反应详情

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.

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