o-(Trifluoromethyl)benzaldehyde → HCID 23503270, compound

Temperature

-78 °C

A solution of lithium diisopropylamide (11.3 mmol) in tetrahydrofuran/hexane (2:1, 16 ml) was added dropwise to a solution of 5-methyl-7-(2-methylpropyl)thieno[2,3-d]pyridazin-4(5H)-one (Example 6 step b, 1.00 g) in tetrahydrofuran (20 ml) at −78° C. under nitrogen. After 5 minutes, 2-trifluoromethylbenzaldehyde (1.57 g) was added. The mixture was stirred at −78° C. for 3 hours, then saturated sodium hydrogen carbonate solution (50 ml) was added, and the mixture was warmed to room temperature and extracted with ethyl acetate (50 ml). The organic extracts were washed twice with saturated sodium hydrogen carbonate solution, then with brine, then dried, filtered and evaporated. The residue was dissolved in trifluoroacetic acid (5 ml) and triethylsilane (2 ml) was added. After 24 hours, additional trifluoroacetic acid (5 ml) and triethylsilane (2 ml) were added. After a further 3 days, the mixture was diluted with water (50 ml) and extracted with ethyl acetate (50 ml). The organic extracts were washed twice with 1M sodium hydroxide solution, then with brine, and then dried, filtered and evaporated. The residue was purified by column chromatography, eluting with an ethyl acetate/isohexane gradient, followed by preparative normal-phase HPLC with gradient dichloromethane/ethanol elution and then with gradient ethyl acetate/isohexane elution to give the title compound (0.055 g).

1. temperaturethe mixture was warmed to room temperature
2. extractionextracted with ethyl acetate (50 ml)
3. washThe organic extracts were washed twice with saturated sodium hydrogen carbonate solution
4. dry with materialwith brine, then dried
5. filtrationfiltered
6. customevaporated
7. dissolutionThe residue was dissolved in trifluoroacetic acid (5 ml)
8. additiontriethylsilane (2 ml) was added
9. waitAfter 24 hours
10. additionadditional trifluoroacetic acid (5 ml) and triethylsilane (2 ml) were added
11. waitAfter a further 3 days
12. additionthe mixture was diluted with water (50 ml)
13. extractionextracted with ethyl acetate (50 ml)
14. washThe organic extracts were washed twice with 1M sodium hydroxide solution
15. dry with materialwith brine, and then dried
16. filtrationfiltered
17. customevaporated
18. customThe residue was purified by column chromatography
19. washeluting with an ethyl acetate/isohexane gradient
20. washfollowed by preparative normal-phase HPLC with gradient dichloromethane/ethanol elution
21. washwith gradient ethyl acetate/isohexane elution

ORD record

ord-fb81740a39c74c66987c319dbc105a41

Source dataset

uspto-grants-2004_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06770646B2