Preparation method of (2r,3r,11br)-dihydrotetrabenazine and related compounds

A technology of dihydrotetrabenazine and tetrabenazine, which is applied in the direction of organic chemistry methods, chemical instruments and methods, organic chemistry, etc., can solve problems such as difficult industrial production, avoid column chromatography purification process, and improve three-dimensional Effects of Selectivity and Chemical Yield

Active Publication Date: 2011-12-21
JIANGSU VCARE PHARMATECH
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  • Abstract
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  • Application Information

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Problems solved by technology

[0005] In view of the fact that (2R, 3R, 11bR)-DHTBZ and its derivatives have very good medicinal prospects, and the existing (2R, 3R, 11bR)-DHTBZ preparation methods are difficult to meet the needs of industrial production, this area is in urgent need of development ( 2R, 3R, 11bR)-DHTBZ and its related compounds are suitable for the synthesis process of industrial production

Method used

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  • Preparation method of (2r,3r,11br)-dihydrotetrabenazine and related compounds
  • Preparation method of (2r,3r,11br)-dihydrotetrabenazine and related compounds
  • Preparation method of (2r,3r,11br)-dihydrotetrabenazine and related compounds

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Embodiment 1

[0022] (2R, 3R, 11bR)-dihydrotetrabenazine ((2R, 3R, 11bR)-DHTBZ)

[0023] (3R, 11bR)-TBZ (1.0g, 3.2mmol) was dissolved in 11ml of tetrahydrofuran, and after the solution was cooled to -20°C, 2M borane-dimethylsulfide-tetrahydrofuran (3.2ml, 6.4mmol) was added dropwise into the reaction solution. After the reaction solution was stirred and reacted at -20°C for 2 h, 11 ml of ammonia water was added, and then the mixed solution was heated to 35°C and stirred overnight. Saturated brine was added, and extracted with ether. The ether extract was washed with saturated NaCl solution, anhydrous Na 2 SO 4 It was dried, filtered, and the solvent was distilled off under reduced pressure to obtain 1.07 g of a white solid. The crude product was recrystallized twice through acetone-water to obtain the pure product (2R, 3R, 11bR)-dihydrotetrabenazine (0.64g white solid, yield 64%), [α] D 21 =+58.93° (c 0.6, MeOH). 1 H NMR (300MHz, CDCl 3 ): δ6.68(s, 1H), 6.58(s, 1H), 3.84(s, 6H), 3.3...

Embodiment 2

[0025] (2S,3S,11bS)-dihydrotetrabenazine ((2S,3S,11bS)-DHTBZ)

[0026] According to the experimental procedure described in Example 1, (3S, 11bS)-TBZ was reduced with borane-dimethyl sulfide to obtain (2S, 3S, 11bS)-dihydrotetrabenazine (white solid, yield 63%) , [α] D 22 =-56.1° (c 0.23, MeOH). 1H NMR (300MHz, CDCl 3 ): δ6.67(s, 1H), 6.58(s, 1H), 3.87(s, 6H), 3.43-3.34(m, 1H), 3.14-2.96(m, 4H), 2.65-2.54(m, 2H) ), 2.53 (ddd, 1H, J=11.1, 11.1, 3.6Hz), 2.01-1.94 (m, 1H), 1.77-1.64 (m, 2H), 1.62-1.36 (m, 2H), 1.10-0.99 (m , 1H), 0.95-0.70 (m, 6H); 13C NMR (75MHz, CDCl 3 )δ147.50, 147.23, 129.36, 126.42, 111.49, 107.96, 74.63, 60.88, 60.08, 55.94, 55.84, 51.89, 41.65, 40.58, 39.70, 29.18, 25.35, 24.12, 32.76; ESI-MS m / z: M+H]+, HRMS-EIS (m / z): 320.2242 [M+H]+ (Calcd for C19H30NO3 320.2226).

Embodiment 3

[0028] (±)-α-dihydrotetrabenazine ((±)-α-DHTBZ)

[0029] According to the experimental procedure described in Example 1, tetrabenazine (TBZ) was reduced with borane-dimethyl sulfide to obtain (±)-α-dihydrotetrabenazine (white solid), 1 H NMR (300MHz, CDCl 3 )δ6.68(s, 1H), 6.58(s, 1H), 3.84(s, 6H), 3.39(m, 1H), 3.16-2.97(m, 4H), 2.67-2.41(m, 3H), 1.99 (t, J=11.3Hz, 1H), 1.75-1.44 (m, 5H), 1.10-1.01 (m, 1H), 0.93 (t, J=6.5Hz, 6H); ESI-MS m / z 320.3 [M +H] + , 342.3[M+Na] + .

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Abstract

The invention relates to a preparation method of (2R, 3R, 11bR)-dihydrotetrabenazine (formula I), (2S, 3S, 11bS)-dihydrotetrabenazine (formula II) and (+_)-alpha-dihydrotetrabenazine. The preparation method comprises the following steps of: adopting borane or various borane complexes, carrying out three-dimensional selective reduction on (3R, 11bR)-tetrabenazine under low temperature, and obtaining the (2R, 3R, 11bR)-dihydrotetrabenazine; and adopting the same method to carry out reduction on the (3R, 11bS)-tetrabenazine and tetrabenazine racemic modification, and respectively preparing the (2S, 3S, 11bS)-dihydrotetrabenazine and the (+_)-alpha-dihydrotetrabenazine. In the preparation method, the three-dimensional selection and the chemical yield of the reduction reaction are greatly improved, so that the very fussy column chromatography purification is avoided, so that the preparation method can be applicable to industrial production.

Description

technical field [0001] The present invention relates to a process for the preparation of (2R, 3R, 11bR)-dihydrotetrabenazine and related compounds, which are inhibitors of vesicular monoamine transporter 2 (VMAT2). Background technique [0002] Tetrabenazine (Tetrabenazine, TBZ) (chemical name 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2, 1-a] isoquinolin-2-one) ( figure 1 ) as a drug for the treatment of hyperkinetic dyskinesia has been used in the United Kingdom, Canada, and Australia for many years, and passed FDA certification in 2008 to become the first drug for the treatment of Huntington's disease in the United States. Its main mechanism of action is to inhibit the uptake of monoamine neurotransmitters into the vesicles of presynaptic neurons by reversibly binding to vesicular monoamine transporter 2 (VMAT2), so that these monoamines remain in the cytoplasm Medium and rapidly degraded by monoamine oxidase (Pettibone et al., Eur. J. Pharmacol. 1984, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D455/06C07B53/00
Inventor 袁方祁小伟魏雪莹龚彦春
Owner JIANGSU VCARE PHARMATECH
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