Tetrabenazine

From The Cure For The Needy

Contents 1 Tetrabenazine (Xenazine, Nitoman) 1.1 Effective Against 1.2 Cost 1.3 Reported Routes of Synthesis 1.4 Submitted Syntheses

Tetrabenazine (Xenazine, Nitoman)

Effective Against

Hyperkinetic movement disorder (symptomatic treatment)

Tetrabenazine works mainly as a VMAT-inhibitor and as such promotes the early metabolic degradation of the neurotransmitter dopamine.

Cost

From Sigma-Aldrich: 88.10 USD (10mg) or 406.50 USD (50mg)

From Tocris Bioscience: 95 USD (10mg) or 422 USD (50mg)

Reported Routes of Synthesis

The condensation of 1-(ethoxycarbonylmethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (I) with isobutylmalonic acid dimethyl ester (II) and paraformaldehyde (III) in refluxing methanol gives the adduct (IV), which is then cyclized and decarboxylated by means of NaOMe in refluxing methanol to obtain the target benzo[a]quinolizine.

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Acylation of 2-(3,4-dimethoxyphenyl)ethylamine with ethyl malonyl chloride (II) gives amido ester (III). Subsequent Bischler-Napieralski cyclization of amide (III) in the presence of POCl3, followed by catalytic hydrogenation of the intermediate imine yields tetrahydroisoquinoline derivative (IV) (1). Mannich reaction of amine (IV) with paraformaldehyde and diethyl isobutylmalonate (V) in refluxing MeOH furnishes triester (VI), which undergoes Dieckmann condensation to the benzoquinolizinone compound (VII) in the presence of NaOMe in toluene at 40°C. Hydrolysis and decarboxylation of ketodiester (VII) by means of HCl at 140-150°C then yields tetrabenazine hydrochloride (VIII), which is finally converted to the corresponding free base by treatment with NaOH (2).

Brossi, A.; Lindlar, H.; Walter, M.; Schnider, O. 16. Syntheseversuche in der Emetin-Reihe. 1.Mitteilung. 2-Oxo-hydrobenzo[a]chinolizine)), Helv Chim Acta 1958, 41(1-3): 119

Lednicer, D. Six membered heterocycles fused to a benzene ring. Strategies for Organic Drug Synthesis and Design, Daniel Lednicer, Wiley , 2008, 429-494

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Lednicer, Daniel. Strategies for Organic Drug Synthesis and Design. Wiley-Interscience: 2008. 464

Cost of Starting Materials and Selected Intermediates:
Dimethoxyphenylethylamine from Sigma-Aldrich: 23.3 USD (25g)
Ethyl malonyl chloride from Sigma Aldrich: 98.2 USD (5 mL, 1.196 g/mL)
Phosphorus oxychloride from Sigma Aldrich: 34.6 USD (25 mL, 1.657 g/mL)
Diethyl isopropylmalonate from Sigma Aldrich: 224.20 USD (5 mL, 0.981 g/mL)

Submitted Syntheses