Water → HCID 58529487, compound

Temperature

100 °C

To a stirred solution of tert-butyl 3-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (300 mg, 0.66 mmol) and tetrakis(triphenylphosphine)palladium(0) (114 mg, 0.099 mmol) in degassed 1,4-dioxane (5 mL) and DMF (5 mL) were added 2-benzyl-3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (345 mg, 0.99 mmol), K2CO3 (274 mg, 1.99 mmol), and H2O (1.0 mL). The reaction was degassed and heated (100° C.) for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (250 mL) and saturated aqueous K2CO3 solution (200 mL). The layers were separated and the organic phase was washed, dried (Na2SO4), and concentrated to dryness. The crude residue was dissolved in dichloromethane (20 mL) and treated with trifluoroacetic acid (5 mL). The solution was allowed to stir for 30 minutes and concentrated. The mixture was partitioned between ethyl acetate (75 mL) and H2O (50 mL). The layers were separated and the organic phase was washed with 1N HCl (50 mL). The combined aqueous phase was transferred to a stirring mixture of ethyl acetate and pH 14 brine and allowed to stir for 30 minutes, keeping the pH above 12 with additional NaOH pellets as needed. The layers were partitioned and aqueous layer was extracted 2× with ethyl acetate (75 mL ea.). The combined organic phase was washed with brine, dried (Na2SO4), and concentrated to dryness. The residue was triturated with Et2O to obtain 135 mg (42%) of the desired product. 1H NMR (300 MHz, DMSO-d6) 7.91 (s, 1 H), 7.78 (d, 1 H), 7.52 (s, 1 H), 7.34-7.19 (m, 5 H), 7.21 (dd, 1H), 6.72 (s, 1H), 5.63 (s, 2H), 5.12 (dd, 1H), 3.73 (dd, 1H), 3.30-3.23 (m, 1H), 2.92 (dd, 1H), 2.75-2.64 (m, 4H), 2.61 (s, 3H), 2.41 (t, 1H), 2.25-2.06 (m, 4H); LC-MS [M+H]+=495, RT=2.17 min.

1. customThe reaction was degassed
2. temperaturecooled to rt
3. customThe mixture was partitioned between ethyl acetate (250 mL) and saturated aqueous K2CO3 solution (200 mL)
4. customThe layers were separated
5. washthe organic phase was washed
6. dry with materialdried (Na2SO4)
7. concentrationconcentrated to dryness
8. dissolutionThe crude residue was dissolved in dichloromethane (20 mL)
9. additiontreated with trifluoroacetic acid (5 mL)
10. concentrationconcentrated
11. customThe mixture was partitioned between ethyl acetate (75 mL) and H2O (50 mL)
12. customThe layers were separated
13. washthe organic phase was washed with 1N HCl (50 mL)
14. additionThe combined aqueous phase was transferred to a stirring mixture of ethyl acetate and pH 14 brine
15. stirringto stir for 30 minutes
16. customThe layers were partitioned
17. extractionaqueous layer was extracted 2× with ethyl acetate (75 mL ea.)
18. washThe combined organic phase was washed with brine
19. dry with materialdried (Na2SO4)
20. concentrationconcentrated to dryness
21. customThe residue was triturated with Et2O

ORD record

ord-83394e7f3a6440cbb0c775fffee294a6

Source dataset

uspto-grants-2013_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08431695B2