Sodium Chloride → HCID 68975311, compound

Diethylmalonate (1.73 g, 1.64 mL, 2.5 eq) was dissolved in isopropyl ether (2 mL), sodium ethoxide (0.73 g, 2.5 eq) was added thereto at room temperature, and the mixture was stirred for 30 min. To the reaction mixture was added the compound of Preparation 3-1) (1.10 g, 4.31 mmol), which was then refluxed for one day. The mixture was extracted with ethyl acetate (50 mL×2), washed with aqueous sodium chloride solution (100 mL), dried (anhydrous Na2SO4), and concentrated under reduced pressure. The residue was separated by column chromatography (10-20% ethyl acetate-hexane) to give 1.34 g (82%) of a 1:1 mixture of 2-(2-benzyl-5-chloro-3-oxo-2,3-dihydro-pyridazin-4-yl)-malonic acid diethyl ester and 2-(1-benzyl-5-chloro-6-oxo-1,6-dihydro-pyridazin-4-yl)-malonic acid diethyl ester. This mixture was dissolved in 12 mL of a solvent mixture (H2O:DMSO=1:5), NaCl (1.0 g, 5 eq) was added thereto, and the mixture was heated to 120° C. for one day. The mixture was concentrated under reduced pressure, and the residue was extracted twice with ethyl acetate (200 mL). The extract was washed with water, saturated sodium hydrogen carbonate solution (NaHCO3, 100 mL×2) and aqueous sodium chloride solution, dried (anhydrous Na2SO4), and concentrated under reduced pressure. The residue was separated by column chromatography (10-20% ethyl acetate-hexane) to give 530 mg (49%) of the title compound.

1. additionTo the reaction mixture was added
2. customthe compound of Preparation 3-1) (1.10 g, 4.31 mmol), which
3. temperaturewas then refluxed for one day
4. extractionThe mixture was extracted with ethyl acetate (50 mL×2)
5. washwashed with aqueous sodium chloride solution (100 mL)
6. dry with materialdried (anhydrous Na2SO4)
7. concentrationconcentrated under reduced pressure
8. customThe residue was separated by column chromatography (10-20% ethyl acetate-hexane)
9. customto give
10. additionwas added
11. temperaturethe mixture was heated to 120° C. for one day
12. concentrationThe mixture was concentrated under reduced pressure
13. extractionthe residue was extracted twice with ethyl acetate (200 mL)
14. washThe extract was washed with water, saturated sodium hydrogen carbonate solution (NaHCO3, 100 mL×2) and aqueous sodium chloride solution
15. dry with materialdried (anhydrous Na2SO4)
16. concentrationconcentrated under reduced pressure
17. customThe residue was separated by column chromatography (10-20% ethyl acetate-hexane)

ORD record

ord-7830b315d03c4eefa020a6b8692b6a16

Source dataset

uspto-grants-2013_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08481537B2