1-[2-Chloro-1-hydroxy-3-(6-quinolinyl)propyl]-2,5-pyrrolidinedione → N-methyl-5-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]pyridine-2-carboxamide

HRID 452041

Reaction equation

[NH2:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH:16][CH3:17])=[O:15])=[N:12][CH:13]=2)=[CH:6][N:7]=1.Cl[CH:19]([CH2:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[N:36]=[CH:35][CH:34]=[CH:33]2)[CH:20](N1C(=O)CCC1=O)O>C(O)CO>[CH3:17][NH:16][C:14]([C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:6]=[N:7][C:2]3[N:3]([C:19]([CH2:29][C:30]4[CH:31]=[C:32]5[C:37](=[CH:38][CH:39]=4)[N:36]=[CH:35][CH:34]=[CH:33]5)=[CH:20][N:1]=3)[N:4]=2)=[CH:13][N:12]=1)=[O:15]

Participants

Conditions

Temperature: 120 °C

Procedure

A mixture of 5-(3-amino-1,2,4-triazin-6-yl)-N-methylpyridine-2-carboxamide (Step 1, 6.5 g, 0.022 mol) and 1-(2-chloro-1-hydroxy-3-quinolin-6-ylpropyl)pyrrolidine-2,5-dione (8.71 g, 0.0273 mol, Example 1, Step 7) in 1,2-ethanediol (100 mL) was stirred at 120° C. overnight. The reaction mixture was concentrated. The mixture was neutralized to pH=10 with methylamine in THF solution (2.0M), and then purified by flash chromatography on a silica gel column with 5% MeOH in dichloromethane to afford the desired product which was contaminated with some starting material. The product was dissolved in 10% MeOH in dichloromethane, and concentrated to a volume of about 2 mL. The resulted solid was filtered, washed with MeOH (2 mL) to afford the pure product (4.50 g, 50%). The product was treated with 2N HCl (aqueous) and acetonitrile, and dried by lyophilization to give the desired product as the HCl salt. LCMS (M+H)+: m/z=396.4. 1H-NMR (400 MHz, DMSO-d6): 9.40 (s, 1H), 9.27 (s, 1H), 9.20 (d, J=5.5 Hz, 1H), 9.10 (d, J=8.0 Hz, 1H), 8.64 (d, J=8.0 Hz, 1H), 8.30 (s, 1H), 8.26 (d, J=8.0 Hz, 1H), 8.20 (d, J=8.0, Hz, 1H), 8.19 (s, 1H), 8.17 (d, J=8.0 Hz, 1H), 7.03 (dd, J=8.0, 5.5 Hz, 1H), 4.76 (s, 2H), 2.81 (s, 3H).

Workup

concentrationThe reaction mixture was concentrated
custompurified by flash chromatography on a silica gel column with 5% MeOH in dichloromethane

Sources & evidence

ORD record: ord-b595fcf5f7a64b69a0a13f0d28dcb01f
Source dataset: uspto-grants-2013_07
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08487096B2

Linked notes

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