1,4-Dioxane → HCID 59371497、化合物

HRID 2095377ノート

反応式

HRID 2095377 の反応式
C(O[Na])(C)(C)C.Br[C:8]1[CH:9]=[N:10][CH:11]=[C:12]([O:14][CH2:15][C@@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:13]=1.Cl.[CH:29]12[CH2:36][CH:33]([CH2:34][CH2:35]1)[CH2:32][NH:31][CH2:30]2.O1CCOCC1>[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.O>[C:24]([O:23][C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:16]1[CH2:15][O:14][C:12]1[CH:13]=[C:8]([N:31]2[CH2:32][CH:33]3[CH2:36][CH:29]([CH2:35][CH2:34]3)[CH2:30]2)[CH:9]=[N:10][CH:11]=1)=[O:22])([CH3:27])([CH3:26])[CH3:25]

参加物

8

反応物 4

HCID 312751,4-DioxaneHCID 15480235(S)-2-((5-Bromopyridin-3-yloxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl esterHCID 229236613-azabicyclo[3.2.1]octane hydrochlorideHCID 178418730sodium 2-methylpropan-2-olate

生成物 1

HCID 59371497HCID 59371497、化合物収率 65%

試薬・触媒・溶媒 3

HCID 23938Palladium触媒HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl触媒HCID 962Water溶媒

反応条件

温度
100 °C

実験手順

Palladium catalyst A (6.2 mg, 7.5 μmol, 83 mequiv.), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (Xphos, 3.7 mg, 7.5 μmol, 83 mequiv.), tert-BuONa (206 mg, 2.1 mmol, 2.8 equiv.), 3-bromo-5-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]pyridine (268 mg, 0.75 mmol) and 3-azabicyclo[3.2.1]octane hydrochloride (Arkè Organics srl, Zona Industriale della Botte No. 4, 56012 Fornacette (PI), Italy; 133 mg, 0.90 mmol, 1.2 equiv.) were filled into a 25 mL round bottom-flask with a side neck. The flask was equipped with a stir bar, a condenser, and rubber septa. The atmosphere was exchanged with Ar (3 times), and anhydrous dioxane (3 mL) was added via syringe. The mixture was stirred at 100° C. for 5 h and cooled to room temperature. Water (10 mL) was added to quench the reaction. The product was extracted into EtOAc (40 mL). The organic phase was washed with brine (10 mL), dried over Na2SO4, and concentrated. The residue was purified by CC (SiO2, 25×2.5 cm, EtOAc) to give the crude product, which was further purified by preparative HPLC (Supelco Discovery C18, 250×21.2 mm, 5 μm particle size, UV detection at 270 nm, flow rate 12.5 mL/min, gradient from 20% to 100% CH3CN in water within 40 min, then 100% CH3CN for 20 min; tR 32.6-36.9 min) to give the title compound as a yellowish oil (198 mg, 65%). MS (EI) m/z 387 (M+, 16%).

後処理

  1. addition133 mg, 0.90 mmol, 1.2 equiv.) were filled into a 25 mL round bottom-flask with a side neck
  2. customThe flask was equipped with a stir bar, a condenser
  3. additionwas added via syringe
  4. temperaturecooled to room temperature
  5. customto quench
  6. customthe reaction
  7. extractionThe product was extracted into EtOAc (40 mL)
  8. washThe organic phase was washed with brine (10 mL)
  9. dry with materialdried over Na2SO4
  10. concentrationconcentrated
  11. customThe residue was purified by CC (SiO2, 25×2.5 cm, EtOAc)
  12. customto give the crude product, which
  13. customwas further purified by preparative HPLC (Supelco Discovery C18, 250×21.2 mm, 5 μm particle size, UV detection at 270 nm, flow rate 12.5 mL/min, gradient from 20% to 100% CH3CN in water within 40 min
  14. wait100% CH3CN for 20 min

出典と根拠

ORDレコード
ord-4090d2e00411477bb1724d531904c418
出典データセット
uspto-grants-2013_05
特許番号
US08445684B2

反応ノート

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