CN1210262C - 1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇的甲磺酸盐三水合物的制备方法 - Google Patents
1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇的甲磺酸盐三水合物的制备方法 Download PDFInfo
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Abstract
本发明涉及一种制备式(I)化合物(1S,2S)-1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇的甲磺酸盐三水合物的方法。本发明还进一步涉及式(I)化合物的D-(-)酒石酸盐的对映体拆分和分离方法。
Description
本发明涉及一种由其D-(-)-酒石酸盐制备式(I)的化合物(1S,2S)-1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇的甲磺酸盐三水合物的方法:
式(I)化合物(1S,2S)-1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇表现出作为NMDA(N-甲基-D-天门冬氨酸)受体拮抗剂的有效活性,并且适用于治疗癫痫、焦虑、脑局部缺血、肌肉痉挛、多梗塞性痴呆、创伤性脑损伤、疼痛、AIDS相关性痴呆、低血糖、偏头痛、肌萎缩性侧索硬化、药物和酒精成瘾、药物和酒精戒断综合征、精神病症、尿失禁和变性CNS(中枢神经系统)紊乱如中风、阿耳茨海默氏病、帕金森氏病和杭廷顿氏舞蹈病。
(1S,2S)-1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇的甲磺酸盐三水合物形式作为活性治疗剂,是因为其特性优于无水甲磺酸盐。甲磺酸盐三水合物具有比无水甲磺酸盐更加稳定的晶形,因此,实质上保存期较长。另外该三水合物在结晶结构中不易被破坏,这归因于该结晶中包合有水。美国专利号6008233公开了(1S,2S)-1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇的甲磺酸盐三水合物、无水甲磺酸盐和游离碱,以及它们的制备方法。
而且,游离碱、无机甲磺酸盐及其制备方法还全面公开在美国专利号US5185343中,该专利在1993年2月9日授权。其在治疗某些上述疾病中的应用特别公开在美国专利号US5272160中,该专利于1993年12月21日授权;和国际专利申请PCT/IB 95/00380中,该申请指定美国,提交于1995年5月18日并且公开为WO 96/06081。其与能够提高且由此复原由丘脑的腹侧神经核进入皮层的兴奋性反馈的平衡来治疗帕金森氏病的化合物的联合应用公开在国际专利申请PCT/IB 95/00398中,该中请指定美国,提交于1995年5月26日并且公开为WO 96/37226。上述美国专利和专利申请在此全文引入作为参考。
发明概述
本发明涉及一种(1S,2S)-1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇的甲磺酸盐三水合物的制备方法:
该方法包括步骤:
(i)将(1S,2S)-1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇的D-(-)-酒石酸盐溶解在甲磺酸水溶液中;和
(ii)由该溶液中分离出甲磺酸盐三水合物。
在上述方法中,甲磺酸与(1S,2S)-1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇的D-(-)酒石酸盐的摩尔比例优选为1.3至1.0。更优选甲磺酸与(1S,2S)-1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇的D-(-)-酒石酸盐的摩尔比例为1.10至1.05;首选在1.10至1.08之间。
在本发明的方法中,步骤(i)的甲磺酸水溶液适宜采用无热原水制成。
本发明还涉及制备(1S,2S)-1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇的甲磺酸盐三水合物的任何上述方法,其中进一步包括步骤:
(i)将含有式(I)和(II)的化合物的外消旋混合物
在D-(-)-酒石酸的存在下溶解在含水甲醇中;和
(ii)由溶液中分离出(1S,2S)-1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇的D-(-)酒石酸盐。在这种方法中,含水甲醇适宜具有5-20%体积的含水量。更优选的实施方案是其中含水甲醇具有7-10%体积的含水量。本发明也涉及式(I)化合物的(D)-(-)-酒石酸盐的对映体拆分和分离的处理步骤。
本发明还涉及式(I)化合物(1S,2S)-1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇的D-(-)-酒石酸盐:
其中(1S,2S)-对映异构体与(1R,2R)-对映体的比例大于97%。更优选(1S,2S)-对映异构体与(1R,2R)-对映体的比例大于98%。
发明详述
(1S,2S)-1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇的甲磺酸盐三水合物为白色结晶固体,其具有单一晶形和在水中良好的溶解度(在pH3和7的缓冲水溶液中溶解度分别为25和15mg/ml)。已知当无水甲磺酸盐在相对湿度为81%的环境中时,可平衡生成甲磺酸盐三水合物。甲磺酸盐三水合物的早期制备方法,如美国专利号US6003233所述,需要采用游离碱作为起始原料,这就在式(I)的游离碱化合物在对映体拆分后分离和干燥的总合成中要求另加该步骤。
然而,本发明能够无需经过游离碱就可直接由(1S,2S)-1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇的D-(-)-酒石酸盐制备甲磺酸盐三水合物。上述方法中所用的D-(-)-酒石酸盐是消旋(1S,2S)-1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇的对映体拆分的产物。所以,本发明提供一种更有效且步骤较少的甲磺酸盐合成方法。
本发明的方法进-步包括(1S,2S)-1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇的D-(-)-酒石酸盐的改进的拆分方法。用于拆分(1S,2S)-1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇消旋体的早先方法如美国专利US6003233包括用旋光酒石酸盐由无水甲醇进行选择性结晶,并且几乎随后都需要重制(结晶)浆和/或重结晶,以获得(1S,2S)达97%或更好的可接受的对映纯度。因此,本发明提供一种省略重复纯化步骤、且在总合成路线中更有效的方式。
下列反应路线举例说明本发明的方法。
路线1
参见路线1,消旋的式(III)苄基保护的酮化合物处于还原条件下,或是用NaBH4在乙醇中于40-50℃下6-7小时或是用selectide钾(CalSelect K)在四氢呋喃中于10-20℃下1-2小时,或任何其它所属领域技术人员已知的湿度试剂和条件下,得到苏型和赤型异构体的混合物,其中苏型异构体以约80∶20或更好的比例在粗反应混合物中占优势。乙醇或THF溶剂中应不含有可感知量的水分,即不超过0.2-0.5%的水分。在由溶剂实际分离后,可以得到近90%苏型定向的产物,即苏型组分为式(IVA)化合物的外消旋混合物(即IVA-1和IVA-2)。采用美国专利号US6008233所述方法获得式(III)的起始原料,该专利在上文中提及并且在此全文作为参考。
参见路线2,通过所属领域技术人员的任何已知方式,由式(IVA)的苏型化合物脱除苄基,优选通过暴露在氢解条件下,首选在氢气的存在下于四氢呋喃中和45-50℃下在碳载钯下暴露5-6小时。所属领域技术人员将了解其它脱除苄基的有效方式。
路线2
上述还原反应的产物,式(I)和(II)的对映体的外消旋混合物随后经过D-(-)-酒石酸盐的生成和选择性结晶而被拆分。由外消旋体(I和II)的无水甲醇溶液通过将该甲醇溶液加热至约50-55℃、进而缓慢加入D-(-)-酒石酸在水中的溶液,可直接制得(1S,2S)-1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇的D-(-)-酒石酸盐(VA)。此后将混合物加热至约60-65℃,可以选择性地加入少量(1S,2S)-1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇的D-(-)-酒石酸盐来促进D-(-)-酒石酸盐的生成。将该混合物在回流温度(60-65℃)下保持约4小时,期间形成稠混悬液。缓慢冷却该浆液,通过过滤收集固体并且用甲醇洗涤。该过程得到(1S,2S)-1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇的D-(-)-酒石酸盐,其具有等于或小于2%的对映体或非对映体杂质。水和甲醇的比例应调至在终溶液中为5-20%体积,优选7-10%体积的水/甲醇。表1显示采用含水甲醇而不是无水甲醇作为溶剂可显著提高D-(-)-酒石酸盐的对映体纯度,如表1所示,可需要至多两次重制浆或重结晶来获得相似水平的(1S,2S)-1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇的D-(-)-酒石酸盐的对映体纯度。
表1.对比在甲醇和含水甲醇中用D-(-)-酒石酸盐拆分外消旋体(化合物I和II)
D-酒石酸 反应
溶剂
摩尔当量 (mL/g粗 时间 温度 收率 需要的重 %-(1R,2R)-对
I/II) 制浆 映体
1.0 甲醇(20) 3小时 65℃ 78% 1 1.8%
1.0 甲醇(20) 3小时 65℃ 78% 1 2.0%
1.0 甲醇(20) 5小时 65℃ 76% 2 1.2%
1.0 甲醇(20) 5.5小时 65℃ 73% 2 1.7%
1.03 甲醇(18) 3.5小时 65℃ 88% 0 2.5%
水(1.6)
1.03 甲醇(18)/ 3.5小时 65℃ 80% 0 1.1%
水(1.6)
实施例1中举例说明了在含水甲醇中拆分消旋1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇形成(1S,2S)-1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇的D-(-)-酒石酸盐,尤其是不含有相应(1R,2R)和其它非对映异构体。实施例2提供采用无水甲醇作为溶剂的参比方法。
路线3
参见路线3,通过将D-(-)-酒石酸盐溶解在存在于1.00-1.15摩尔当量,优选1.05-1.10摩尔当量甲磺酸的水中,将该混合物加热至约60-65℃,随后过滤该溶液除去任何外源性颗粒物,可由D-(-)-酒石酸盐直接生成(1S,2S)-1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇的甲磺酸盐三水合物。所述热溶液此后缓慢冷却至15-20℃得到稠的白色混悬液,进一步冷却至0-5℃,并且在0-5℃下成颗粒1小时。通过过滤分离该产物后,用冷水(0-5℃)洗涤,在惰性气氛下干燥该甲磺酸盐。表2显示出在不同的甲磺酸与(1S,2S)-1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇的摩尔当量比例下进行的甲磺酸盐三水合物的制备。
表2.由式VA的化合物制备式VI的化合物
当量 水 收率 对映体 非对映体
化合物(VA) CH3SO3H 体积 化合物(VI) 起始 最终 起始 最终
(mol) (Mol) (mL/g VA)
1.0 1.0 3.5 89.0%(混浊) 1.7% 0.19% 0.4% 0.13
1.0 1.05 3.5 90.4%(混浊) 1.7% 0.05% 0.4% 0.08
1.0 1.10 3.5 93.8% 1.7% 0.05% 0.4% 0.08
1.0 1.15 3.25 92.4% 2.5% 0.07% 0.2% -
1.0 1.10 4.0 84.8% 3.2% 0.18% - <0.1%
1.0 1.15 3.25 87.0% 4.4% 0.68% 0.2% 0.18
VI的重结晶 1.5 91.9% 0.68% 0.1% 0.18% 0.02
与无水甲磺酸盐和游离碱相似,基于其抗局部缺血活性和阻断兴奋性氨基酸受体的能力,甲磺酸盐三水合物具有选择性神经保护作用。评估该化合物神经保护作用的优选方法如Ismail A.Shalaby等人在《药理学与实验治疗学杂志》260,925(1992)中所述。该文献在此全文引入作为参考并且如下文所述。
细胞培养 17天胎鼠(CD,Charles River BreedingLaboratories,Inc.,Wilmington,Mass)海马细胞在血清中于PRIMARIA培养平板(Falcon Co.,lincoln Park,N.J.)上培养2-3周,血清中含有培养基(含有非必需氨基酸的极限必需培养基,含有2mM谷酰胺、21mM葡萄糖、青霉素/链霉素(分别5000U)、10%胎牛血清(1-17天)和10%马血清(1-21天))。将细胞或者以80,000细胞/孔的密度铺在96孔微量滴定平板上,或以250,000细胞/孔的密度铺板在24孔培养平板上。培养物在37℃下在含有5%CO2/95%空气的加温CO2组织培养恒温箱中生长。通过在第6至8天向培养物中加入20μM尿苷和20μM5-氟-2-脱氧尿苷(Sigma Chemical Co.,St.Louis,Mo.)来控制非神经元细胞的增殖。用每2至2天用新鲜储备液更换培养介质。
谷氨酸盐毒性 由开始铺板2-4周对培养物进行谷氨酸盐的毒性。除去培养介质并且用CSS(以毫摩尔计)将培养物漂洗2次:NaCl12-;KCl,5.4;MgCl2,0.8;CaCl2,1.8;葡萄糖,15;和4-(2-羟乙基)-1-哌嗪乙磺酸,25mM(pH7.4)。随后令培养物暴露在不同浓度的谷氨酸盐下15分钟(37℃)。温育后,用无谷氨酸盐CSS将培养物漂洗3次并且用无血清的新鲜培养基漂洗2次。随后将该培养物在无血清的培养基中培养20至24小时。加入2分钟后并且在暴露于谷氨酸盐下15分钟期间对化合物进行试验。在一些实验中,在暴露于谷氨酸盐后和随后20-24小时内在不同时间加入化合物。
一般是在兴奋毒素(excitotoxin)暴露后20-24小时内通过测定胞质酶LDH(乳酸脱氢酶)的活性来评估细胞的生存力。由96孔微量滴定平板的各孔的培养基来测定LDH活性。将50μl的培养基样品加入等体积的磷酸钠缓冲液(0.1M,pH7.4)中,该缓冲液含有1.32mM丙酮酸钠和2.9mM NADH。利用自动分光光度微量滴定平板读数器(Molecular Devices;Menlo Park,Calif.)在2分钟内每5秒监测96孔各孔中总反应混合物在340nm下的吸光度。利用IBM SOFTmax程序(1.01版;Molecular Devices)自动计算吸光率并且用作LDH活性的指标。
利用片段对比显微法(phase contrast microscopy)测定神经元生存力的形态学评估。96孔培养平板无法得到良好的片段对比成象,出于此目的在24孔平板上进行培养。数量上,两种培养平板对于谷氨酸盐毒性同样敏感,并且在暴露于0.1至1.0mM谷氨酸盐24小时后LDH的活性提高了2至3倍。
试剂 DTG可购自Aldrich Chemical Company(Milwaukee,Wis.),并且氟哌啶醇得自Research Biochemicals In.(Natick,Mass.)。精胺可购自Sigma Chemical Co.(St.Louis Mo.)。马和胎牛血清可购自Hyclone(Logan,Utah)。培养基、谷酰胺和青霉素/链霉素可购自Gibco Co.(Grand Island,N.Y.)。
数据分析 通过测定在暴露到谷氨酸盐20至24小时后培养基中存在的LDH的活性,可以定量测出神经毒性。培养基中提高的LDH活性与神经元的破坏和变性相关(Koh & Choi,1987)。由于LDH的实际水平因不同的培养而改变,所以通常相对于同一培养平板的缓冲液处理姐妹孔来表示数据。为了由谷氨酸盐和药物处理培养物获得LDH活性的指标,应从处理组的LDH值减去对照培养物的LDH值。对于各试验药物,处理的数据表示为由1mM谷氨酸盐(或NMDA)诱发的LDH增量的百分率。利用对数-概率单位分析,由三个独立试验的合并结果计算出逆转半数兴奋毒素诱发性LDH增量所需要的NMDA拮抗剂浓度。
本发明甲磺酸盐三水合物的选择性神经保护性抗缺血和兴奋氨基酸阻断活性使其可有效治疗选自下列的疾病:变性CNS紊乱如中风、阿耳茨海默氏病、帕金森氏病和杭廷顿氏舞蹈病;癫痫、焦虑、脑局部缺血、肌肉痉挛、多梗塞性痴呆、创伤性脑损伤、疼痛、AIDS相关性痴呆、低血糖、偏头痛、肌萎缩性侧索硬化、药物和酒精成瘾、药物和酒精戒断综合征、精神病症和尿失禁。
在上述疾病的全身性治疗中,剂量一般为约0.02至250mg/kg·天(在体重为50kg的典型人体中为0.001-12.5g/天),剂量可以是一次或分次给药,与给药途径无关。更优选的剂量范围是约0.15mg/kg·天至约250mg/kg·天。显然,根据疾病的确切本质和患者的状况,主治医生可以指定超出这个范围的剂量。通常优选口服给药途径,采取片剂、硬或软明胶胶囊、混悬液、颗粒剂、散剂等的形式;或肠胃外给药,以可注射溶液或混悬液等的形式;和局部给药,以溶液、洗剂、软膏、油膏等的形式。
下列实施例举例说明本发明的方法和本发明化合物的制备。熔点未经校正。NMR数据以每百万的份数(ppm)(δ)计并且参比于样本溶剂(全氘代二甲基亚砜(d6-DMSO),除非另外说明)的氘固定信号。所用市售试剂无需进一步纯化。
实施例1
用D-(-)-酒石酸在含水甲醇中拆分1-(4-羟苯基)-2-(4-羟基-4-苯
基哌啶-1-基)-1-丙醇
消旋1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇(78.0kg,207.7mol)和无水甲醇(1223L)加入保持在氮气氛下的洁净反应釜中。搅拌该化合物且加热至50-55℃。使该溶液在50-55℃下保持1小时后,在10分钟内加入D-(-)-酒石酸(32.1kg,214mol)在水(105L)中的溶液。将该反应加热至60-65℃且加入存在于甲醇(0.5L)中的(1S,2S)-1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇的D-(-)-酒石酸盐。令该溶液在回流(60-65℃)下保持4小时,期间生成稠的混悬液。在1.5小时内使该浆液冷却至30-35℃并且在30-35℃下过滤。用甲醇(204L)洗涤滤饼且随后在40-45℃下真空干燥20-30小时。分离出(1S,2S)-1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇的D-(-)-酒石酸盐,收率为40%(重量)(理论值的80%)。[α]D 25=35.2(0.0185,水)。手性HPLC显示,固体中含有1.2%的(1R,2R)-对映体和0.8%的(1R,2S)-和(1S,2R)-非对映异构体。
实施例1
用D-(-)-酒石酸在无水甲醇中拆分1-(4-羟苯基)-2-(4-羟基-4-苯
基哌啶-1-基)-1-丙醇
向维持在氮气氛下的适当烧瓶中加入1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇(189.5g,0.58mol)和甲醇(3.8L)。将该混合物加热至50-55℃,随后加热D-(-)-酒石酸(87.0g,0.58mol)。该混合物在回流(~65℃)下加热5小时。使浆液冷却至30-35℃,随后在30-35℃下成颗粒1小时。过滤出产物,滤饼用新鲜甲醇(135ml)洗涤。由湿滤饼取样进行手性HPLC分析以测定对映体纯度水平。将湿滤饼悬浮在甲醇(1.6L)中,所得浆液在回流(~65℃)和氮气氛下加热5小时。冷却该浆液至30-35℃,在30-35℃成颗粒1小时,随后过滤。用甲醇(136L)洗涤滤饼且随后在40-45℃下真空干燥18-24小时。取样进行手性HPLC分析。得到(1S,2S)-1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇(118.0g)的D-(-)-酒石酸盐。因此,如表1所示的结果,需要一个附加甲醇二次浆液将(1R,2R)-对映体杂质的量减少至小于2.5%。
实施例3
(1S,2S)-1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇甲磺
酸盐三水合物的制备
(1S,2S)-1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇的D-(-)-酒石酸盐(5.0g,10.5mmol)、水(17.5ml)和聚合物(1.05g,11.0mmol)混合在处于氮气氛下的50ml三颈圆底烧瓶中。将浆液加热至60-65℃得到一个溶液,过滤该溶液。滤液在1小时内缓慢冷却至15-20℃,得到稠的白色混悬液。该浆液进一步被冷却至0-5℃并且在0-5℃下成颗粒1小时。过滤该产物,滤饼用2.5ml冷水(0-5℃)洗涤且随后在氮气流和20-25℃下干燥。分离出(1S,2S)-1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇甲磺酸盐三水合物(4.53g),总收率为90.4%,其为白色结晶固体。分离的三水合物的物理和化学性质与真实样品相同:1H NMR(d6-DMSO)δ9.58(s,1H),8.91(S,1H),7.48(m,2H),7.35(m,2H),7.21(m,3H),6.77(d,J=8.5Hz,2H)6.35(s,1H),5.52(s,1H),4.58(d,J=8.1Hz,1H),3.40(m,11H),2.63(m,1H),2.3(s,3H),1.78(m,2H),0.95(d,J=6.6Hz,3H).13C NMR(d6-DMSO)δ158.13,148.61,132.27,129.27,128.80,127.51,125.26,115.89,72.12,68.89,66.30,47.40,42.91,35.71,35.37。计算值C20H25NO3·CH3SO3H·3H2O:C,52.81;H,7.39;N,2.93;S,6.71。实测值:C,52.77;H,7.50;N,2.94;S,6.96.αD=+54.5。(无水基准)。
如果在上述过程中采用低热原水和无热原条件,(1S,2S)-1-(4-羟苯基)-2-(4-羟基-4-苯基哌啶-1-基)-1-丙醇适合用来制备肠胃外药品。表2报导了利用不同当量甲磺酸制备的三水合物。显然,当采用低当量的甲磺酸(1.0-1.05)时,产物三水合物在溶于水中时具有残余混浊(痕量不溶物),这个特性是肠胃外制剂无法接受的。
Claims (8)
2.按照权利要求1的方法,其中甲磺酸与式(I)化合物的D-(-)酒石酸盐的摩尔比例为1.3至1.0。
3.按照权利要求1的方法,其中甲磺酸与式(I)化合物的D-(-)酒石酸盐的摩尔比例为1.10至1.05。
4.按照权利要求1的方法,其中甲磺酸与式(I)化合物的D-(-)酒石酸盐的摩尔比例为1.10至1.08。
5.按照权利要求1的方法,其中所述甲磺酸水溶液采用无热原水制备。
6.按照权利要求1的方法,进一步包括步骤:
(i)将含有式(I)和(II)化合物的外消旋混合物
在D-(-)-酒石酸的存在下溶解在含水甲醇中;和
(ii)由该溶液中分离出式(I)化合物的D-(-)-酒石酸盐。
7.按照权利要求5的方法,其中所述含水甲醇具有5-20%体积的含水量。
8.按照权利要求5的方法,其中所述含水甲醇具有7-10%体积的含水量。
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