Acetic Acid → 8-Bromo-2-(2-isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene

Temperature

100 °C

A suspension of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid N-isopropyl-N′-(2-methoxy-acetyl)-hydrazide (2.66 g, 5.86 mmol) in phosphorus (V) oxychloride (26 mL) was stirred at 100° C. for 18 h. The reaction mixture was concentrated in vacuo and the resultant residue azeotroped with toluene (×4) affording a brown solid. The solid was treated with acetic acid (26 mL) and ammonium acetate (4.51 g, 58.6 mmol) before the mixture was stirred at 125° C. for 1 h. A further addition of ammonium acetate (2.31 g, 30.0 mmol) was made and the reaction stirred at 125° C. for 2 h before being concentrated in vacuo. The resultant residue was diluted with water and extracted with DCM (×2) before the combined organic extracts were washed with saturated sodium bicarbonate solution followed by brine, then dried (Na2SO4) and concentrated in vacuo to give a pale brown solid. The solid was treated with phosphorus (V) oxychloride (26 mL) and stirred at 100° C. for 24 h before being concentrated in vacuo then treated with acetic acid (23 mL) and ammonium acetate (4.23 g, 55.0 mmol). The mixture was stirred at 125° C. for 1.5 h then concentrated in vacuo and azeotroped with toluene (×4). The resultant residue was diluted with water and extracted with DCM (×2) and the combined organic extracts were washed with saturated sodium bicarbonate solution followed by brine, then dried (Na2SO4) and concentrated in vacuo to give a brown solid. The solid was recrystallised from methanol/chloroform to give the title compound as a dark brown solid (1.17 g, 2.69 mmol, 46%). LCMS RT=4.97 min, [M+H]+=435/437. 1H NMR 400 MHz (DMSO-d6) δ: 8.23 (1H, d, J=8.58 Hz), 7.36 (1H, dd, J=8.58, 2.10 Hz), 7.26 (1H, d, J=2.07 Hz), 5.72-5.71 (1H, m), 4.39 (2H, s), 4.35 (2H, t, J=5.02 Hz), 3.39 (2H, t, J=5.02 Hz), 3.29 (3H, s), 1.49 (6H, d, J=6.59 Hz).

1. concentrationThe reaction mixture was concentrated in vacuo
2. customthe resultant residue azeotroped with toluene (×4)
3. customaffording a brown solid
4. stirringwas stirred at 125° C. for 1 h
5. stirringthe reaction stirred at 125° C. for 2 h
6. concentrationbefore being concentrated in vacuo
7. additionThe resultant residue was diluted with water
8. extractionextracted with DCM (×2) before the combined organic extracts
9. washwere washed with saturated sodium bicarbonate solution
10. dry with materialdried (Na2SO4)
11. concentrationconcentrated in vacuo
12. customto give a pale brown solid
13. stirringstirred at 100° C. for 24 h
14. concentrationbefore being concentrated in vacuo
15. stirringThe mixture was stirred at 125° C. for 1.5 h
16. concentrationthen concentrated in vacuo
17. customazeotroped with toluene (×4)
18. additionThe resultant residue was diluted with water
19. extractionextracted with DCM (×2)
20. washthe combined organic extracts were washed with saturated sodium bicarbonate solution
21. dry with materialdried (Na2SO4)
22. concentrationconcentrated in vacuo
23. customto give a brown solid
24. customThe solid was recrystallised from methanol/chloroform

ORD record

ord-c8e74421a820457f9bf41d6857d06f16

Source dataset

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09175009B2