Ethanol → (3R,11bR)-1,3,4,6,7,11b-Hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo(a)quinolizin-2-one

HRID 1807440

反応式

HRID 1807440 の反応式
[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[N:8][CH2:7][CH2:6]2.[CH3:15][CH2:16][OH:17].[CH2:18]([C@@H:22]1[CH2:39][N:26]2[CH2:27][CH2:28][C:29]3[C:34]([C@H:25]2[CH2:24][C:23]1=[O:40])=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=3)[CH:19]([CH3:21])[CH3:20]>O>[CH3:21][CH:19]([CH2:18][C@H:22]1[C:23](=[O:40])[CH2:24][C@H:25]2[N:26]([CH2:27][CH2:28][C:29]3[C:34]2=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=3)[CH2:39]1)[CH3:20].[CH3:20][CH:19]([CH2:18][C@@H:22]1[C:16](=[O:17])[CH2:15][C@@H:9]2[N:8]([CH2:7][CH2:6][C:5]3[C:10]2=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:23]1)[CH3:21]

参加物

6

反応物 3

HCID 702EthanolHCID 300583,4-Dihydro-6,7-dimethoxyisoquinolineHCID 667453(3R,11bR)-1,3,4,6,7,11b-Hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo(a)quinolizin-2-one

生成物 2

HCID 667453(3R,11bR)-1,3,4,6,7,11b-Hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo(a)quinolizin-2-oneHCID 11634155(-)-Tetrabenazine

試薬・触媒・溶媒 1

HCID 962Water溶媒

反応条件

温度
80 °C

実験手順

To a round bottom flask was added 6,7-dimethoxy-3,4-dihydroisoquinoline (13 g, 67.8 mmol), 3-dimethylaminomethyl-5-methyl-hexan-2-one methiodide 1b (26 g, 81.4 mmol) and EtOH (130 mL). The suspension was heated to 80° C. overnight. The reaction mixture was allowed to cool to room temperature and H2O (200 mL) was added forming a precipitate. The EtOH was removed in vacuo and CH2Cl2 (400 mL) was added. A 10% NaOH solution was added to the mixture until basic. The aqueous layer was then extracted 3× with CH2Cl2 (250 mL). The organic layers were combined, dried over MgSO4 and concentrated. The crude reaction mixture was purified via flash column chromatography (0.5:9.5 Acetone:CH2Cl2) and further recrystallized from EtOAc and Hexanes to give 16.1 g (51 mmol) of a racemic mix of (3S,11bS) and (3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-pyrido[2,1-a]isoquinolin-2-one 1c (tetrabenazine, TBZ) in a 75% yield. The enantiomers of tetrabenazine were separated by SFC utilizing a Chiralpak AD-H column with 15% CAN/MeOH plus 0.5% DMEA at 2.5 mL/min at 100 bar and 35° C. to yield 4.3 g of (3R,11bR)-tetrabenazine 1c.1 and 4.3 g of (3S,11bS)-tetrabenazine 1c.2. (3R,11bR)-tetrabenazine 1c.1: MS calcd: (317). Found 318.7 (M+H). (3S,11bS)-tetrabenazine 1c.2: MS calcd: (317). Found 318.7 (M+H).

後処理

  1. temperatureto cool to room temperature
  2. customforming a precipitate
  3. customThe EtOH was removed in vacuo and CH2Cl2 (400 mL)
  4. additionwas added
  5. additionA 10% NaOH solution was added to the mixture until basic
  6. extractionThe aqueous layer was then extracted 3× with CH2Cl2 (250 mL)
  7. dry with materialdried over MgSO4
  8. concentrationconcentrated
  9. customThe crude reaction mixture
  10. customwas purified via flash column chromatography (0.5:9.5 Acetone:CH2Cl2)
  11. customfurther recrystallized from EtOAc and Hexanes
  12. customto give 16.1 g (51 mmol) of
  13. customThe enantiomers of tetrabenazine were separated by SFC
  14. customat 100 bar and 35° C.

出典と根拠

ORDレコード
ord-8273613f38ec4573b0a0c61a33ab1870
出典データセット
uspto-grants-2013_01
特許番号
US08357697B2

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