Potassium Carbonate → (+)-2-(4-Ethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(3-methoxyquinolin-7-yl)phenyl)acetamide

HRID 1525941ノート

反応式

HRID 1525941 の反応式
Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:25][CH2:24][C:15]3([O:20][CH2:19][C:18](=[O:21])[N:17]([CH2:22][CH3:23])[CH2:16]3)[CH2:14][CH2:13]2)[C:9]([NH2:11])=[O:10])=[C:4]([F:26])[CH:3]=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C([O-])(=O)C.[K+].Br[C:51]1[CH:60]=[C:59]2[C:54]([CH:55]=[C:56]([O:61][CH3:62])[CH:57]=[N:58]2)=[CH:53][CH:52]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH2:22]([N:17]1[CH2:16][C:15]2([CH2:24][CH2:25][N:12]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([C:51]4[CH:60]=[C:59]5[C:54]([CH:55]=[C:56]([O:61][CH3:62])[CH:57]=[N:58]5)=[CH:53][CH:52]=4)=[CH:3][C:4]=3[F:26])[C:9]([NH2:11])=[O:10])[CH2:13][CH2:14]2)[O:20][CH2:19][C:18]1=[O:21])[CH3:23]

参加物

8

反応物 5

HCID 11430Potassium CarbonateHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 533932397-Bromo-3-methoxyquinolineHCID 712709392-(4-Bromo-2-fluorophenyl)-2-(4-ethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide

生成物 1

HCID 71270843(+)-2-(4-Ethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(3-methoxyquinolin-7-yl)phenyl)acetamide

試薬・触媒・溶媒 2

HCID 178418807HCID 178418807、化合物触媒HCID 312751,4-Dioxane溶媒

反応条件

温度
120 °C

実験手順

To a solution of 2-(4-bromo-2-fluorophenyl)-2-(4-ethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide (198 mg, 0.46 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (117 mg, 0.46 mmol), and potassium acetate (91 mg, 0.92 mmol) in 1,4-dioxane (2.5 mL) was added PdCl2(dppf)-CH2Cl2 adduct (38 mg, 0.046 mmol). The reaction mixture was purged with nitrogen and heated at 120° C. for 4 h. The reaction mixture was cooled and 7-bromo-3-methoxyquinoline (110 mg, 0.46 mmol) and 2M aq K2CO3 (0.51 mL, 1.02 mmol) were added. The reaction mixture was purged with nitrogen and was heated with stirring at 100° C. for 1 h. The reaction mixture was diluted with dichloromethane (60 mL) and any salts were filtered away. The organic mixture was filtered through a plug of celite and sodium sulfate and the filtrate was treated with a small amount of Silicycle Si-thiol resin for 30 min. The mixture was filtered and concentrated in vacuo. Purification of the residue by reverse phase HPLC (10-70% acetonitrile:water with 0.1% NH4OH) afforded the racemic title product, which was resolved by chiral HPLC (Chromegachiral CC4, methanol) to afford the title product in >98% ee (45 mg, 19% yield). αD=+56° (c=0.02, methanol); MS(ES)+ m/e 507 [M+H]+; 1H NMR (400 MHz, CD2Cl2) δ ppm 1.12 (t, J=7.07 Hz, 3 H) 1.68-1.80 (m, 2 H) 1.90-2.02 (m, 2 H) 2.31-2.41 (m, 1 H) 2.58-2.71 (m, 2 H) 2.72-2.80 (m, 1 H) 3.18 (s, 2 H) 3.41 (d, J=7.33 Hz, 2 H) 4.01 (s, 3 H) 4.02 (d, J=1.77 Hz, 2 H) 4.52 (s, 1 H) 5.65 (d, J=4.55 Hz, 1 H) 7.21-7.33 (m, 1 H) 7.44-7.56 (m, 3 H) 7.61 (dd, J=7.96, 1.89 Hz, 1 H) 7.81-7.94 (m, 2 H) 8.30 (s, 1 H) 8.71 (d, J=3.03 Hz, 1 H).

後処理

  1. customThe reaction mixture was purged with nitrogen
  2. temperatureThe reaction mixture was cooled
  3. customThe reaction mixture was purged with nitrogen
  4. temperaturewas heated
  5. additionThe reaction mixture was diluted with dichloromethane (60 mL)
  6. filtrationany salts were filtered away
  7. filtrationThe organic mixture was filtered through a plug of celite and sodium sulfate
  8. additionthe filtrate was treated with a small amount of Silicycle Si-thiol resin for 30 min
  9. filtrationThe mixture was filtered
  10. concentrationconcentrated in vacuo
  11. customPurification of the residue by reverse phase HPLC (10-70% acetonitrile:water with 0.1% NH4OH)

出典と根拠

ORDレコード
ord-7cdb4447f41e4ad297546578941d0496
出典データセット
uspto-grants-2015_07
特許番号
US09084794B2

反応ノート

読み込み中…