반응 #75511

반응 방정식

6-chloro-7-(morpholin-4-yl)-2H-1,2,4-triazolo[4,3-b]pyridazin-3-one

phosphoryl bromide

ammonia

→

3-bromo-6-chloro-7-(morpholin-4-yl)-1,2,4-triazolo[4,3-b]pyridazine

수율 43.8%

반응 조건

후처리

1. 1
   온도Upon cooling the mixture
2. 2
   workup.ADDITIONwas treated with ice
3. 3
   추출The aqueous was then extracted with dichloromethane (×3)
4. 4
   건조The combined extracts were dried (Na2SO4)
5. 5
   여과filtered
6. 6
   기타evaporated
7. 7
   기타The residue was purified by chromatography on silica gel
8. 8
   세척eluting with 5% methanol/dichloromethane

실험 절차

A mixture of 6-chloro-7-(morpholin-4-yl)-2H-1,2,4-triazolo[4,3-b]pyridazin-3-one (1.1 g, 4.3 mmol) and phosphoryl bromide (25 g) was stirred and heated at 80° C. for 24 hours. Upon cooling the mixture was treated with ice. The aqueous was then basified with aqueous ammonia. The aqueous was then extracted with dichloromethane (×3). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with 5% methanol/dichloromethane to give 3-bromo-6-chloro-7-(morpholin-4-yl)-1,2,4-triazolo[4,3-b]pyridazine (600 mg). 1H NMR and mass spectrum revealed the product to a mixture of the desired compound and the 6-bromo compound. This mixture was used without further purification. Sodium hydride (60% dispersion in oil, 80 mg, 2.0 mmol) was added in one portion to a stirred solution of the product from above (600 mg) and (1-methyl-1 H-1,2,4-triazol-3-yl)methanol (240 mg, 2.1 mmol; EP-A-421210) in dry DMF at 0° C. under nitrogen. The ice bath was removed and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with water and then partitioned between ethyl acetate and water. The aqueous layer was further extracted with dichloromethane (×3). The combined organic extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with 5 to 8% methanol/dichloromethane to give the title compound (358 mg, 48% for 2 steps). 1H NMR (360 MHz, d6-DMSO) δ3.20-3.22 (4H, m), 3.69-3.71 (4H, m), 3.68 (3H, s), 5.47 (2H, s), 7.41 (1H, s), 8.49 (1H, s); MS (ES+) m/e 395, 397 [MH+].

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