3][C:4]([C:6]1[C:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:17][C:9]2[C@H:10]3[N:14]([C:15](=[O:16])[C:8]=2[C:7]=1[C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1)[CH2:13][CH2:12][CH2:11]3)=[O:5])[CH3:2].[N:36]1([NH2:45])[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38][CH2:37]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:36]1([NH:45][C:31]([C:30]2[CH:29]=[CH:28][C:27]([C:7]3[C:8]4[C:15](=[O:16])[N:14]5[C@H:10]([C:9]=4[N:17]=[C:18]([CH2:19][C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)[C:6]=3[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:12][CH2:13]5)=[CH:35][CH:34]=2)=[O:32])[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38][CH2:37]1

Komponenten

7

Edukt 5

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 516892Sodium BicarbonateHCID 27609322,3-dihydro-1H-indol-1-amineHCID 697432854-[(9aS)-3-(ethoxycarbonyl)-2-(4-fluorobenzyl)-5-oxo-7,8,9,9a-tetrahydro-5H-pyrido[2,3-a]pyrrolizin-4yl]benzoic acid

Produkt 1

HCID 86598180Ethyl (9aS)-4-{4-[(2,3-dihydro-1H-indol-1-ylamino)carbonyl]phenyl}-2-(4-fluorobenzyl)-5-oxo-7,8,9,9a-tetrahydro-5H-pyrido[2,3-a]pyrrolizine-3-carboxylateAusbeute 83 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6344DichloromethaneLösungsmittel2×

Versuchsvorschrift

A solution of 4-[(9aS)-3-(ethoxycarbonyl)-2-(4-fluorobenzyl)-5-oxo-7,8,9,9a-tetrahydro-5H-pyrido[2,3-α]pyrrolizin-4yl]benzoic acid (0.200 g, 0.42 mmol, 1 equiv) in CH2Cl2 (1.0 mL) was treated with the 1-indolinamine (ref. Wijngaarden, I. et al., J Med Chem, 1993, 36, 3693–99) (0.113 g, 0.84 mmol, 2 equiv), EDCI (0.113 g, 0.59 mmol, 1.4 equiv), and HOBt (0.080 g, 0.59 mmol, 1.4 equiv). After 12 h at ambient temperature, the diluted with CH2Cl2 (1.0 mL) and treated with saturated aqueous NaHCO3. The organic potion was the washed with 1N HCl (1 mL) followed by brine (1 mL). Concentration gave a brown oil the was chromatographed radially (SiO2, 2 mm plate, 50% hexanes-EtOAc) to provide the title compound as a white solid (0.206 g, 83%): 1H NMR (CDCl3, 400 MHz) δ 7.86 (d, J=8.2 Hz, 2H), 7.68 (s, 1H), 7.45 (d, J=8.0 Hz, 2H ), 7.25–7.21 (m, 2H), 7.15–7.10 (m, 2H), 6.94 (t, J=8.6 Hz, 2H), 6.86 (t, J=7.4 Hz, 1H), 6.71 (d, J=7.7 Hz, 1H), 4.74 (dd, J=10.4, 6.2 Hz, 1H), 4.35 (d, J=14.3 Hz, 1H), 4.29 (d, J=14.3 Hz, 1H), 3.90 (q, J=6.8 Hz, 2H), 3.69–3.61 (m, 3H), 3.36–3.31 (m, 1H), 3.09–3.05 (m, 2H), 2.53–2.47 (m, 1H), 2.35–2.27 (m, 2H), 1.45–1.34 (m, 1H), 0.84 (t, J=7.1 Hz, 3H).

Aufarbeitung

  1. washwashed with 1N HCl (1 mL)
  2. concentrationConcentration
  3. customgave a brown oil the
  4. customwas chromatographed radially (SiO2, 2 mm plate, 50% hexanes-EtOAc)

Quellen und Nachweise

ORD-Eintrag
ord-685c38834a8f433eb235f50b576b2af6
Quelldatensatz
uspto-grants-2007_03
Patentnummer
US07189851B2

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