Dichloromethane → HCID 491969, compound

HRID 1060607Notes

Reaction equation

HRID 1060607 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.ClCCl.[CH3:34][NH:35][CH2:36][C:37]#[CH:38]>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.CCN(CC)CC>[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:38]=[C:37]([CH2:36][NH:35][CH3:34])[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

7

Reactant 3

HCID 6344DichloromethaneHCID 96160N-methylpropyn-2-ylamineHCID 178522928N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide

Product 1

HCID 491969HCID 491969, compound

Reagents, catalysts & solvents 3

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

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 N-methylpropargylamine (0.055 mL). The reaction is stirred at room temperature for 10 days. The reaction is concentrated under reduced pressure, treated with ethanol (5 mL) and heated to 70° C. for 2 days. The reaction is cooled to room temperature and concentrated under reduced pressure. The residue is adsorbed onto silica and flash column chromatographed eluting with 2% to 10% methanol in dichloromethane. Product-containing fractions are combined and concentrated under reduced pressure to afford a solid which is crystallized from acetonitrile. The crystals are treated with hydrochloric acid (2 mL, 4 N in dioxane). The suspension is diluted with methanol and concentrated under reduced pressure. The residue is triturated with small volumes of methanol-toluene, methanol-ether, toluene, and ether. The solid is treated with dichloromethane and partitioned against saturated aqueous sodium carbonate. The basic aqueous layer is extracted with two additional portions of dichloromethane. The combined organic layers are washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford 0.09 g of the title compound as an off-white solid.

Workup

  1. additionTo a flame-dried flask under a nitrogen atmosphere is added
  2. additionThe flask is back-filled with nitrogen gas
  3. concentrationThe reaction is concentrated under reduced pressure
  4. additiontreated with ethanol (5 mL)
  5. temperatureheated to 70° C. for 2 days
  6. temperatureThe reaction is cooled to room temperature
  7. concentrationconcentrated under reduced pressure
  8. customchromatographed
  9. washeluting with 2% to 10% methanol in dichloromethane
  10. concentrationconcentrated under reduced pressure
  11. customto afford a solid which
  12. customis crystallized from acetonitrile
  13. additionThe crystals are treated with hydrochloric acid (2 mL, 4 N in dioxane)
  14. additionThe suspension is diluted with methanol
  15. concentrationconcentrated under reduced pressure
  16. customThe residue is triturated with small volumes of methanol-toluene, methanol-ether, toluene, and ether
  17. additionThe solid is treated with dichloromethane
  18. custompartitioned against saturated aqueous sodium carbonate
  19. extractionThe basic aqueous layer is extracted with two additional portions of dichloromethane
  20. washThe combined organic layers are washed with brine
  21. dry with materialdried over sodium sulfate
  22. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-c8c5993cd13a49d29eef266b07a2ac3c
Source dataset
uspto-grants-2003_02
Patent number
US06525049B2

Reaction notes

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