Diethyl Oxalate → 5-Ethyl-2-(4-fluorobenzyl)-8-hydroxy-2,3,4,4a,5,6-hexahydro-2,6-naphthyridine-1,7-dione

HRID 1436882ノート

反応式

HRID 1436882 の反応式
[NH2:1][CH:2]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7](=[O:19])[CH2:6]1)[CH2:3][CH3:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:30](OCC)(=[O:36])[C:31](OCC)=[O:32]>C1COCC1>[CH2:3]([CH:2]1[NH:1][C:31](=[O:32])[C:30]([OH:36])=[C:6]2[CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:7]2=[O:19])[CH3:4]

参加物

5

反応物 3

HCID 7268Diethyl OxalateHCID 2733832Lithium Hexamethyldisilazide2 回HCID 690684334-(1-Aminopropyl)-1-(4-fluorobenzyl)piperidin-2-one

生成物 1

HCID 579392435-Ethyl-2-(4-fluorobenzyl)-8-hydroxy-2,3,4,4a,5,6-hexahydro-2,6-naphthyridine-1,7-dione

試薬・触媒・溶媒 1

HCID 8028Tetrahydrofuran溶媒

反応条件

温度
-78 °C

実験手順

To a cooled (−78° C.) solution of 4-(1-aminopropyl)-1-(4-fluorobenzyl)piperidin-2-one (2.0 g, 8 mmol) in anhydrous THF (20 mL) was added LiHMDS (1M in THF, 18.9 mL, 18.9 mmol) under an atmosphere of nitrogen. After stirring at −78° C. for 5 min, diethyl oxalate (3.32 g, 22.7 mmol) was added to the reaction mixture. After stirring for 2 hours at −78° C., then for 0.5 hour at −20° C., LiHMDS (1M in THF, 22 mL, 22 mmol) was added. After stirring at room temperature for 24 hours, the reaction mixture was quenched with 1N HCl. The mixture was partitioned between EtOAc and water. The organic extract was dried with Na2SO4, filtered, concentrated under vacuum, then filtered through a plug of silica gel and eluting with 1% methanol in CH2Cl2. The diastereomers were separated using reverse phase HPLC on a C18 stationary phase eluting with 5%-95% acetonitrile (0.1% TFA) in H2O (0.1% TFA) to afford the title compounds. Diastereomer 1, the hydrogens at positions 4a and 5 have a cis relationship to one another: 1H NMR (400 MHz, CDCl3) δ 13.67 (br, 1H), 7.26 (m, 2H), 7.04 (t, J=8.6 Hz, 2H), 4.68 (d, J=14.7 Hz, 1H), 4.52 (d, J=14.7 Hz, 1H), 3.35 (m, 4H), 1.79 (m, 3H), 1.48 (m, 1H), 0.97 (t, J=7.3 Hz, 3H) ppm. ES MS M+1=319. Diastereomer 2, the hydrogens at positions 4a and 5 have a trans relationship to one another: 1H NMR (400 MHz, CDCl3) δ 7.26 (m, 2H), 7.04 (t, J=8.6 Hz, 2H), 6.54 (br, 1H), 4.72 (d, J=14.7 Hz, 1H), 4.49 (d, J=14.7 Hz, 1H), 3.34 (m, 3H), 2.73 (dt, J=4, 13 Hz, 1H), 1.99 (m, 1H), 1.78 (m, 1H), 1.57 (m, 2H), 1.01 (t, J=7.5 Hz, 3H) ppm. ES MS M+1=319.

後処理

  1. stirringAfter stirring for 2 hours at −78° C.
  2. waitfor 0.5 hour at −20° C.
  3. stirringAfter stirring at room temperature for 24 hours
  4. customthe reaction mixture was quenched with 1N HCl
  5. customThe mixture was partitioned between EtOAc and water
  6. extractionThe organic extract
  7. dry with materialwas dried with Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated under vacuum
  10. filtrationfiltered through a plug of silica gel
  11. washeluting with 1% methanol in CH2Cl2
  12. customThe diastereomers were separated
  13. washeluting with 5%-95% acetonitrile (0.1% TFA) in H2O (0.1% TFA)

出典と根拠

ORDレコード
ord-d880268a6a224c21aac98710550cdf34
出典データセット
uspto-grants-2009_11
特許番号
US07619086B2

反応ノート

読み込み中…