反応 #1894622

反応方程式

(3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-pyrido[2,1-a]isoquinolin-2-one

6,7-dimethoxy-3,4-dihydroisoquinoline

EtOH

→

(3S,11bS)-tetrabenazine

(3R,11bR)-tetrabenazine

溶媒

H2O

反応条件

後処理

1. 1
   温度to cool to room temperature
2. 2
   その他forming a precipitate
3. 3
   その他The EtOH was removed in vacuo and CH2Cl2 (400 mL)
4. 4
   workup.ADDITIONwas added
5. 5
   workup.ADDITIONA 10% NaOH solution was added to the mixture until basic
6. 6
   抽出The aqueous layer was then extracted 3× with CH2Cl2 (250 mL)
7. 7
   乾燥dried over MgSO4
8. 8
   濃縮concentrated
9. 9
   その他The crude reaction mixture
10. 10
    その他was purified via flash column chromatography (0.5:9.5 Acetone:CH2Cl2)
11. 11
    その他further recrystallized from EtOAc and Hexanes
12. 12
    その他to give 16.1 g (51 mmol) of
13. 13
    その他The enantiomers of tetrabenazine were separated by SFC
14. 14
    その他at 100 bar and 35° 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).

出典