3-Butyn-1-OL → N-(4-Chlorobenzyl)-2-(2-hydroxyethyl)-8-(4-morpholinylmethyl)-6-oxo-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide

HRID 1060600Notes

Reaction equation

HRID 1060600 reaction equation
[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.[CH2:31]([OH:35])[CH2:32][C:33]#[CH:34]>CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([CH:34]=[C:33]([CH2:32][CH2:31][OH:35])[N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1

Participants

6

Reactant 2

HCID 135663-Butyn-1-OLHCID 178522928N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide

Product 1

HCID 491953N-(4-Chlorobenzyl)-2-(2-hydroxyethyl)-8-(4-morpholinylmethyl)-6-oxo-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamideYield 56%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 8471TriethylamineSolvent

Procedure

To a suspension of N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (581.4 mg) and PdCl2(PPh3)2 (37.9 mg) in Et3N (20 mL) is added CuI (10.3 mg) and 3-butyn-1-ol (0.082 mL). The reaction is stirred at room temperature for 2 days under N2. After 2 days the solvent evaporates. The resulting solid is dissolved in CH2Cl2 and partitioned against H2O. The aqueous layer is extracted with CH2Cl2 (2×). The combined organic layers are washed with brine (1×), dried over Na2SO4, filtered, and condensed. The crude solid is adsorbed onto silica and chromatographed (Biotage flash 40S, gradient from CH2Cl2 to 3% MeOH in CH2Cl2). Product-containing fractions are combined and concentrated to yield a creme solid. The solid is recrystallized from hot acetonitrile to afford 290 mg (56%) of N-(4-chlorobenzyl)-2-(2-hydroxyethyl)-8-(4-morpholinylmethyl)-6-oxo-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide as an off-white solid, m.p. 169-172° C.

Workup

  1. customAfter 2 days the solvent evaporates
  2. dissolutionThe resulting solid is dissolved in CH2Cl2
  3. custompartitioned against H2O
  4. extractionThe aqueous layer is extracted with CH2Cl2 (2×)
  5. washThe combined organic layers are washed with brine (1×)
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. customcondensed
  9. customchromatographed (Biotage flash 40S, gradient from CH2Cl2 to 3% MeOH in CH2Cl2)
  10. concentrationconcentrated
  11. customto yield a creme solid
  12. customThe solid is recrystallized from hot acetonitrile

Sources & evidence

ORD record
ord-e65995e653d447ac9db40235b57593e0
Source dataset
uspto-grants-2003_02
Patent number
US06525049B2

Reaction notes

Loading…