Ethanol → N-(4-Chlorobenzyl)-2-[(eethylsulfanyl)methyl]-8-(4-morpholinylmethyl)-6-oxo-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide

HRID 1841536Notes

Reaction equation

HRID 1841536 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.CCN(CC)CC.[CH2:38]([S:40][CH2:41][C:42]#[CH:43])[CH3:39].CCO>ClCCl.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:43]=[C:42]([CH2:41][S:40][CH2:38][CH3:39])[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

8

Reactant 4

HCID 702EthanolHCID 8471Triethylamine2×HCID 5224803-(Ethylsulfanyl)prop-1-yneHCID 178522928N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide

Product 1

HCID 491967N-(4-Chlorobenzyl)-2-[(eethylsulfanyl)methyl]-8-(4-morpholinylmethyl)-6-oxo-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 6344DichloromethaneSolvent2×

Procedure

To a flame-dried flask under a nitrogen atmosphere is added N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (269 mg) of Preparation 26, PdCl2(PPh3)2 (35 mg), and CuI (12 mg). The flask is back-filled with nitrogen gas and charged with dichloromethane (5 mL), Et3N (0.15 mL), and propargyl ethyl sulfide (0.066 mL). The reaction is stirred at room temperature for 4 days. The reaction mixture is diluted with dichloromethane and partitioned against dilute aqueous sodium bicarbonate. The aqueous phase is extracted with two portions of dichloromethane. The combined organic layers are washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel eluting with 1% to 2% methanol in ethyl acetate. Product containing fractions are combined and condensed to afford a mixture of cyclized and uncyclized materials. To a flask is added the mixture, EtOH (2 mL), and Et3N (0.1 mL). The suspension is heated at 75° C. overnight tightly capped. The reaction mixture is cooled to room temperature, concentrated under reduced pressure, adsorbed onto silica, and flash column chromatographed eluting with 2% to 4% methanol in ethyl acetate. Product-containing fractions are combined and concentrated under reduced pressure to afford a solid. The solid is crystallized from acetonitrile to give 0.12 g of the title compound as light tan product.

Workup

  1. additionTo a flame-dried flask under a nitrogen atmosphere is added
  2. additionThe flask is back-filled with nitrogen gas
  3. custompartitioned against dilute aqueous sodium bicarbonate
  4. extractionThe aqueous phase is extracted with two portions of dichloromethane
  5. washThe combined organic layers are washed with brine
  6. dry with materialdried over sodium sulfate
  7. concentrationconcentrated under reduced pressure
  8. customThe residue is chromatographed on silica gel eluting with 1% to 2% methanol in ethyl acetate
  9. additionProduct containing fractions
  10. customcondensed
  11. customto afford
  12. additiona mixture of cyclized and uncyclized materials
  13. temperatureThe suspension is heated at 75° C. overnight
  14. customtightly capped
  15. temperatureThe reaction mixture is cooled to room temperature
  16. concentrationconcentrated under reduced pressure
  17. customchromatographed
  18. washeluting with 2% to 4% methanol in ethyl acetate
  19. concentrationconcentrated under reduced pressure
  20. customto afford a solid
  21. customThe solid is crystallized from acetonitrile

Sources & evidence

ORD record
ord-8e502eb0f7d44b0091de780e3f5042f6
Source dataset
uspto-grants-2004_01
Patent number
US06683181B2

Reaction notes

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