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 1767692노트

반응식

HRID 1767692 반응식
[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

참가 물질

5

반응물 3

HCID 8028Tetrahydrofuran2회HCID 11241405Methyl 7-methyl-alpha-oxo-1H-indole-3-acetateHCID 117709232-[3-(4,7-Diaza-spiro[2.5]oct-7-yl)-isoquinolin-1-yl]-acetamide

생성물 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

시약·촉매·용매 1

HCID 962Water용매

실험 절차

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]+.

후처리

  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)

출처 및 근거

ORD 기록
ord-ab9e72c4561642ebacb10f92eaaf1356
출처 데이터셋
uspto-grants-2007_06
특허 번호
US07235555B2

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