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Resolution method of tetrabenazine

A technology of tetrabenazine and levotetrabenazine, applied in the field of chemistry, can solve the problems that optically active tetrabenazine is not suitable for industrial production

Inactive Publication Date: 2011-03-16
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above two methods for preparing optically active tetrabenazine are not suitable for industrialized production

Method used

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  • Resolution method of tetrabenazine
  • Resolution method of tetrabenazine
  • Resolution method of tetrabenazine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Dissolve 0.3g (0.95mmol) of tetrabenazine and 0.2g (0.95mmol) of (+)-camphorsulfonic acid in an appropriate amount of acetone, reflux for 30 minutes, cool and crystallize, and filter to obtain white crystals of (3R, 11bR)-butylene Benazine.(+)-Camphorsulfonate (0.19 g). The ee value of (3R,11bR)-tetrabenazine free base obtained after dissociation of the salt was 47.8%.

Embodiment 2

[0034] Dissolve 0.3g (0.95mmol) of tetrabenazine and 0.11g (0.48mmol) of (+)-camphorsulfonic acid in an appropriate amount of acetone, reflux for 30 minutes, cool and crystallize, and filter to obtain white crystals of (3R, 11bR)-butylene Benazine (+)-Camphorsulfonate (0.10g), [α]D 25 : +33.2 (MeOH); 1 H 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 (3R, 11bR)-butylbenzene obtained after the dissociation of the salt The ee value of nazine free base is 98.4%.

Embodiment 3

[0036] Dissolve 0.8g (2.52mmol) of tetrabenazine and 0.3g (1.29mmol) of (-)-camphorsulfonic acid in an appropriate amount of acetone, reflux for 30 minutes, cool and crystallize, and filter to obtain white crystals of (3S, 11bS)-butylene Benazine (-)-camsylate (0.22g), [α] D 25 : -36.4 (MeOH). 1 H NMR (300MHz, MeOD) δ: 6.86(s, 1H), 6.83(s, 1H), 4.51-4.38(m, 1H), 3.84-3.68(m, 7H), 3.50-3.07(m, 6H), 2.75-2.58(m, 2H), 2.35-2.28(m, 1H), 2.21-1.51(m, 7H), 1.41-1.30(m, 1H), 1.10(s, 3H), 0.99-0.92(m, 6H) ), 0.83(s, 3H). The ee value of the (3S, 11bS)-tetrabenazine free base obtained after the dissociation of the salt was 97.7%.

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Abstract

The invention relates to a chiral resolution method of tetrabenazine and provides a salt formed by tetrabenazine and dextrorotatory or levorotatory chiral acid and a preparation method thereof. Tetrabenazine racemate is served as a raw material, and the dextrorotatory or levorotatory camphorsulfonic acid and the other chiral acids are served as a resolving agent to simply and efficiently prepare high-purity (+)-(3R, 11bR)-tetrabenazine and (-)-(3R, 11bS)-tetrabenazine.

Description

technical field [0001] The invention relates to the field of chemistry, in particular to the preparation of optically active tetrabenazine. This patent application utilizes the priority of the Chinese patent application (application number 200910031847.5). Background technique [0002] Tetrabenazine (Tetrabenazine, TBZ, Ro 1-9569) is a benzoquinazine derivative, its chemical name is 2-oxo-3-isobutyl-9,10-dimethoxy-1,2 , 3,4,6,7-hexahydrobenzo[α]quinazine (see figure 1 ). Tetrabenazine was listed in Switzerland in the late 1950s and was initially used for the treatment of schizophrenia. After a period of clinical use, it was found that TBZ is a dopamine receptor blocking drug. TBZ has been tested and found to have 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 mainly reduces the supply of monoamines, such as serotonin, dopamine and nor...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D455/06C07B57/00
Inventor 孙宏斌姚彰彧
Owner CHINA PHARM UNIV
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