Application of Tetrabenazine_Kain Industrial Additive

Background and overview^[1][2]

Tetrabenazine was first marketed in Switzerland and was initially used for the treatment of schizophrenia. In August 2008, it was approved for marketing by the U.S. Food and Drug Administration (FDA) with fast-track approval status, becoming the first and only drug to treat Huntington’s disease (HD) in the United States. HD is a hereditary, fatal brain degenerative disease characterized by personality changes, slurred speech, emotional instability, involuntary movements, and intoxication. It usually develops in middle age. Due to the death of cells in the caudate nucleus of the brain, the ability to speak, move, think and swallow is gradually lost. The disease will continue to develop for about 15 to 20 years and eventually lead to death.

Tetrabenazine mainly produces pharmacological effects by reversibly inhibiting monoamine transporter 2 (VMAT 2) in the central nervous system to reduce the supply of monoamine compounds, such as 5-hydroxytryptamine, dopamine and norepinephrine. active. In addition to inhibiting VMAT 2, tetrabenazine also has a certain antagonistic effect on presynaptic and postsynaptic dopamine receptors. Tetrabenazine is a safe and effective drug for the treatment of various hyperkinesia disorders. Compared with traditional antipsychotics, tetrabenazine does not cause tardive dyskinesia. .

Physical and chemical properties^[1]

Tetrabenazine (TBZ, Ro 1-9569) is a benzoquinolizine derivative, its chemical name is 2-oxo-3-isobutyl-9,10-dimethoxy- 1,2,3,4,6,7-hexahydrobenzo[α]quinolizine (see Figure 1). Tetrabenazine was launched in Switzerland in the late 1950s and was initially used to treat schizophrenia. After clinical use for a period of time, it was discovered that TBZ is a dopamine receptor blocking drug. After testing, it was found that TBZ has a wider range of uses, especially in hyperkinesia. In 2008, TBZ became the first drug approved by the FDA for the treatment of Huntington’s disease in the United States. Tetrabenazine produces pharmacological activity mainly by reversibly inhibiting monoamine transporter 2 (VMAT 2) in the central nervous system to reduce the supply of monoamines, such as 5-hydroxytryptamine, dopamine and norepinephrine. In addition to inhibiting VMAT 2, TBZ also has certain antagonistic effects on presynaptic and postsynaptic dopamine receptors.

Tetrabenazine is a safe and effective drug for the treatment of various hyperkinesia disorders. Compared with traditional antipsychotics, TBZ does not cause tardive dyskinesia. However, TBZ still causes some dose-related side effects, such as sedation, parkinsonism, depression, insomnia, and akathisia, all of which are reversible. Although TBZ may cause some side effects, it is generally relatively safe, has a low chance of serious side effects, and is well tolerated.

Tetrabenazine has two chiral centers: position 3 and position 11b. Because the hydrogens at positions 3 and 11b are in a thermodynamically stable configuration when they are in trans, the TBZ on the market is a racemate mixture of the (3R, 11bR) configuration and the (3S, 11bS) configuration.

Tetrabenazine is rapidly metabolized in the human body into dihydrotetrabenazine (DTBZ), which is also its main active form. Because TBZ is a racemate mixture of RR configuration and SS configuration, DTBZ also has four forms: (+)-α-DTBZ (2R, 3R, 11bR), (-)-α-DTBZ (2S, 3S, 11bS), (+)-β-DTBZ (2S, 3R, 11bR) and (-)-β-DTBZ (2R, 3S, 11bS). Among them, (+)-α-DTBZ (2R, 3R, 11bR) has the highest binding capacity with VMAT2, and has demonstrated much stronger pharmacological activity than the other three isomers in in vivo experiments. Correspondingly, the in vivo pharmacological activity of optically pure (3R, 11bR)-tetrabenazine should also be significantly stronger than that of (3S, 11bS)-tetrabenazine. In the in vitro activity test, the affinity of (+)-tetrabenazine for VMAT-2 (Ki=4.61nM) was 2.4 times that of (-)-tetrabenazine (Ki=11.20nM).

Preparation^[2]

(1) Synthesis of tetramethylmethylenediamine

In a 1 L three-necked bottle, add 162 g of formaldehyde aqueous solution. After cooling to 0~5°C, slowly add 545 g of dimethylamine aqueous solution dropwise. Warm up to room temperature (28°C) naturally and stir for 8 hours. After cooling the reaction solution to 0~5°C, slowly add 250 g of potassium hydroxide solid, separate the organic phase, and dry with 50 g of sodium hydroxide. After filtration, the organic phase was distilled under normal pressure to obtain 172 g of tetramethylmethanediamine, with a yield of 84% and an HPLC purity of 99%.

(2) Synthesis of 3-[(dimethylamino)methyl]-5-methyl-2-hexanone

In a 1 L three-necked flask, add 240 ml N, N-dimethylformamide and 122 g tetramethylmethanediamine. After cooling to 0~5°C, add 94 g acetyl chloride dropwise and stir for 2 hours. . Add 123 g of 5-methyl-2-hexanone dropwise, slowly raise the temperature to 70~75°C, and stir for 8 hours. After cooling to room temperature (28°C), add 480 ml of water, then 200 ml of ethyl acetate and 100 ml of 1M hydrochloric acid. After layering, adjust the pH value of the aqueous phase to 10-11 with 4 M sodium hydroxide solution, then extract with ethyl acetate (150 ml × 3), combine the organic phases, concentrate and distill under reduced pressure (20 mmHg, 95-105°C ) to obtain 120 g of 3-[(dimethylamino)methyl]-5-methyl-2-hexanone, with a yield of 64% and an HPLC purity of 99%.

(3) Synthesis of Tetrabenazine

Under stirring, 358 g of 6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride and 236 g of 3-[(dimethylamino)methyl]-5-methyl ‑2‑Hexanone was added to 1000 mL of water. Add 1 g of tetrabenazine seed crystals and stir at room temperature for 72 hours. Pressure reduction filtrationA large amount of solid was obtained, washed with 300 mL of water, then washed with 300 mL of n-heptane, and vacuum dried at 50 degrees for 16 hours to obtain 347 g of yellow solid tetrabenazine, with a yield of 86% and an HPLC purity of 99%.

The splitting of tetrabenazine:

Tetrabenazine 0.3g (0.95mmol) and (+)-camphorsulfonic acid 0.11g (0.48mmol) were dissolved in an appropriate amount of acetone, refluxed for 30 minutes, cooled and crystallized, and filtered to obtain white crystals (3R, 11bR )-Tetrabenazine·(+)-camphorsulfonate (0.10g), [α]D25: +33.2(MeOH); 1H NMR (300MHz, MeOD)δ: 6.85(s, 1H), 6.82(s , 1H), 4.64-4.39(m, 1H), 4.06-3.68(m, 7H), 3.53-3.30(m, 3H), 3.23-2.99(m, 3H), 2.73-2.57(m, 2H), 2.34 (t, 1H, J=9.3Hz), 2.28 (t, 1H, J=9.4Hz), 2.20-1.49 (m, 9H), 1.22-1.16 (m, 1H), 1.09 (s, 3H), 0.98- 0.91 (m, 6H), 0.82 (s, 3H).

The ee value of (3R, 11bR)-tetrabenazine free base obtained after dissociation of this salt is 98.4%.

Main reference materials

[1] Yao Zhangyu. (2010). Asymmetric synthesis attempt of optically pure tetrabenazine. Journal of China Pharmaceutical University, 41(4), 321-325.

[2] Liu Yang (compiler), & Hu Chun (reviewer). (2009). Tetrabenazine (xenazine). Chinese Journal of Medicinal Chemistry, 19(1), 80-80.

[3] Yang Jiuxia, Zhang Yuping, Zhang Hongmiao, & Yan Pei. (2009). Drug for treating chorea—tetrabenazine. Chinese Pharmaceutical Journal, 44(12), 959-960.