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

HRID 1966377Notes

Reaction equation

HRID 1966377 reaction equation
[NH2:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)=[CH:6][N:7]=1.Cl[CH:18]([CH2:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][CH:33]=[CH:32]2)[CH:19](N1C(=O)CCC1=O)O>C(O)CO>[F:16][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[N:7][C:2]3[N:3]([C:18]([CH2:28][C:29]4[CH:30]=[C:31]5[C:36](=[CH:37][CH:38]=4)[N:35]=[CH:34][CH:33]=[CH:32]5)=[CH:19][N:1]=3)[N:4]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]

Participants

4

Reactant 2

HCID 445128971-[2-Chloro-1-hydroxy-3-(6-quinolinyl)propyl]-2,5-pyrrolidinedioneHCID 445129004-(3-Amino-1,2,4-triazin-6-yl)-2-fluorobenzonitrile

Product 1

HCID 445128962-Fluoro-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzonitrileYield 185.4%

Reagents, catalysts & solvents 1

HCID 174Ethylene GlycolSolvent

Conditions

Temperature
135 °C

Procedure

A 22 L reactor equipped with a overhead stirring, a thermocouple, a distillation apparatus, and a nitrogen inlet was purged with nitrogen before 4-(3-amino-1,2,4-triazin-6-yl)-2-fluorobenzonitrile (20, 300 g, 1.39 mol), 1-(2-chloro-1-hydroxy-3-(quinolin-6-yl)propyl)pyrrolidine-2,5-dione (11, 635 g, 1.99 mol, 1.43 equiv), and ethylene glycol (3.0 L) were charged to the reactor at room temperature. The resulting reaction mixture was heated to 130-140° C. with nitrogen bubbled through continuously. The distillate was collected with the distillation apparatus. After 3-4 h, HPLC indicated the reaction was deemed complete (presence of <1.5% of starting material 20). The reaction mixture was gradually cooled to room temperature. A 2.5% aqueous sodium carbonate solution (Na2CO3, 14.1 L) was added with stirring to the reactor over 60 min and the mixture was stirred at room temperature for 1-2 h. The mixture was then filtered, and the solid was washed with water (9.6 L) and dried under vacuum to afford the desired crude product (13, 980.4 g), which was combined with several other batches for purification as described below.

Workup

  1. customA 22 L reactor equipped with a overhead
  2. additionwere charged to the reactor at room temperature
  3. customThe resulting reaction mixture
  4. custombubbled through continuously
  5. distillationThe distillate was collected with the distillation apparatus
  6. temperatureThe reaction mixture was gradually cooled to room temperature
  7. additionA 2.5% aqueous sodium carbonate solution (Na2CO3, 14.1 L) was added
  8. stirringwith stirring to the reactor over 60 min
  9. stirringthe mixture was stirred at room temperature for 1-2 h
  10. filtrationThe mixture was then filtered
  11. washthe solid was washed with water (9.6 L)
  12. customdried under vacuum

Sources & evidence

ORD record
ord-c93e0dd0da2245dba649b0bede1784de
Source dataset
uspto-grants-2013_04
Patent number
US08420645B2

Reaction notes

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