WO2012000308A1

WO2012000308A1 - A method for resolution of tetrabenazine

Info

Publication number: WO2012000308A1
Application number: PCT/CN2011/001060
Authority: WO
Inventors: 孙宏斌; 姚彰彧
Original assignee: 中国药科大学
Priority date: 2010-06-29
Filing date: 2011-06-27
Publication date: 2012-01-05

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

Method for the resolution of tetrabenazine

The invention relates to the field of chemistry, and in particular to a method for resolution of tetrabenazine. Background technique

Tetrabenazine (TBZ) is a benzoquinazine derivative whose chemical name is 2-oxo-3-isobutyl-9, 10-dimethoxy-1, 2, 3, 4, 6, 7-Hexahydrobenzo[α]quinolizine (see Formula 1).

Terfenazin was marketed in Switzerland in the late 1950s and was originally used for the treatment of schizophrenia. After a period of clinical use, it was found that tetrabenazine is a dopamine receptor blocker. It has been tested and found that tetrabenazine has a wider range of uses, especially in terms of hyperkinesia. In 2008, tetrabenazine became the first drug in the United States to be approved by the FDA for the treatment of Huntington's disease. Tetrabenazine mainly reduces the supply of monoamines such as serotonin, dopamine and norepinephrine by reversibly inhibiting the monoamine transporter 2 (VMAT 2) of the central nervous system to produce pharmacological activity. In addition to inhibiting VMAT 2, tetrabenazine also has some antagonistic effects on presynaptic and postsynaptic dopamine receptors. Tebuconazine is a safe and effective drug for the treatment of various motor hyperactivity disorders. It does not cause tardive dyskinesia compared with traditional antipsychotics. However, tetrabenazine also causes some dose-related side effects such as sedation, Parkinson's syndrome, depression, insomnia, and meditation. All side effects are reversible. Although tetrabenazine may cause some side reactions, it is generally relatively safe, with a small chance of serious side effects and good tolerance. Terfenazin has 2 chiral centers: 3 and lib. Since the hydrogen in the 3 and lib positions is in a thermodynamically stable configuration, the listed tetrabenazine is (3R, llbR)-tetrabenazine (see formula 2) and (3S, llbS)-butylbenzene. A racemic mixture of naazine (see formula 3).

Tebuconazine is rapidly metabolized in the human body to dihydrotetrabenazine (DHTBZ), which is also its main active form. Because tetrabenazine is a racemic mixture of the RR configuration and the SS configuration, dihydrotetrabenazine is also available in 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 formula 7).

Among them, (+) _-dihydrotetrabenazine (2R, 3R, llbR) (Formula 4) has the highest binding affinity to VMAT 2 and is much stronger in vivo than the other three isomers. 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) - The activity of tetrabenazine (formula 2) is also stronger than that of (3S, llbS)-tetrabenazine (formula 3). Since the enantiomers of chiral drugs generally have significant differences in efficacy and safety, preparation of optically pure (3R, llbR)-tetrabenazine has important practical significance.

The existing methods for preparing optically active tetrabenazine are mainly by chiral column splitting method (W0 2008058261) or asymmetric synthesis method (W0 2008154243; US 20080306267; US 20080306269; J. Org. Chem. 2009, 74, 4001-4004). Both of the above methods for preparing optically active tetrabenazine are not suitable for industrial production. Therefore, there is an urgent need to establish an economical and simple method for preparing optically active tetrabenazine. Summary of the invention

The present invention provides a method for resolution of tetrabenazine. The method uses the racemic tetrabenazine as a raw material to form a salt with a right-handed or a left-handed chiral acid, and obtains the corresponding chiral acid salt of tetrabenazine according to the difference in solubility, and further dissociates to obtain a corresponding configuration. Tebufenazide, as shown below:

Among them, HX represents a right-handed or left-handed chiral acid.

As indicated by the above formula, the present invention provides chiral acid salts of (3R, llbR)-tetrabenazine (see formula 8) or (3S, l lbS)-tetrabenazine (see formula 9). And its preparation method. The invention provides a preparation method of (3R, llbR)-tetrabenazine or (3S, llbS)-tetrabenazine, comprising: dissolving the racemic tetrabenazine and the dextrorotatory or levodomic acid in a solvent. The salt is formed, then cooled and crystallized, and filtered to obtain a chiral acid salt of (3R, llbR)-tetrabenazine or a chiral acid salt of (3S, llbS)-tetrabenazine, which is further recrystallized with a solvent to obtain pure The product is adjusted to basic with an aqueous alkaline solution to form (3R, llbR)-tetrabenazine or (3S, llbS)-tetrabenazine.

The chiral acid used may be selected from camphorsulfonic acid, tartaric acid, dibenzoyltartaric acid, 2'-nitroaniline tartaric acid, mandelic acid, malic acid, camphoric acid or phenoxypropionic acid. Camphorsulfonic acid, camphoric acid, tartaric acid or dibenzoyltartaric acid is preferred.

The molar ratio of the racemic tetrabenazine to the right-handed or left-handed chiral acid is 1: 0.2 to 1.8, and the preferred molar ratio is 1: 0.4 to 1.2.

The solvent used for the salt formation with the chiral acid may be selected from the group consisting of water, dichloromethane, acetonitrile, acetone, tetrahydrofuran, 1,2-dichloroethane, chloroform, toluene,

A mixture of one or more of R ₂ 0R3, R ₂ 0H or dioxane. among them,! ^ a linear or branched 'fluorenyl group representing a hydrogen atom or 5 carbon atoms; R ₂ , R ₃ independently represent a straight or branched alkyl group having 5 carbon atoms, preferably water, methanol, ethanol, acetonitrile, A mixture of one or more of acetone or ethyl acetate is used as a resolving solvent, and more preferably ethyl acetate, methanol, acetonitrile or acetone is used as a resolving solvent.

The ratio of the racemate tetrabenazine to the resolution solvent is 1 g _: 3 ml TlOO mL, preferably in a ratio of 1 g : 10 mL to 50 mLo

The salt formation temperature of the racemic tetrabenazine and the chiral acid is from 0 °C to 150 °C, and the preferred salt formation temperature is from 20 °C to 100 °C.

In the above splitting process, the crystallization temperature is - 20 °C~50. C, a preferred crystallization temperature is 5 ° C to 35 ° C. The high purity (3R, llbR)-tetrabenazine or the chiral acid salt of (3S, llbS)-tetrabenazine precipitated during the above resolution can be directly dissociated (3R, llbR). - tetrabenazine or (3S, llbS) - tetrabenazine.

In addition, the crude (3R,llbR)-tetrabenazine or (3S,llbS)-tetrabenazine salt precipitated in the above resolution may be subjected to one or more times in a suitable solvent. The solvent used for recrystallization and recrystallization may be selected from the group consisting of water, dichloromethane, acetonitrile, acetone, tetrahydrofuran, 1,2-dichloroethane, chloroform, toluene,

A mixture of one or more of R ₂ 0R ₃ , R ₂ 0H or dioxane. among them,! ^ a linear or branched fluorenyl group representing a hydrogen atom or a broad 5 carbon atoms; R ₂ , R ₃ independently represent a straight or branched 'fluorenyl group having 5 carbon atoms, preferably water, methanol, ethanol, acetonitrile, a mixture of one or more of acetone or ethyl acetate as a recrystallization solvent Ethyl acetate, methanol, acetonitrile or acetone was selected as the recrystallization solvent.

The method of the invention has the advantages of simple operation, low cost, high purity of the product obtained by the separation, is advantageous for large-scale industrial production, and has great application value. DRAWINGS

Figure 1. Chiral HPLC chromatogram of the racemic tetrabenazine;

Figure 2 (3R, llbR) - Chiral HPLC chromatogram of tetrabenazine;

Figure 3 (3S, llbS) - Chiral HPLC chromatogram of tetrabenazine. detailed description

The invention is further illustrated by the following examples, but the examples do not limit the scope of protection of the invention.

The melting point was measured with a RY-1 type melting point apparatus, and the thermometer was not corrected; 1H NMR was performed with a BRUKER ACF-300 type nuclear magnetic resonance apparatus (TMS internal standard). The optical purity was determined using a Chiralpak IC chiral column (4.6 X 250 mm) with a mobile phase of ethanol/diethylamine = 100/0.1 at a flow rate of 0.5 mL/min. Example 1

The racemate tetrabenazine (0.3 g, 0.95 ππηοΐ) and (+)-camphorsulfonic acid (0.2 g, 0.95 ramol) were dissolved in 5 mL of acetone, refluxed for 30 minutes, then cooled to room temperature and crystallized. Crystal (3R, llbR) - (+)-camphorsulfonate of tetrabenazine (0.19 g). The salt was dissolved in 2 mL of methanol, adjusted to pH 8 with aqueous ammonia, and then 15 mL of water was added, and the precipitated solid was filtered, washed with water, and dried under vacuum at room temperature to obtain (3R, llbR) - tetrabenazine, ee = 47.8%. Example 2

The racemate tetrabenazine (0.3 g, 0.95 诵ol) and (+)-camphorsulfonic acid (0.11 g, 0.48 mmol) were dissolved in 5 mL of acetone, refluxed for 30 minutes, cooled to room temperature, and filtered. 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). Dissolve the salt in 2 mL of methanol, adjust the pH to 8 with ammonia water, add 15 mL of water, filter the precipitated solid, wash with water, and dry at room temperature under vacuum to obtain (3R, llbR) - tetrabenazine, ee =98.4%. Example 3

The racemate tetrabenazine (0.8 g, 2.52 mmol) and (-)-camphorsulfonic acid (0.3 g, 1.29 mmol) were dissolved in 13 mL of acetone, refluxed for 30 minutes, cooled to room temperature and crystallized. Crystal (3S, llbS) - (-)-camphorsulfonate of tetrabenazine (0.22 g), [a] D ²⁵ : -36.4 (eOH). 3⁄4 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). Dissolve in 3 mL of methanol, adjust the pH to 8 with ammonia water, add 20 mL of water, filter the precipitated solid, wash with water, and dry at room temperature under vacuum to obtain (3S, llbS) - tetrabenazine, ee = 97.7%. Example 4

(3R, llbR) - (+)-camphorsulfonate of tetrabenazine (0.2 g, de = 96.8%) suspended in 10 mL of water, adjusted to pH 8 with ammonia water under vigorous stirring, and the obtained solid was pumped Filtration, washing with water, vacuum drying at room temperature, (3R, llbR) - tetrabenazine (0.1 g, ee = 99.2%). 3⁄4 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, corpse 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) - (+)-camphorsulfonate of tetrabenazine (0.5 g, de = 98.1%) dissolved in 1.5 mL of methanol, adjusted to pH 7.5-8 with aqueous ammonia, and added to 15 mL of water. A large amount of solid precipitated, stirred for 15 minutes, suction filtered, washed with water, and dried under vacuum at room temperature to give (3R, llbR) - tetrabenazine (0.26 g, ee = 98.9%), [a] _D ²⁵ : +67.5 (MeOH) . Example 6

(3S, llbS) - tetrabenazine (-)-camphorsulfonate (0.6 g, de=97.7%) dissolved in 2.5 mL of methanol, adjusted to pH 7.5-8 with aqueous ammonia, added 15 mL of 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丽(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, J3⁄4=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

The racemate tetrabenazine (1.7 g, 5.36 mmol) and (+)-camphorsulfonic acid (0.62 g, 2.67 mmol) were dissolved in 23 mL of acetone, refluxed for 30 min, then cooled to room temperature and then filtered. Crystal (3R, llbR) - (+)-camphorsulfonate of tetrabenazine 0.8 g. The salt was suspended in 8 mL of acetone, stirred and refluxed for 15 minutes, allowed to stand at room temperature overnight, and filtered (3R, llbR) - butyl benzopyrazine (+)-camphorsulfonate 0.65 g. The salt was dissolved in 2.6 mL of methanol, the pH of the solution was adjusted to 8 with ammonia water, 19 mL of water was added, a large amount of solid was precipitated, stirred for 15 minutes, suction filtered, washed with water, and dried under vacuum at room temperature to obtain a white solid (3R, llbR) - Tebuconazine (0.34 g, ee = 98.7%). Example 8

The racemate tetrabenazine (0.5 g, 1.6 mmol) and (+)-camphorsulfonic acid (0.37 g, 1.6 mmol) were dissolved in 7 mL of acetone, refluxed for 30 minutes, cooled to 15 ° crystallization, filtered to give white The crystal was 0.36 g. The crude salt was recrystallized twice from acetone (5 mL per acetone, heated to reflux to dissolve the solid, and then cooled to crystallize) to give a white solid (3R, llbR) - tetrabenazine (-) Salt (50mg), [α] Λ +37.5 (MeOH)

The above (3R,llbR)-tetrabenazine (+)-camphorsulfonate was suspended in 5 mL of water, adjusted to pH 8 with NaHC0 ₃ , extracted with dichloromethane (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%. The racemate tetrabenazine (0.5 g, 1.6 mmol) and (+)-camphorsulfonic acid (0.37 g, 1.6 mmol) were dissolved in 6 mL ethyl acetate, refluxed for 30 min, cooled to 5 ° crystallization, filtered A white crystal was obtained. The crude salt was recrystallized from acetone three times (5 mL per acetone, heated to reflux to dissolve the solid, and then cooled and crystallized) to give a white solid (3R, llbR) - tetrabenazine (-)-camphorsulfonic acid salt.

The above (3R, llbR)-tetrabenazine (+)-camphorsulfonate was suspended in 5 mL of water, and the pH of the solution was adjusted to 8 with an aqueous solution of N3⁄4C0 ₃ and extracted with ethyl acetate (10 mL× ₃ ). The aqueous sodium sulfate was dried, filtered, and evaporated to dryness to give (3R, llbR) - tetrabenazine. Example 10

The racemate tetrabenazine (0.5 g, 1.6 mmol) and (+)-camphorsulfonic acid (0.37 g, 1.6 mmol) were dissolved in 4 mL of methanol, refluxed for 30 minutes, cooled to 5 ° crystallization, filtered to give white Crystal. The crude salt was recrystallized from acetone three times (5 mL per acetone, heated to reflux to dissolve the solid, and then cooled to crystallize) to give a white solid (3R, llbR) - tetrabenazine (but) Acid salt.

The above (3R, llbR)-tetrabenazine (+)-camphorsulfonate was dissolved in 2 mL of methanol, the pH of the solution was adjusted to 8 with aqueous ammonia, 10 mL of water was added, and a solid was precipitated, stirred for 15 minutes, and suction filtered. Washed, vacuum dried at room temperature, get (3R, discussion) - tetrabenazine. Example 11

The racemate tetrabenazine (0.5 g, 1.6 mmol) and (+)-camphorsulfonic acid (0.19 g, 0.8 mmol) were dissolved in 3 mL of acetonitrile, refluxed for 30 minutes, cooled to 5 ° crystallization, filtered to give white Crystal. The crude salt was recrystallized two times in C (3 mL per acetone, heated to reflux to dissolve the solid, and then cooled and crystallized) to give a white solid (3R, llbR) - tetrabenazine (+)-camphor Sulfonate.

The above (3R, llbR)-tetrabenazine (+)-camphorsulfonate was dissolved in 2 mL of methanol, the pH of the solution was adjusted to 8 with aqueous ammonia, 10 mL of water was added, and a solid was precipitated, stirred for 15 minutes, and suction filtered. Washed with water and dried under vacuum at room temperature to obtain (3R, llbR)-tetrabenazine.

Claims

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A method for dissolving tetrabenazine, characterized in that the resolution method uses racemic tetrabenazine as a raw material, and forms a salt with a right-handed or a left-handed chiral acid in a solvent to obtain a corresponding buprene. The chiral acid salt of the azine is further dissociated to obtain the optically active tetrabenazine of the corresponding configuration, as shown in the following formula:

Among them, HX represents a right-handed or left-handed chiral acid.

The method according to claim 1, wherein the method comprises dissolving the racemic tetrabenazine and the right-handed or left-handed chiral acid in a solvent to form a salt, then cooling and crystallization, and filtering. (3R, llbR) - a chiral acid salt of tetrabenazine or a chiral acid salt of (3S, llbS)-tetrabenazine, further recrystallized from a solvent to obtain a pure product; (3R, llbR) - tetrabenz a chiral acid salt of a azine or a chiral acid salt of (3S, llbS)-tetrabenazine, mixed with a solvent, using a base The aqueous solution is made alkaline and dissociated to form (3R, llbR)-tetrabenazine or (3S, llbS)-tetrabenazine.

3. The method according to claim 1 or 2, wherein the chiral acid is selected from the group consisting of camphorsulfonic acid, tartaric acid, dibenzoyltartaric acid, 2'-nitroaniline tartaric acid, mandelic acid, Malic acid, camphoric acid or phenoxypropionic acid.

4. The method according to claim 3, wherein the chiral acid is camphorsulfonic acid, camphoric acid, tartaric acid or dibenzoyltartaric acid.

The method according to claim 1 or 2, wherein the molar ratio of the racemic tetrabenazine to the chiral acid is 1:0.2 to 1.8, and the preferred molar ratio is 1:0. 4~1. 2.

The method according to claim 1 or 2, wherein the solvent used is selected from the group consisting of water, dichloromethane, acetonitrile, acetone, tetrahydrofuran, 1,2-dichloroethane, chloroform, toluene, hydrazine « a mixture of one or more of 0, R ₂ 0R ₃ , R ₂ 0H or dioxane; wherein, a linear or branched alkyl group representing a hydrogen atom or 5 carbon atoms; R ₂ , R ₃ independently represents a linear or branched fluorenyl group having 5 carbon atoms, and the preferred solvent is ethyl acetate, methanol, acetonitrile or acetone.

7. A method according to claim 1 or 2, characterized in that the ratio of tetrabenazine to the resolving solvent is 1 g: 3 mL ^ 100 mL, preferably in a ratio of 1 g : 10 mL to 50 mL.

The method according to claim 1 or 2, wherein the salt formation temperature of (3R, llbR)-tetrabenazine or (3S, llbS)-tetrabenazine and chiral acid is 0 XT150 ° C, a preferred salt formation temperature is 20 TlOO. C.

The method according to claim 1 or 2, wherein the (3R, llbR)-tetrabenazine or (3S, llbS)-tetrabenazine has a cleavage temperature of -20 ° C~50 V , the preferred crystallization temperature is 5 °C~35. C.

The method according to claim 2, wherein the recrystallization solvent of (3R, llbR)-tetrabenazine or (3S, llbS)-tetrabenazine salt is selected from the group consisting of water and dichloro a mixture of one or more of methane, acetonitrile, acetone, tetrahydrofuran, 1,2-dichloroacetamidine, chloroform, toluene, R OOR^ R ₂ 0R ₃ , R ₂ 0H or dioxane; ^A linear or branched fluorenyl group representing a hydrogen atom or a wide range of 5 carbon atoms; R ₂ and R 3 independently represent a linear or branched fluorenyl group having 5 carbon atoms; preferably the solvent is ethyl acetate, methanol, acetonitrile or acetone.