Hydrochloric Acid → 2-(4-Ethoxyphenyl)-3-[4-(methylsulfonyl)phenyl]pyrazolo[1,5-b]pyridazine

Temperature

40 °C

Titanium tetrachloride (26 mL) was added to a stirred suspension of 1-(4-ethoxyphenyl)-2-(4-methanesulfonyl-phenyl)-ethanone (75.0 g), N-amino-pyridazinium hexafluorophosphate (59.6 g) in DCM (1125 mL) at about 20° C. N-Methyl-pyrrolidinone (23 mL) was added and TMEDA (50 mL) was added over a period of about 4 hours and the reaction mixture heated at 40° C. for 4.5 hours. The reaction mixture was stirred at about 20° C. for about 2 hours and further TMEDA (93 mL) was added over about 15 minutes. The mixture was stirred for about 18 hours and iodine (63 g) was added. After about a further 5 hours, IMS (55 mL) was added, followed by 3.3M hydrochloric acid (1125 mL) and the layers were separated. The organic extract was further washed with 3.3M hydrochloric acid (375 mL), aqueous sodium carbonate solution (20% w/v, 375 mL), aqueous sodium thiosulfate solution (20% w/v, 2×375 mL) and aqueous sodium chloride solution (3% w/v, 2×375 mL). The organic extract was then concentrated by distillation to a residual volume of about 450 mL and iso-octane (about 187 mL) was added at about 38° C. The resultant slurry was cooled to about 0-5° C. and filtered. The crude product was washed with DCM/iso-octane (1:1, 2×150 mL) and iso-octane (400 mL), dried, and then dissolved in acetone (1200 mL). This solution was heated to about 50° C. and treated with charcoal (19 g) for about 1 hour before filtering. The charcoal was washed with hot acetone (750 mL) and the combined filtrates and washings were concentrated by distillation to a residual volume of about 825 mL. Further acetone (375 ml) was added to the concentrate, which was concentrated again to a residual volume of about 825 mL. Maintaining the temperature at about 50° C., water (450 mL) was added over about 1 hour, causing the product to crystallise. After cooling the slurry to about 0-5° C. the product was isolated by filtration, washed with chilled acetone/water (1:1, 2×150 mL), and dried in vacuo at 65° C. to give the title compound as a pale yellow crystalline solid (63.6 g, 68.6%), spectroscopically identical to the product of Example 7.

1. stirringThe mixture was stirred for about 18 hours
2. waitAfter about a further 5 hours
3. customthe layers were separated
4. extractionThe organic extract
5. washwas further washed with 3.3M hydrochloric acid (375 mL), aqueous sodium carbonate solution (20% w/v, 375 mL), aqueous sodium thiosulfate solution (20% w/v, 2×375 mL) and aqueous sodium chloride solution (3% w/v, 2×375 mL)
6. extractionThe organic extract
7. concentrationwas then concentrated by distillation to a residual volume of about 450 mL and iso-octane (about 187 mL)
8. additionwas added at about 38° C
9. temperatureThe resultant slurry was cooled to about 0-5° C.
10. filtrationfiltered
11. washThe crude product was washed with DCM/iso-octane (1:1, 2×150 mL) and iso-octane (400 mL)
12. customdried
13. dissolutiondissolved in acetone (1200 mL)
14. temperatureThis solution was heated to about 50° C.
15. additiontreated with charcoal (19 g) for about 1 hour
16. filtrationbefore filtering
17. washThe charcoal was washed with hot acetone (750 mL)
18. concentrationthe combined filtrates and washings were concentrated by distillation to a residual volume of about 825 mL
19. additionFurther acetone (375 ml) was added to the concentrate, which
20. concentrationwas concentrated again to a residual volume of about 825 mL
21. temperatureMaintaining the temperature at about 50° C.
22. additionwater (450 mL) was added over about 1 hour
23. customto crystallise
24. temperatureAfter cooling the slurry to about 0-5° C. the product
25. customwas isolated by filtration
26. washwashed with chilled acetone/water (1:1, 2×150 mL)
27. customdried in vacuo at 65° C.

ORD record

ord-eb7da936a3254edbbced774501013efa

Source dataset

uspto-grants-2004_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06803463B2