反应详情

温度

80 °C

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).

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.