Formamide → 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 1767693Notes

Reaction equation

HRID 1767693 reaction equation
C(O[C:4](=[O:31])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([N:16]2[CH2:23][C:20]3([CH2:22][CH2:21]3)[N:19](CC3C=CC=CC=3)[CH2:18][CH2:17]2)[N:7]=1)C.[CH:32]([NH2:34])=[O:33].C[O-].[Na+].O.[CH3:39][N:40]([CH:42]=O)C>CO.CCOC(C)=O>[CH2:21]1[C:20]2([CH2:23][N:16]([C:8]3[N:7]=[C:6]([C:5]4[C:4](=[O:31])[NH:34][C:32](=[O:33])[C:14]=4[C:13]4[C:12]5[C:39](=[C:6]([CH3:5])[CH:15]=[CH:10][CH:11]=5)[NH:40][CH:42]=4)[C:15]4[C:10]([CH:9]=3)=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH2:17][CH2:18][NH:19]2)[CH2:22]1

Participants

8

Reactant 5

HCID 713FormamideHCID 962WaterHCID 6228DimethylformamideHCID 10942334Sodium MethoxideHCID 11327484[3-(4-Benzyl-4,7-diaza-spiro[2.5]oct-7-yl)-isoquinolin-1-yl]-acetic acid ethyl ester

Product 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

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
105 °C

Procedure

[3-(4-Benzyl-4,7-diaza-spiro[2.5]oct-7-yl)-isoquinolin-1-yl]-acetic acid ethyl ester (700 mg, 1.68 mmol) is dissolved in dry DMF under an atmosphere of argon. Formamide (224 μl, 254 mg, 5.64 mmol) is added, and the reaction mixture is heated to 105° C. At this temperature, NaOMe (312 μl of a 5.4 M solution in MeOH, 91 mg, 1.68 mmol) is added dropwise during 20 minutes. After 30 minutes at 105° C., TLC analysis indicates complete conversion of starting material. Cooling the reaction mixture to RT is followed by addition of water and extraction with EtOAc. The organic layers are washed with H2O (twice), dried over Na2SO4 and concentrated. The residue is purified by FCC (hexanes/EtOAc 1:1 to 1:3 to 0:100 to EtOAc/MeOH 98:2) to afford the title compound. 1H NMR (DMSO, 400 MHz) δ 0.68 -0.70 (m, 2H), 0.82 -0.88 (m, 2H), 3.08 (t, J=4.4, 2H), 3.45 (s, 2H), 3.58 (t, J=4.4, 2H), 3.96 (s, 2H), 4.27 (s, 2H), 5.3 -5.5 (br, 1H), 6.55 -6.7 (br, 1H), 6.72 (s, 1H), 7.26-7.36 (m, 6H), 7.51 (t, J=8.8, 1H), 7.60 d, J=9.9, 1H), 8.02 (d, J=9.9, 1H); ES-MS: 387 [M+H]+.

Workup

  1. temperatureCooling the reaction mixture to RT
  2. washThe organic layers are washed with H2O (twice),
  3. dry with materialdried over Na2SO4
  4. concentrationconcentrated
  5. customThe residue is purified by FCC (hexanes/EtOAc 1:1 to 1:3 to 0:100 to EtOAc/MeOH 98:2)

Sources & evidence

ORD record
ord-c408515dc2604bbcab91d5ca2b572e13
Source dataset
uspto-grants-2007_06
Patent number
US07235555B2

Reaction notes

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