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A method for resolution of tetrabenazine
WO2012000308A1
WIPO (PCT)
Description
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丁苯那嗪的拆分方法 技术领域 Method for the resolution of tetrabenazine
本发明涉及化学领域， 具体涉及丁苯那嗪的拆分方法。 背景技术 The invention relates to the field of chemistry, and in particular to a method for resolution of tetrabenazine. Background technique
丁苯那嗪（Tetrabenazine, TBZ)是苯并喹嗪类衍生物， 它的化学名称为 2-氧 -3-异丁基 -9, 10-二甲氧基 -1, 2, 3, 4, 6， 7-六氢苯并 [ α ] 喹嗪（见式 1 )。 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).
丁苯那嗪在人体内迅速代谢成为二氢丁苯那嗪（Dihydrotetrabenazine, DHTBZ), 这也是它的主要活性形式。 因为丁苯那嗪是 RR构型和 SS构型的消旋体混合物， 所 以二氢丁苯那嗪也有四种形式： （+)- -二氢丁苯那嗪（2R，3R，llbR) (见式 4 )， (-) - -二氢丁苯那嗪（2S, 3S, llbS) (见式 5)， （+) - β -二氢丁苯那嗪（2S, 3R，llbR) (见式 6)和 (-) - β _二氢丁苯那嗪 (2R，3S，llbS) (见式 7)。 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).
现有的制备光学活性丁苯那嗪的方法主要是通过手性色谱柱拆分法 （W0 2008058261 )或不对称合成方法（W0 2008154243; US 20080306267； US 20080306269；
J. Org. Chem. 2009， 74， 4001-4004)。 上述两种制备光学活性丁苯那嗪的方法均 不适合于工业化生产。 因此， 迫切需要建立一种经济、 简便的制备光学活性丁苯那 嗪的方法。 发明内容 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
本发明提供了一种丁苯那嗪的拆分方法。该方法以消旋体丁苯那嗪为原料， 与右 旋或左旋手性酸成盐， 根据溶解度的差异获得相应的丁苯那嗪的手性酸盐， 进一步 解离即得到相应构型的丁苯那嗪， 如下式所示： 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:
如上式所示，本发明提供了（3R, llbR)-丁苯那嗪的手性酸盐 (见式 8)或 (3S, l lbS) -丁苯那嗪的手性酸盐（见式 9)及其制备方法。
本发明提供（3R,llbR) -丁苯那嗪或 (3S,llbS) -丁苯那嗪的制备方法， 包括： 将消旋体丁苯那嗪和右旋或左旋手性酸溶于溶剂中成盐， 然后冷却析晶， 过滤即得 到 （3R, llbR) -丁苯那嗪的手性酸盐或 (3S，llbS) -丁苯那嗪的手性酸盐， 用溶剂进 一步重结晶得到纯品， 再用碱性水溶液调至碱性， 解离生成（3R, llbR) -丁苯那嗪 或 (3S, llbS) -丁苯那嗪。 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.
所采用的手性酸可选自樟脑磺酸、 酒石酸、 二苯甲酰酒石酸、 2' -硝基苯胺酒 石酰胺酸、 扁桃酸、 苹果酸、 樟脑酸或苯氧丙酸。 优先采用樟脑磺酸、 樟脑酸、 酒 石酸或二苯甲酰酒石酸。 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.
消旋体丁苯那嗪与右旋或左旋手性酸的摩尔比为 1： 0.2~1.8， 优先选择的摩尔 比为 1 ： 0.4~1.2。 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.
与手性酸成盐所采用的溶剂可选自水、二氯甲烷、 乙腈、丙酮、 四氢呋喃、 1,2 - 二氯乙垸、 氯仿、 甲苯、
R20R3、 R20H或二氧六环中的一种或多种的混合物。 其中，！^代表氢原子或广 5个碳原子的直链或支链'垸基； R2， R3独立代表广 5个碳原 子的直链或支链烷基， 优选水、 甲醇、 乙醇、 乙腈、 丙酮或乙酸乙酯中的一种或多 种的混合物作为拆分溶剂， 更优选乙酸乙酯、 甲醇、 乙腈或丙酮作为拆分溶剂。 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.
消旋体丁苯那嗪与拆分溶剂的比例为 1 g : 3 mlTlOO mL, 优选比例为 1 g ： 10 mL〜50 mLo 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
消旋体丁苯那嗪与手性酸的成盐温度为 0 °C~150 "C, 优选的成盐温度为 20 °C~100 °C。 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.
在上述拆分过程中， 析晶温度为- 20 °C~50 。C, 优选的析晶温度为 5 °C〜35 °C。 将上述拆分过程中所析出的高纯度的 （3R，llbR) -丁苯那嗪或 (3S，llbS) -丁苯 那嗪的手性酸盐直接进行解离即可制备 （3R,llbR) -丁苯那嗪或 (3S, llbS) -丁苯那 嗪。 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.
此外， 也可将上述拆分过程中所析出的 （3R，llbR) -丁苯那嗪或 (3S，llbS) -丁 苯那嗪的手性酸盐粗品在适当溶剂中进行 1 次或多次重结晶， 重结晶所采用的溶剂 可选自水、二氯甲垸、乙腈、丙酮、四氢呋喃、 1,2-二氯乙烷、氯仿、 甲苯、
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,
R20R3、 R20H或二氧六环中的一种或多种的混合物。其中，！^代表氢原子或广 5个碳原 子的直链或支链垸基； R2， R3独立代表广 5个碳原子的直链或支链'垸基， 优选水、 甲醇、 乙醇、 乙腈、 丙酮或乙酸乙酯中的一种或多种的混合物作为重结晶溶剂， 优
选乙酸乙酯、 甲醇、 乙腈或丙酮作为重结晶溶剂。 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.
本发明方法操作简单， 成本低， 拆分得到的产品纯度高， 有利于规模化的工业 生产， 有较大的应用价值。 附图说明 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
图 1消旋体丁苯那嗪的手性 HPLC图谱； Figure 1. Chiral HPLC chromatogram of the racemic tetrabenazine;
图 2 (3R, llbR) -丁苯那嗪的手性 HPLC图谱； Figure 2 (3R, llbR) - Chiral HPLC chromatogram of tetrabenazine;
图 3 (3S,llbS) -丁苯那嗪的手性 HPLC图谱。 具体实施方式 Figure 3 (3S, llbS) - Chiral HPLC chromatogram of tetrabenazine. detailed description
下面通过实施例对本发明做进一步的说明， 但实施例并不限制本发明的保护范 围。 The invention is further illustrated by the following examples, but the examples do not limit the scope of protection of the invention.
熔点用 RY- 1型熔点仪， 温度计未校正； 1HNMR用 BRUKER ACF-300型核磁共振 仪完成 （TMS内标）。 光学纯度测定采用 Chiralpak IC手性柱（4.6 X 250 mm), 流 动相用乙醇 /二乙胺 =100/0.1， 流速为 0.5 mL/min。 实施例 1 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
消旋体丁苯那嗪（0.3 g， 0.95 ππηοΐ) 和（+)-樟脑磺酸（0.2 g, 0.95 ramol) 溶于 5 mL丙酮中， 回流 30分钟后， 冷却至室温析晶， 过滤得到白色晶体（3R，llbR) -丁苯那嗪的 (+)-樟脑磺酸盐（0.19 g)。 将该盐溶于 2 mL甲醇， 用氨水调 pH至 8， 再 加入水 15mL， 将析出的固体过滤， 水洗， 常温真空干燥， 得（3R，llbR) -丁苯那嗪， ee =47.8%。 实施例 2 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
消旋体丁苯那嗪 (0.3 g， 0.95誦 ol)和（+)-樟脑磺酸 (0.11 g， 0.48 mmol) 溶于 5 mL丙酮中， 回流 30分钟后， 冷却至室温析晶， 过滤得到白色晶体（3R，llbR) -丁苯那嗪 的（+)-樟脑磺酸盐 (0.10 g)， [a] +33.2 (MeOH)； lH 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). 将该盐溶于 2 mL甲醇， 用氨水调 pH至 8， 再加入水 15mL， 将析出的固体过滤， 水洗， 常温真空干燥， 得 （3R,llbR) -丁苯那 嗪， ee =98.4%。 实施例 3 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
消旋体丁苯那嗪 (0.8 g， 2.52 mmol)和（-) -樟脑磺酸（0.3 g, 1.29 mmol)溶 于 13 mL丙酮中， 回流 30分钟后， 冷却至室温析晶， 过滤得到白色晶体 (3S,llbS) - 丁苯那嗪 的 (-) -樟脑磺酸盐（0.22 g)， [a] D25: -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). 将该盐 溶于 3 mL甲醇， 用氨水调 pH至 8， 再加入水 20 mL， 将析出的固体过滤， 水洗， 常 温真空干燥， 得 (3S，llbS) -丁苯那嗪， ee =97.7%。 实施例 4 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) -丁苯那嗪 的（+)-樟脑磺酸盐 （0.2 g， de =96.8%) 悬浮于 10 mL 水中， 在剧烈搅拌下用氨水调至 pH 8， 将得到的固体抽滤， 水洗， 常温真空干燥， 得 （3R, llbR) -丁苯那嗪（0.1 g， ee =99.2%)。 ¾ NMR (300 MHz, CDC13) 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, 尸 6.2Hz， /*=11.5Hz), 3.17-3.06 (m, 2H), 2.90 (dd, IH, Ja=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). 实施例 5 (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) -丁苯那嗪 的 (+)-樟脑磺酸盐 (0.5 g， de =98.1%) 溶于 1.5 mL 甲醇中， 用氨水调溶液至 pH至 7.5-8， 加入 15mL水， 有大量固体析出， 搅拌 15分 钟， 抽滤， 水洗， 常温真空干燥， 得（3R，llbR) -丁苯那嗪（0.26 g， ee =98.9%)， [a] D 25: +67.5 (MeOH)。
实施例 6 (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) -丁苯那嗪的（-) -樟脑磺酸盐（0.6 g， de=97.7%)溶于 2.5 mL甲醇 中， 用氨水调溶液 pH至 7.5-8， 加入 15mL水， 有大量固体析出， 搅拌 15分钟， 抽 滤， 水洗， 常温真空干燥， 得 (3S, llbS) -丁苯那嗪 （0.3 g， ee =98.1%)， [a] D 25: -65.7 (MeOH)。 'Η丽 (300 MHz, CDC13) ： 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). 实施例 7 (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
消旋体丁苯那嗪（1.7 g， 5.36 mmol)和（+)-樟脑磺酸 （0.62 g, 2.67 mmol) 溶于 23 mL丙酮中，回流 30分钟后，冷却至室温析晶，过滤得到白色晶体（3R, llbR) -丁苯那嗪 的 (+)-樟脑磺酸盐 0.8 g。 将该盐悬浮在 8 mL丙酮中搅拌回流 15分钟， 室温放置过夜， 抽滤得（3R，llbR) -丁苯那嗪 的 (+)-樟脑磺酸盐 0.65g。 将该盐溶 于 2.6 mL甲醇中， 用氨水调溶液 pH至 8， 加 19 mL水， 有大量固体析出， 搅拌 15 分钟， 抽滤， 水洗， 常温真空干燥， 得白色固体（3R,llbR) -丁苯那嗪（0.34 g， ee =98.7%)。 实施例 8 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
消旋体丁苯那嗪（0.5 g， 1.6 mmol)和（+)_樟脑磺酸 （0.37 g, 1.6 mmol) 溶于 7 mL丙酮中， 回流 30分钟， 冷却至 15度析晶， 过滤得到白色晶体 0.36 g。 该粗 品盐经过丙酮两次重结晶 （每次丙酮用量为 5 mL, 加热至回流溶解固体， 再冷却析 晶）得白色固体（3R,llbR) -丁苯那嗪 的 (+)_樟脑磺酸盐（50mg)， [α] Λ +37.5 (MeOH) 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)
将上述（3R,llbR) -丁苯那嗪 的 (+)_樟脑磺酸盐悬浮于 5 mL水中， 用 NaHC03调 溶液 pH至 8， 用二氯甲烧萃取 （10 mL x 3), 合并有机层用无水硫酸钠干燥， 过滤， 蒸干得 (3R, llbR) -丁苯那嗪， [a] +44.0 (CH2C12), ee =98.60%。
消旋体丁苯那嗪（0.5 g， 1.6 mmol)和（+)-樟脑磺酸 （0.37 g， 1.6 mmol) 溶于 6 mL乙酸乙酯中， 回流 30分钟， 冷却至 5度析晶， 过滤得到白色晶体。 该粗品盐 经过丙酮 3次重结晶 （每次丙酮用量为 5 mL, 加热至回流溶解固体， 再冷却析晶）得 白色固体（3R，llbR) -丁苯那嗪 的 (+)-樟脑磺酸盐。 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.
将上述（3R,llbR) -丁苯那嗪 的 (+)-樟脑磺酸盐悬浮于 5 mL水中， 用 N¾C03水 溶液调溶液 pH至 8， 用乙酸乙酯萃取（10mLx3)， 有机层用无水硫酸钠干燥， 过滤， 蒸干， 得 (3R,llbR) -丁苯那嗪。 实施例 10 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
消旋体丁苯那嗪（0.5 g， 1.6 mmol)和（+)-樟脑磺酸 （0.37 g, 1.6 mmol) 溶于 4 mL甲醇中， 回流 30分钟， 冷却至 5度析晶， 过滤得到白色晶体。 该粗品盐经过 丙酮 3次重结晶 （每次丙酮用量为 5 mL, 加热至回流溶解固体， 再冷却析晶），得白 色固体（3R，llbR) -丁苯那嗪 的 (+)-樟脑磺酸盐。 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.
将上述（3R,llbR) -丁苯那嗪 的 (+)-樟脑磺酸盐溶于 2mL甲醇中， 用氨水调溶 液 pH至 8， 加水 10 mL, 有固体析出， 搅拌 15分钟， 抽滤， 水洗， 常温真空干燥， 得 (3R,議) -丁苯那嗪。 实施例 11 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
消旋体丁苯那嗪 （0.5 g， 1.6 mmol) 和（+)-樟脑磺酸 （0.19 g, 0.8 mmol)溶 于 3 mL乙腈中， 回流 30分钟， 冷却至 5度析晶， 过滤得到白色晶体。 该粗品盐经过丙 兩 3次重结晶 （每次丙酮用量为 5 mL, 加热至回流溶解固体， 再冷却析晶） ，得白色 固体（3R,llbR) -丁苯那嗪 的 (+)-樟脑磺酸盐。 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.
将上述（3R,llbR) -丁苯那嗪 的 (+)-樟脑磺酸盐溶于 2mL甲醇中， 用氨水调溶 液 pH至 8， 加水 10 mL, 有固体析出， 搅拌 15分钟， 抽滤， 水洗， 常温真空干燥， 得 (3R, llbR) -丁苯那嗪。
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.
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1、 丁苯那嗪的拆分方法， 其特征在于， 所述拆分方法以消旋的丁苯那嗪为原料， 与右旋或左旋手性酸在溶剂中成盐， 得到相应丁苯那嗪的手性酸盐， 进一步解离即得 到相应构型的光学活性丁苯那嗪， 如下式所示： 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:
其中， HX代表右旋或左旋手性酸。 Among them, HX represents a right-handed or left-handed chiral acid.
2、根据权利要求 1所述的拆分方法， 其特征在于， 所述方法将消旋的丁苯那嗪与 右旋或左旋手性酸溶于溶剂中成盐， 然后冷却析晶， 过滤得到 (3R, llbR) -丁苯那嗪的 手性酸盐或（3S，llbS) -丁苯那嗪的手性酸盐， 用溶剂进一步重结晶得到纯品； (3R, llbR) -丁苯那嗪的手性酸盐或 (3S, llbS) -丁苯那嗪的手性酸盐与溶剂混合， 用碱 性水溶液调至碱性， 解离生成 （3R, llbR) -丁苯那嗪或 （3S, llbS) -丁苯那嗪。 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、 根据权利要求 1或 2所述的方法， 其特征在于， 所述手性酸选自樟脑磺酸、酒 石酸、 二苯甲酰酒石酸、 2' -硝基苯胺酒石酰胺酸、 扁桃酸、 苹果酸、 樟脑酸或苯氧 丙酸。 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、 根据权利要求 3所述的方法， 其特征在于， 所述手性酸为樟脑磺酸、 樟脑酸、 酒石酸或二苯甲酰酒石酸。 4. The method according to claim 3, wherein the chiral acid is camphorsulfonic acid, camphoric acid, tartaric acid or dibenzoyltartaric acid.
5、根据权利要求 1或 2所述的方法， 其特征在于， 消旋的丁苯那嗪与手性酸的摩 尔比为 1 ： 0. 2~1. 8, 优选的摩尔比为 1 ： 0. 4〜1. 2。 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.
6、根据权利要求 1或 2所述的方法， 其特征在于， 所采用的溶剂选自水、 二氯甲 烷、 乙腈、 丙酮、 四氢呋喃、 1， 2-二氯乙垸、 氯仿、 甲苯、 Ι« )0 、 R20R3、 R20H或二 氧六环中的一种或多种的混合物； 其中， 代表氢原子或广 5个碳原子的直链或支链 烷基； R2， R3独立代表广 5个碳原子的直链或支链焼基， 优选溶剂为乙酸乙酯、 甲醇、 乙腈或丙酮。 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、根据权利要求 1或 2所述的方法， 其特征在于， 丁苯那嗪与拆分溶剂的比例为 1 g ： 3 mL^lOO mL, 优选比例为 1 g ： 10 mL~50 mL。 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.
8、 根据权利要求 1 或 2 所述的方法， 其特征在于， （3R, llbR) -丁苯那嗪或 (3S, llbS) -丁苯那嗪与手性酸的成盐温度为 0 XT150 °C，优选的成盐温度为 20 TlOO 。C。 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.
9、 根据权利要求 1 或 2 所述的方法， 其特征在于， （3R, llbR) -丁苯那嗪或 (3S, llbS) -丁苯那嗪的手性酸盐析晶温度为 -20 °C~50 V , 优选的析晶温度为 5 °C〜35 。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.
10、根据权利要求 2所述的方法,其特征在于，（3R， llbR) -丁苯那嗪或 （3S, llbS) - 丁苯那嗪手性酸盐的重结晶溶剂选自水、 二氯甲烷、 乙腈、 丙酮、 四氢呋喃、 1，2-二 氯乙垸、 氯仿、 甲苯、 R OOR^ R20R3、 R20H或二氧六环中的一种或多种的混合物； 其 中， ！^代表氢原子或广 5个碳原子的直链或支链垸基； R2， R3独立代表广 5个碳原子的 直链或支链垸基， 优选溶剂为乙酸乙酯、 甲醇、 乙腈或丙酮。 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.