WO2012000308A1 - A method for resolution of tetrabenazine - Google Patents

A method for resolution of tetrabenazine Download PDF

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WO2012000308A1
WO2012000308A1 PCT/CN2011/001060 CN2011001060W WO2012000308A1 WO 2012000308 A1 WO2012000308 A1 WO 2012000308A1 CN 2011001060 W CN2011001060 W CN 2011001060W WO 2012000308 A1 WO2012000308 A1 WO 2012000308A1
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tetrabenazine
acid
chiral
3r
salt
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PCT/CN2011/001060
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Chinese (zh)
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孙宏斌
姚彰彧
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中国药科大学
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D455/00Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/04Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
    • C07D455/06Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine containing benzo [a] quinolizine ring systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00Separation of optically-active compounds

Abstract

A method for resolution of tetrabenazine is disclosed. Racemic tetrabenazine is used as starting material and salified with D- or L-chiral acid to form the corresponding tetrabenazine enantiomer chiral acid salt according to dissolubility distinction. The tetrabenazine enantiomer chiral acid salt is further dissociated to obtain (3R,1 lbR)-tetrabenazine or (3S,1 lbS)-tetrabenazine with high optical purity.

Description

TECHNICAL FIELD resolution tetrabenazine

The present invention relates to the field of chemistry, particularly relates to a resolution process of tetrabenazine. Background technique

Tetrabenazine (Tetrabenazine, TBZ) benzo quinolizine derivatives, its chemical name is 2-oxo-3-isobutyl-9,10-dimethoxy-1, 2, 3, 4, 6, 7-hexahydro-benzo [[alpha]] quinolizine (see formula 1).

Figure imgf000002_0001
Tetrabenazine listed in Switzerland in the late fifties, was originally used to treat schizophrenia. After the period of time that clinical use, tetrabenazine is a dopamine receptor blockers. Tetrabenazine has been tested and found to have a more widespread use, especially in terms of hyperthyroidism motor function. In 2008, tetrabenazine became the first medication approved by the FDA for the treatment of Huntington's chorea. Tetrabenazine mainly through reversible inhibition of CNS monoamine transporter 2 (VMAT 2) to reduce monoamines, such as serotonin, dopamine and norepinephrine, thereby generating supply pharmacologically active. In addition to inhibiting tetrabenazine VMAT 2, but also on the presynaptic and postsynaptic dopamine receptors has some antagonism. Tetrabenazine is a safe and effective in treating a variety of hyperkinetic movement disorders drug, compared with conventional antipsychotic drugs, it does not cause tardive dyskinesia. However, tetrabenazine will still bring some dose-related side effects, such as sedation, Parkinson's disease, depression, insomnia, and akathisia and so on, all the side effects are reversible. Although tetrabenazine may cause some side effects, but the whole is still relatively safe, the probability of serious adverse events occur is very small, with better tolerability. Tetrabenazine has two chiral centers: 3 and lib bit. Because the bits 3 and lib when hydrogen is in the trans configuration are thermodynamically stable, it is listed tetrabenazine (3R, llbR) - tetrabenazine (see Formula 2) and (3S, llbS) - butylbenzene that triazine (see formula 3) racemic mixtures.

Figure imgf000003_0001

Tetrabenazine is rapidly metabolized in the body to become dihydrotetrabenazine (Dihydrotetrabenazine, DHTBZ), which is also its main active form. Because the tetrabenazine RR configurations and are racemic mixtures SS configuration, the dihydrotetrabenazine has four forms: (+) - - dihydrotetrabenazine (2R, 3R, llbR) ( see formula 4), (-) - - dihydrotetrabenazine (2S, 3S, llbS) (see formula 5), ​​(+) - β - dihydrotetrabenazine (2S, 3R, llbR) (see formula 6) and (-) - β _ dihydrotetrabenazine (2R, 3S, llbS) (see Equation 7).

Figure imgf000003_0002
Wherein the (+) _ - dihydrotetrabenazine (2R, 3R, llbR) (Formula 4) and VMAT 2 has the highest binding force, and reflect much stronger than the other three isomers in vivo experiments pharmacological activity (Mol Pharmacol 1987, 33, 72-77;... Eur J. Pharmacol 1995, 278, 249-252;.... Appl Radiat Isot 1993, 44, 1487-1489) o corresponding optically pure (3R, llbR) - tetrabenazine (formula 2) is also stronger than the activity of (3S, llbS) - tetrabenazine (formula 3). Since enantiomers are generally significant differences in terms of efficacy and safety of chiral drugs, therefore, the preparation of optically pure (3R, llbR) - tetrabenazine has important practical significance.

The conventional method of producing optically active tetrabenazine mainly by chiral column chromatography resolution method (W0 2008058261) or asymmetric synthesis methods (W0 2008154243; US 20080306267; US 20080306269;. J. Org Chem 2009, 74. , 4001-4004). Both the preparation of optically active tetrabenazine methods are not suitable for industrial production. Accordingly, an urgent need to establish an economical, simple method for the preparation of optically active tetrabenazine. SUMMARY

The present invention provides a method of resolving tetrabenazine. The method of tetrabenazine racemate material, dextrorotatory or levorotatory chiral acid addition salt thereof, to obtain the corresponding tetrabenazine chiral salt The difference in solubility, i.e. further dissociated to give the corresponding configuration tetrabenazine, the following formula:

Figure imgf000004_0001
Wherein, HX Representative dextrorotatory or levorotatory chiral acid.

As shown in the above formula, the present invention provides (3R, llbR) - tetrabenazine chiral salt (see Formula 8) or (3S, l lbS) - tetrabenazine chiral salt (see Formula 9 ) and its preparation method. The present invention provides (3R, llbR) - tetrabenazine or (3S, llbS) - Preparation of tetrabenazine, comprising: tetrabenazine racemate or left-handed and right-handed chiral acid in a solvent salification, crystallization was then cooled, filtered to give (3R, llbR) - tetrabenazine chiral acid or (3S, llbS) - tetrabenazine chiral acid salt with a solvent to give further recrystallized pure product, and then made basic alkaline aqueous solution, the dissociation generates (3R, llbR) - tetrabenazine - tetrabenazine or (3S, llbS).

Chiral acid employed can be selected from camphorsulfonic acid, tartaric acid, dibenzoyltartaric acid, 2 '- nitroaniline acid-tartaric acid, mandelic acid, malic acid, camphoric acid or phenoxy propionic acid. Precedence camphorsulfonic acid, camphoric acid, tartaric acid or dibenzoyl tartaric acid.

The molar ratio of tetrabenazine racemate with dextrorotatory or levorotatory chiral acid is from 1: 0.2 to 1.8, preferred molar ratio is from 1: 0.4 to 1.2.

With a chiral acid addition salt employed solvent selected from water, dichloromethane, acetonitrile, acetone, tetrahydrofuran, 1,2 - dichloro embankment acetate, chloroform, toluene,

Figure imgf000005_0001
R 2 0R3, one kind of R 2 0H or dioxane or more thereof. among them,! ^ Represents a hydrogen atom or a wide 5 carbon atoms, a straight-chain or branched-chain 'embankment group; R 2, R 3 independently represent a wide 5 carbon atoms, a straight-chain or branched-chain alkyl group, preferably water, methanol, ethanol, acetonitrile, acetone or a mixture of one or more of ethyl acetate as resolving solvent, more preferably ethyl acetate, methanol, acetonitrile or acetone as the solvent resolved.

Tetrabenazine racemate splitting ratio triazine and solvent is 1 g: 3 mlTlOO mL, preferably a ratio of 1 g: 10 mL~50 mLo

Tetrabenazine racemate triazine salified with a chiral acid to a temperature of 0 ° C ~ 150 "C, preferably salt-forming temperature of 20 ° C ~ 100 ° C.

In the above resolution process, the crystallization temperature - 20 ° C ~ 50. C, the crystallization temperature is preferably 5 ° C~35 ° C. The above-described resolution process precipitated in high purity (3R, llbR) - tetrabenazine or (3S, llbS) - tetrabenazine chiral acid dissociation can be directly prepared by (3R, llbR) - tetrabenazine or (3S, llbS) - tetrabenazine.

Further, the above resolution process can be precipitated as (3R, llbR) - tetrabenazine or (3S, llbS) - tetrabenazine chiral acid salt crude product in a suitable solvent one or more times recrystallization, recrystallization solvent employed may be selected from water, of dichloromethane, acetonitrile, acetone, tetrahydrofuran, 1,2-dichloroethane, chloroform, toluene,

Figure imgf000005_0002

R 2 0R 3, one kind of R 2 0H or dioxane or more thereof. among them,! ^ Represents a hydrogen atom or a wide 5 carbon atoms, a straight-chain or branched-chain alkyl; R 2, R 3 independently represent a wide 5 carbon atoms, a straight-chain or branched-chain 'embankment group, preferably water, methanol, ethanol, acetonitrile, one kind of acetone or ethyl acetate or a mixture of more as a recrystallization solvent, preferably ethyl acetate, methanol, acetonitrile or acetone as recrystallization solvent.

The method of the present invention is simple, low cost, high product purity obtained split, facilitate large-scale industrial production, a greater value. BRIEF DESCRIPTION

Chiral HPLC profiles of FIG. 1 that tetrabenazine racemate triazine;

FIG 2 (3R, llbR) - tetrabenazine chiral HPLC chromatogram;

FIG 3 (3S, llbS) - Chiral HPLC profiles of tetrabenazine. detailed description

The following further illustrate the present invention through examples, but the examples do not limit the scope of the present invention.

Melting points RY- type 1 melting point apparatus, the thermometer uncorrected; 1HNMR by BRUKER ACF-300 type nuclear magnetic resonance apparatus is completed (TMS internal standard). The optical purity was determined by Chiralpak IC chiral column (4.6 X 250 mm), mobile phase ethanol / diethylamine = 100 / 0.1, flow rate 0.5 mL / min. Example 1

Tetrabenazine racemate (0.3 g, 0.95 ππηοΐ) and (+) - camphor sulfonic acid (0.2 g, 0.95 ramol) was dissolved in 5 mL of acetone, refluxed for 30 minutes, cooled to room temperature crystallization, filtration to give a white crystalline (3R, llbR) - tetrabenazine (+) - camphorsulfonic acid salt (0.19 g). The salt was dissolved in 2 mL of methanol, adjusted to pH 8 with aqueous ammonia, then water was added to 15mL, and the precipitated solid was filtered, washed with water, and dried in vacuo at room temperature to afford (3R, llbR) - tetrabenazine, ee = 47.8%. Example 2

Tetrabenazine racemate (0.3 g, 0.95 recite OL) and (+) - camphor sulfonic acid (0.11 g, 0.48 mmol) was dissolved in 5 mL of acetone, refluxed for 30 minutes, cooled to room temperature crystallization, filtration to give white crystals (3R, llbR) - tetrabenazine (+) - camphorsulfonic acid salt (0.10 g), [a] +33.2 (MeOH); l H NMR (300 MHz, 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, 9.3 Hz), 2.28 (t, IH, 9.4 Hz), 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 salt was dissolved in 2 mL of methanol, adjusted to pH 8 with aqueous ammonia, then water was added to 15mL, and the precipitated solid was filtered, washed with water, and dried in vacuo at room temperature to give (3R, llbR) - tetrabenazine, ee = 98.4%. Example 3

Tetrabenazine racemate (0.8 g, 2.52 mmol) and (-) - camphor sulfonic acid (0.3 g, 1.29 mmol) was dissolved in 13 mL of acetone, refluxed for 30 minutes, cooled to room temperature crystallization, filtration to give a white crystalline (3S, llbS) - tetrabenazine (-) - camphorsulfonic acid salt (0.22 g), [a] D 25:. -36.4 (eOH) ¾ NMR (300 MHz, MeOD) δ: 6.86 (s , IH), 6.83 (s, IH), 4.51-4.38 (m, IH), 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 salt was dissolved in 3 mL of methanol, adjusted to pH 8 with aqueous ammonia, then water was added to 20 mL, and the precipitated solid was filtered, washed with water, and dried in vacuo at room temperature to give (3S, llbS) - tetrabenazine, ee = 97.7%. Example 4

(3R, llbR) - tetrabenazine (+) - camphorsulfonic acid salt (0.2 g, de = 96.8%) was suspended in 10 mL of water, under vigorous stirring with aqueous ammonia was adjusted to pH 8, the resulting solid was pumped It was filtered off, washed with water, and dried in vacuo at room temperature to afford (3R, llbR) - tetrabenazine (0.1 g, ee = 99.2%).¾ NMR (300 MHz, CDC1 3 ) δ: 6.62 (s, 1H), 6.55 (s, IH), 3.85 (s, 3H), 3.83 (s, 3H,), 3.51 (m, 1H), 3.29 (dd , IH, dead 6.2Hz, /*=11.5Hz), 3.17-3.06 (m , 2H), 2.90 (dd, IH, J a = 3.1 Hz, = 10.6 Hz), 2.77-2.49 (m, 4H), 2.35 (t, IH, 11.7 Hz), 1.85-1.76 (m, 1H), 1.71-1.59 (m, 1H), 1.08-0.99 (m, 1H), 0.93-0.89 (m, 6H). Example 5

(3R, llbR) - tetrabenazine (+) - camphorsulfonic acid salt (0.5 g, de = 98.1%) was dissolved in 1.5 mL of methanol, to the solution was adjusted with ammonia to pH 7.5-8, adding 15mL water, there are large amount of solid precipitate, stirred for 15 minutes, filtered off with suction, washed with water, and dried in vacuo at room temperature to afford (3R, llbR) - tetrabenazine (0.26 g, ee = 98.9% ), [a] D 25: +67.5 (MeOH) . Example 6

(3S, llbS) - tetrabenazine (-) - camphorsulfonic acid salt (0.6 g, de = 97.7%) was dissolved in 2.5 mL of methanol, the solution was adjusted with ammonia to pH 7.5-8, adding 15mL water, large amount of solid precipitate, stirred for 15 minutes, filtered off with suction, washed with water, and dried in vacuo at room temperature to give (3S, llbS) - tetrabenazine (0.3 g, ee = 98.1% ), [a] D 25: -65.7 (MeOH). 'Η Korea (300 MHz, CDC1 3): 6.62 (s, 1H), 6.55 (s, 1H), 3.85 (s, 3H), 3.82 (s, 3H,), 3.49 (m, 1H), 3.28 (dd , 1H, Ja = 6.2 Hz, J¾ = 11.5 Hz), 3.20-3.05 (m, 2H), 2.89 (dd, 1H, / a = 3.1 Hz, = 10.6 Hz), 2.79-2.48 (m, 4H), 2.35 (t, 1H, 11.6 Hz), 1.85-1.57 (m, 2H), 1.07-0.96 (m, 1H), 0.92-0.89 (m, 6H). Example 7

Tetrabenazine racemate (1.7 g, 5.36 mmol) and (+) - camphor sulfonic acid (0.62 g, 2.67 mmol) was dissolved in 23 mL of acetone, refluxed for 30 minutes, cooled to room temperature crystallization, filtration to give a white crystalline (3R, llbR) - tetrabenazine (+) - camphorsulfonate 0.8 g. The salt was suspended in 8 mL of acetone was stirred at reflux for 15 minutes, left at room temperature overnight, filtered off with suction to give (3R, llbR) - tetrabenazine (+) - camphorsulfonate 0.65g. The salt was dissolved in 2.6 mL of methanol, the solution was adjusted with ammonia to pH 8, was added 19 mL of water, a large number of solid precipitate, stirred for 15 minutes, filtered off with suction, washed with water, and dried in vacuo at room temperature to give a white solid (3R, llbR) - tetrabenazine (0.34 g, ee = 98.7%). Example 8

Tetrabenazine racemate (0.5 g, 1.6 mmol) and (+) _ camphorsulfonic acid (0.37 g, 1.6 mmol) was dissolved in 7 mL of acetone, refluxed for 30 minutes, cooled to 15 ° crystallization, filtration to give a white crystals 0.36 g. The crude salt was recrystallized twice after acetone (amount of acetone used each of 5 mL, heated to reflux to dissolve solids, then cooled crystallization) as a white solid (3R, llbR) - tetrabenazine (+) camphorsulfonic acid _ salt (50mg), [α] Λ +37.5 (MeOH)

The above-mentioned (3R, llbR) - tetrabenazine (+) _ camphorsulfonate is suspended in 5 mL of water, with a NaHC0 3 solution was adjusted to pH 8, and extracted with methylene burning (10 mL x 3), combined The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give (3R, llbR) - tetrabenazine, [a] +44.0 (CH 2 C1 2), ee = 98.60%. Tetrabenazine racemate (0.5 g, 1.6 mmol) and (+) - camphorsulfonic acid (0.37 g, 1.6 mmol) was dissolved in 6 mL of ethyl acetate, refluxed for 30 minutes, cooled to 5 degrees crystallization, filtration to give white crystals. The crude salt was recrystallized three times after acetone (amount of acetone used each of 5 mL, heated to reflux to dissolve solids, then cooled crystallization) as a white solid (3R, llbR) - tetrabenazine (+) - camphorsulfonic acid salt.

The above-mentioned (3R, llbR) - tetrabenazine (+) - camphorsulfonate are suspended in 5 mL of water, adjusted with aqueous N¾C0 3 solution to pH 8, extracted with ethyl acetate (10 mL x 3), the organic layer was over anhydrous sodium sulfate, filtered and evaporated to dryness to give (3R, llbR) - tetrabenazine. Example 10

Tetrabenazine racemate (0.5 g, 1.6 mmol) and (+) - camphorsulfonic acid (0.37 g, 1.6 mmol) was dissolved in 4 mL of methanol, refluxed for 30 minutes, crystallization was cooled to 5 ° and filtered to give a white crystals. The crude salt was recrystallized three times after acetone (amount of acetone used each of 5 mL, heated to reflux to dissolve solids, then cooled crystallization) as a white solid (3R, llbR) - tetrabenazine (+) - camphor sulfonic salt.

The above-mentioned (3R, llbR) - tetrabenazine (+) - camphorsulfonic acid salt was dissolved in 2mL of methanol, the solution was adjusted with ammonia to pH 8, adding water 10 mL, solid precipitate, stirred for 15 minutes, filtered off with suction, washed with water, and dried in vacuo at room temperature to afford (3R, Yee) - tetrabenazine. Example 11

Tetrabenazine racemate (0.5 g, 1.6 mmol) and (+) - camphorsulfonic acid (0.19 g, 0.8 mmol) was dissolved in 3 mL of acetonitrile, refluxed for 30 minutes, crystallization was cooled to 5 ° and filtered to give a white crystals. After the crude salt was recrystallized three times with propan-two (amount of acetone used each of 5 mL, heated to reflux to dissolve solids, then cooled crystallization) as a white solid (3R, llbR) - tetrabenazine (+) - camphor sulfonate.

The above-mentioned (3R, llbR) - tetrabenazine (+) - camphorsulfonic acid salt was dissolved in 2mL of methanol, the solution was adjusted with ammonia to pH 8, adding water 10 mL, solid precipitate, stirred for 15 minutes, filtered off with suction, washed with water, and dried in vacuo at room temperature to afford (3R, llbR) - tetrabenazine.

Claims

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1, resolution methods tetrabenazine, characterized in that the resolution method of racemic tetrabenazine material, dextrorotatory or levorotatory chiral acid salt in a solvent to give the corresponding tetrabenazine chiral piperazine salt, i.e. further dissociated to give the corresponding optically active configuration tetrabenazine, shown in the following formula:
Figure imgf000010_0001
Wherein, HX Representative dextrorotatory or levorotatory chiral acid.
2, according to the resolution method of claim 1, wherein said method tetrabenazine racemic and dextrorotatory or a levorotatory chiral acid was dissolved into a salt in a solvent, crystallization and then cooled and filtered to give (3R, llbR) - tetrabenazine chiral acid or (3S, llbS) - tetrabenazine chiral salt, to give the pure product was further recrystallized from a solvent; (3R, llbR) - tetrabenazine piperazine or chiral salt (3S, llbS) - a chiral salt with a solvent mixture of tetrabenazine, made alkaline with an alkaline aqueous solution, the dissociation generates (3R, llbR) - tetrabenazine or ( 3S, llbS) - tetrabenazine.
3. The method according to claim 1 or claim 2, wherein said acid is selected from chiral camphorsulfonic acid, tartaric acid, dibenzoyltartaric acid, 2 '- nitroaniline acid-tartaric acid, mandelic acid, malic acid, camphoric acid or phenoxy propionic acid.
4. The method of claim 3, wherein said chiral acid is camphorsulfonic acid, camphoric acid, tartaric acid or dibenzoyl tartaric acid.
5. The method of claim 1 or claim 2, wherein the molar ratio of tetrabenazine and racemic chiral acid is 1: 0.2 ~ 18, preferably a molar ratio of 1: 0 . 4~1. 2.
6. The method of claim 1 or claim 2, characterized in that the solvent used is selected from water, dichloromethane, acetonitrile, acetone, tetrahydrofuran, 1,2-dichloroethane embankment, chloroform, toluene, iota « ) 0, R 2 0R 3, one kind of R 2 0H or dioxane or more thereof; wherein the linear or branched alkyl group represents a hydrogen atom or a wide 5 carbon atoms; R 2, R 3 independently represent a wide 5 carbon atoms, straight-chain or branched-chain firing group, the preferred solvent is ethyl acetate, methanol, acetonitrile or acetone.
7. The method according to claim 1 or claim 2, characterized in that the ratio of triazine and solvent-butylbenzene was split 1 g: 3 mL ^ lOO mL, preferably a ratio of 1 g: 10 mL ~ 50 mL.
8. A method according to claim 1 or claim 2, characterized in that, (3R, llbR) - tetrabenazine or (3S, llbS) - tetrabenazine-triazine salified with a chiral acid to a temperature of 0 XT150 ° C, preferably salt-forming temperature of 20 TlOO. C.
9. The method of claim 1 or claim 2, characterized in that, (3R, llbR) - tetrabenazine or (3S, llbS) - tetrabenazine chiral salt crystallization temperature of -20 ° C ~ 50 V, preferably the crystallization temperature of 5 ° C~35. C.
10. The method of claim 2, characterized in that, (3R, llbR) - tetrabenazine or (3S, llbS) - tetrabenazine recrystallized chiral piperazine salt solvent is selected from water, dichloro methane, acetonitrile, acetone, tetrahydrofuran, 2 0R 3, of 6 - ring, or R 2 0H or a mixture of more dioxo-1,2-dichloro embankment acetate, chloroform, toluene, R OOR ^ R; where! ^ Represents a hydrogen atom or a wide 5 carbon atoms, a straight-chain or branched-chain alkyl; R 2, R3 independently represent a wide 5 carbon atoms, a straight-chain or branched-chain alkyl group, preferably the solvent is ethyl acetate, methanol, acetonitrile or acetone.
PCT/CN2011/001060 2009-07-15 2011-06-27 A method for resolution of tetrabenazine WO2012000308A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018067945A1 (en) 2016-10-06 2018-04-12 Assia Chemical Industries Ltd. Solid state forms of valbenazine

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008058261A1 (en) * 2006-11-08 2008-05-15 Neurocrine Biosciences, Inc. Substituted 3-isobutyl-9, 10-dimethoxy-1,3,4,6,7,11b-hexahydro-2h-pyrido[2,1-a] isoquinolin-2-ol compounds and methods relating thereto
WO2008154243A1 (en) * 2007-06-08 2008-12-18 General Electric Company Method for making tetrabenazine compounds
CN101985447A (en) * 2009-07-15 2011-03-16 中国药科大学 Resolution method of tetrabenazine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008058261A1 (en) * 2006-11-08 2008-05-15 Neurocrine Biosciences, Inc. Substituted 3-isobutyl-9, 10-dimethoxy-1,3,4,6,7,11b-hexahydro-2h-pyrido[2,1-a] isoquinolin-2-ol compounds and methods relating thereto
WO2008154243A1 (en) * 2007-06-08 2008-12-18 General Electric Company Method for making tetrabenazine compounds
CN101985447A (en) * 2009-07-15 2011-03-16 中国药科大学 Resolution method of tetrabenazine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ZHANGYU YAO ET AL.: "Preparation and evaluation of tetrabenazine enantiomers and all eight stereoisomers of dihydrotetrabenazine as VMAT2 inhibitors", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 46, no. 5, May 2011 (2011-05-01), pages 1841 - 1848, XP028370954, DOI: doi:10.1016/j.ejmech.2011.02.046 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018067945A1 (en) 2016-10-06 2018-04-12 Assia Chemical Industries Ltd. Solid state forms of valbenazine

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