Tetrahydrofuran → 3-[3-(4,7-diazaspiro[2.5]octan-7-yl)isoquinolin-1-yl]-4-(7-methyl-1H-indol-3-yl)pyrrole-2,5-dione

HRID 1767692Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1767692
[CH2:1]1[C:3]2([CH2:8][N:7]([C:9]3[N:10]=[C:11]([CH2:19][C:20]([NH2:22])=[O:21])[C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:6][CH2:5][NH:4]2)[CH2:2]1.C[O:24][C:25](=O)[C:26]([C:28]1[C:36]2[C:31](=[C:32]([CH3:37])[CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)=O.C1COCC1>O>[CH2:2]1[C:3]2([CH2:8][N:7]([C:9]3[N:10]=[C:11]([C:19]4[C:20](=[O:21])[NH:22][C:25](=[O:24])[C:26]=4[C:28]4[C:36]5[C:31](=[C:32]([CH3:37])[CH:33]=[CH:34][CH:35]=5)[NH:30][CH:29]=4)[C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:6][CH2:5][NH:4]2)[CH2:1]1

Komponenten

5

Edukt 3

HCID 8028Tetrahydrofuran2×HCID 11241405Methyl 7-methyl-alpha-oxo-1H-indole-3-acetateHCID 117709232-[3-(4,7-Diaza-spiro[2.5]oct-7-yl)-isoquinolin-1-yl]-acetamide

Produkt 1

HCID 102171983-[3-(4,7-diazaspiro[2.5]octan-7-yl)isoquinolin-1-yl]-4-(7-methyl-1H-indol-3-yl)pyrrole-2,5-dione

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 962WaterLösungsmittel

Versuchsvorschrift

2-[3-(4,7-Diaza-spiro[2.5]oct-7-yl)-isoquinolin-1-yl]-acetamide (4.95 g, 16.70 mmol) and (7 -Methyl-1H-indol-3-yl)-oxo-acetic acid methyl ester (5.44 g, 25.05 mmol) are azeotroped twice with dry THF. Dry THF (100 ml) is then added, and under an atmosphere of argon KOtBu (1.0 M in THF, 50 ml, 50 mmol) is added dropwise during 20 min. After an additional 90 min, TLC analysis indicates complete conversion of starting materials. The reaction mixture is diluted with H2O and extracted twice with EtOAc. The combined organic layers are washed twice with saturated aq NH4Cl solution (back extracted), dried over Na2SO4 and concentrated. Purification by FCC (CH2Cl2/MeOH 100:0 to 98:2 to 96:4 to 94:6 to 92:8 to 90:10) yields the title compound, which is converted to its acetate salt by concentration of a EtOH/AcOH solution. 1H NMR (DMSO, 400 MHz) δ 0.26 -053 (br, 4H), 1.89 (s, 3H, CH3COOH), 2.36 (s, 3H), 2.80 (br m, 2H), 3.15 -3.48 (br m, 2H), 6.14 (d, J=8.2 HZ, 1H), 6.44(dd, J=8.2/7.4 Hz, 1H), 6.75 (d, J=7.4 Hz, 1H), 7.00 (s, 1H), 7.02 (dd, J=8.2/8.2 Hz, 1H), 7.40 (dd, J=8.2/8.2 Hz, 1H), 7.59 (d, J=8.2 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.63(d, J=8.2 Hz, 1H), 7.97 (d, J=2.9 Hz, 1H), 11.04-11.21 (br, 1H), 11.86(d, J=2.9 Hz, 1H); ES-MS: 464 [M+H]+.

Aufarbeitung

  1. additionunder an atmosphere of argon KOtBu (1.0 M in THF, 50 ml, 50 mmol) is added dropwise during 20 min
  2. extractionextracted twice with EtOAc
  3. washThe combined organic layers are washed twice with saturated aq NH4Cl solution (back extracted)
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated
  6. customPurification by FCC (CH2Cl2/MeOH 100:0 to 98:2 to 96:4 to 94:6 to 92:8 to 90:10)

Quellen und Nachweise

ORD-Eintrag
ord-ab9e72c4561642ebacb10f92eaaf1356
Quelldatensatz
uspto-grants-2007_06
Patentnummer
US07235555B2

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