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

HRID 47233

反応式

HRID 47233 の反応式
[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:4][C:5]2[N:6]([C:8](=O)[NH:9][N:10]=2)[N:7]=1.P(Br)(Br)([Br:20])=O.N>>[Br:20][C:8]1[N:6]2[N:7]=[C:2]([Cl:1])[C:3]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:4][C:5]2=[N:10][N:9]=1

参加物

4

反応物 3

HCID 222AmmoniaHCID 24613Phosphorus oxybromideHCID 227441686-chloro-7-(morpholin-4-yl)-2H-1,2,4-triazolo[4,3-b]pyridazin-3-one

生成物 1

HCID 227441713-Bromo-6-chloro-7-(morpholin-4-yl)-1,2,4-triazolo[4,3-b]pyridazine収率 43.8%

反応条件

温度
80 °C

実験手順

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+].

後処理

  1. temperatureUpon cooling the mixture
  2. additionwas treated with ice
  3. extractionThe aqueous was then extracted with dichloromethane (×3)
  4. dry with materialThe combined extracts were dried (Na2SO4)
  5. filtrationfiltered
  6. customevaporated
  7. customThe residue was purified by chromatography on silica gel
  8. washeluting with 5% methanol/dichloromethane

出典と根拠

ORDレコード
ord-fa87cac9f52b44899eb4a73f63c31f69
出典データセット
uspto-grants-2004_03
特許番号
US06699859B1

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