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6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride (118.2 kg) was dissolved in water (3 volumes). 34(Dimethylamino)methyl)-5-methylhexan-2-one (99.1 kg) in n-heptane (1.5 volumes) was added and the mixture stirred vigorously for at least 48 hours at about 35° C. until less than 10percent 6,7-dimethoxy-3,4-dihydroisoquinoline was remaining against a standard solution. The solid was filtered, washed with water then heptane, and then dried under vacuum to provide 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one (141.1 kg, 85.6percent yield).
79%
at 30℃; Large scale
The 3-((dimethylamino)methyl)-5-methylhexan-2-one-heptane solution was added to a solution of 6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride (126.1 kg) in water (315:2 L) and the mixture was stirred at about 30° C. The reaction was judged to be complete when less than 10percent 6,7-dimethoxy-3,4-dihydroisoquinoline was remaining against a standard solution. The mixture was cooled to room temperature and the solids were filtered, washed with water (176.5 L) then n-heptane (277.4 L) both stabilized at a temperature between 15-20° C., and then dried under vacuum to provide 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one (139 kg, 79percent yield).
73.3%
With N-benzyl-N,N,N-triethylammonium chloride In water at 50 - 60℃; for 24 h;
Intermediate (3-dimethylaminomethyl-5-methyl-2-hexanone, 30 g, 0.175 mol) and 6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride (39.8 g, 0.175 mol) was added to 300 ml of water and the catalyst (TEBAC, 4.0 g, 0.018 mol,0.1N), heating reaction. The temperature was controlled at 50-60°C and the reaction time was 24 h. Stop stirring, reduce to room temperature, filter solids, 100mlIt was washed twice with water to give 41.5 g of crude tetrabenazine as an off-white solid in a yield of 81.3percent. Recrystallization from anhydrous ethanol gives tetrabenazineThe refined product was 40.6 g, the total yield was 73.3percent, and the HPLC purity was >99.5percent.
Reference：
[1] Patent: US2017/183346, 2017, A1, . Location in patent: Paragraph 0165
[2] Patent: US2017/183346, 2017, A1, . Location in patent: Paragraph 0162; 0164
[3] Patent: CN107698582, 2018, A, . Location in patent: Paragraph 0019
[4] Journal of Labelled Compounds and Radiopharmaceuticals, 2011, vol. 54, # 7, p. 367 - 370
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