CN1419554A - 制备卡麦角林结晶ⅰ型的方法 - Google Patents

制备卡麦角林结晶ⅰ型的方法 Download PDF

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CN1419554A
CN1419554A CN01807005A CN01807005A CN1419554A CN 1419554 A CN1419554 A CN 1419554A CN 01807005 A CN01807005 A CN 01807005A CN 01807005 A CN01807005 A CN 01807005A CN 1419554 A CN1419554 A CN 1419554A
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cabergoline
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CN1188412C (zh
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A·托马斯
S·马格尼斯
M·安格里
G·雷米拉
G·帕兰扎
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Pfizer Italia SRL
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
    • C07D457/04—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 8
    • C07D457/06—Lysergic acid amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
    • C07D457/04—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 8
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    • A—HUMAN NECESSITIES
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Abstract

生产卡麦角林I型结晶的方法，该方法包括从含粗制卡麦角林的甲苯/***混合物中结晶出所需的结晶型，然后回收并干燥所得晶体。也提供可用作中间体的一种新的卡麦角林溶剂合物V型。

Description

制备卡麦角林结晶I型的方法
本发明涉及一种新的制备卡麦角林结晶I型的方法。
卡麦角林是一种与D2多巴胺受体相互作用的麦角碱衍生物，具有不同的有效药物活性，并用于对高催乳素血症、中枢神经***病症(CNS)和其他相关疾病的治疗。
卡麦角林是美国专利第4526892中所记述并要求保护的1((6-烯丙基麦角碱-8β-基)-羰基)-1-(3-二甲基氨基丙基)-3-乙脲的俗名。Eur.J.Med.Chem.，24，421，(1989)和GB-2103603-B中报道了卡麦角林分子的合成。卡麦角林结晶I型，卡麦角林的一种无水、非溶剂化的形式，可按Il Farmaco，50(3)，175-178(1995)中所述方法，从***中结晶制备得到。
卡麦角林I型，同卡麦角林一样，对催乳素有显著的抑止作用，具有能用于治疗处于催乳素水平异常相关病理状况的病人的治疗效性质，因此对人类和兽用医疗有用。卡麦角林，单独或复合使用，对可逆阻塞性呼吸道疾病的治疗、控制眼内压并治疗青光眼有活性。它也应用于兽医领域，用作抗催乳素药物并可以很大程度降低脊椎动物的增殖。在WO9948484，WO9936095，US705510，WO9505176，EP040325中有关于卡麦角林几种用途的例述。卡麦角林I型对治疗帕金森症(PD)、多动腿综合病症(RLS)，治疗类似进行性核上麻痹(PSP)和多***萎缩(MSA)的疾病特别有效。
在我们的开发工作中，我们发现了一种新的制备结晶I型的方法。因此，本发明涉及卡麦角林I型和可用作中间体的一种新的卡麦角林溶剂合物V型的制备方法。
附图简述
图1，卡麦角林I型的XRD粉末图。
图2，卡麦角林I型的DSC曲线。
图3，卡麦角林I型(样品以KBr粉末技术制备)的红外光谱。
图4，卡麦角林I型的固态13C-核磁共振谱。
图5，卡麦角林溶剂合物V型的XRD粉末图。
图6，卡麦角林溶剂合物V型的DSC曲线。
图7，卡麦角林溶剂合物V型(样品以KBr粉末技术制备)的红外光谱。
图8，卡麦角林溶剂合物V型的固态13C-核磁共振谱。
根据本发明，从原料开始，通过从甲苯/***混合物中结晶，经过一种新的卡麦角林溶剂合物V型可以容易地制得I型。本方法制备I型以其更高的重复性优于原有方法。
表征
使用X光粉末衍射(XRD)，差示扫描量热法(DSC)，红外(IR)光谱和固态13C-NMR(核磁共振)表征此新形式的性质。
X光粉末衍射
用Scintag X1或X2先进衍射***(AdVanced DiffractionSystem)，分别在Scintag DMS/NT Ver 1.30a和1.36b，及微软WindowsNT4.0TM软件下操作完成粉末X-光衍射。该***使用保持在45kV和40mA、发射1.5406埃CuKα1的铜X光源和固态Peltier冷却检测器。光束孔径用管分歧(tube divergence)、2及4mm的抗散射缝隙控制，检测器用抗散射和0.5及0.3mm的接受缝控制。以每点一秒计时，用每点0.03°扫描步长(step scan)，从2°到30°的2-θ角搜集数据。样品用杵和研钵手工磨碎，并包入带有12mm(直径)×0.5mm空腔的铝样品盘。
DSC
用Mettler TA 4000热分析***得到差示扫描量热测定的测量值。在DSC盘中准确称量约8.5mg样品。密封盘子，并在盘盖上扎一个针孔。针孔用于释放压力，而同时保证热反应在控制条件下进行。样品放入DSC炉，以每分钟5℃速率最终加热到135℃。
IR光谱
卡麦角林V型和I的IR光谱由Perkin Elmer FT-IR分光光度仪PARAGON 1000得到。样品由记录反射光谱的KBr粉末技术制备。
固态13C-核磁共振
固态13C-核磁共振谱获自备有固态设备和可变温度幻角度旋转探头的MSL 300Bruker仪器。交叉极化(cross polarisation)实验由50KHz的去偶场及单脉冲幻角度旋转实验以从10到100记录范围循环次数完成。
I型的X射线粉末衍射图(图1)显示在大约9.7，10.4和24.8deg2-θ处具有有用的特色峰的晶体结构。
I型的DSC曲线(图2)显示在大约100-105℃处有熔融吸热。整体的熔融吸热有大约60J/g的熔化热。
图3显示I型的红外光谱。
图4显示I型的固态13C-核磁共振谱。
这些数据说明卡麦角林I型是一种以XRD和固态13C-核磁共振谱技术易于鉴定的结晶多晶型物。DSC和IR是表征该多晶型物的另外两种有用的技术。本发明生产卡麦角林结晶I型的方法的特征在于是从甲苯/***混合物中结晶。该方法包括，以适量优选约1∶1混合的甲苯/***混合物溶解从Eur.J.Med.Chem.，24，421(1989)所述合成产生的最终油状卡麦角林粗品。将得到的溶液在-25到-9℃，优选-12℃，冷却17个小时。在此条件下，得到一种甲苯溶剂合物，称为V型，其可以通过常规步骤回收，例如通过减压过滤或离心过滤，然后平稳干燥所得固体。进一步干燥，所得V型晶体就会转变为I型。以本发明方法制备的卡麦角林I型晶体，其多晶型物纯度优选＞95％，更优选地＞98％。甲苯溶剂合物V型也是本发明的一个目的，V型的X射线粉末衍射图(图5)展示一种晶体结构。
溶剂合物V型的DSC曲线(图6)显示在大约60-65℃处有熔融吸热。
图7显示溶剂合物V型的红外光谱。
图8显示V型的固态13C-核磁共振谱。
这些数据说明以XRD、DSC和固态13C-核磁共振谱技术容易鉴定卡麦角林溶剂合物V型。IR，结合另外的分析技术，是鉴定该多晶型物的又一种技术。
本发明的溶剂合物V是具有固定组成，即每摩尔卡麦角林约0.5摩尔甲苯的真溶剂合物。
实施例1
将在Eur.J.Med.Chem.，24，421(1989)所述制备的合成途径的最终步骤之后由色谱柱纯化得到的、含有100g纯卡麦角林的油溶解于甲苯，得到243g的卡麦角林甲苯溶液。将溶液放入预冷到-12℃的反应器，加入182g甲苯，使溶剂中卡麦角林的浓度为23.5％w/w。再冷至-12℃后，加入362ml***。再冷却至-12℃，并在此温度下搅拌约17个小时。得到的沉淀经真空过滤并平稳干燥。通过XRD、DSC、IR和NMR鉴定所得的溶剂合物V型晶体。图5到8分别展示相应数据。
基于纯的卡麦角林的起始含量的产率为约45％w/w。
实施例2
实施例1中得到的溶剂合物V型晶体在真空40℃到真空65℃之间干燥。干燥后，通过XRD、DSC、IR和NMR鉴定所得的晶体I型。图1到4分别展示相应数据。基于纯的卡麦角林起始含量的产率为约40％。测定的多晶型物纯度为＞98％。

Claims (9)

1.生产卡麦角林I型的方法，该方法包括从含粗制卡麦角林的甲苯/***混合物中结晶出所需的结晶型，然后回收并干燥所得晶体。
2.根据权利要求1的方法，其中结晶包括将粗制卡麦角林溶解于甲苯/***混合物，冷却所得溶液，收集所得的具有图5所示XRD粉末图的卡麦角林溶剂合物V型，并通过干燥将该溶剂合物转变为卡麦角林I型。
3.根据权利要求1或2的方法，其中甲苯/***混合物是1∶1混合物。
4.根据权利要求2或3的方法，其中甲苯/***混合物冷却至-25到-9℃的温度。
5.根据权利要求4的方法，其中甲苯/***混合物被冷却至约-12℃。
6.具有图5所示XRD粉末图的卡麦角林溶剂合物V型。
7.生产权利要求6的卡麦角林溶剂合物V型的方法，该方法包括在甲苯/***混合物中溶解粗制的卡麦角林，冷却所得溶液并收集所得卡麦角林溶剂合物V型。
8.根据权利要求9的方法，其中甲苯/***混合物是1∶1混合物。
9.根据权利要求7或8的方法，其中甲苯/***混合物被冷却至-25到-12℃的温度，并且通过减压过滤或离心过滤收集溶剂合物V型，然后平稳干燥所得固体。
CNB018070051A 2000-03-24 2001-03-19 制备卡麦角林结晶ⅰ型的方法 Expired - Fee Related CN1188412C (zh)

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MXPA02009283A (es) 2003-03-12
AU6211001A (en) 2001-10-03
AU2005203071B2 (en) 2007-10-18
JP4184666B2 (ja) 2008-11-19
EE05088B1 (et) 2008-10-15
SK13582002A3 (sk) 2003-04-01
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ATE250601T1 (de) 2003-10-15
NO20024321L (no) 2002-09-10
HK1052348A1 (en) 2003-09-11
CN1188412C (zh) 2005-02-09
US6727363B2 (en) 2004-04-27
US6953854B2 (en) 2005-10-11
HUP0300591A3 (en) 2009-01-28
MY134189A (en) 2007-11-30
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GB0007308D0 (en) 2000-05-17
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US20030149067A1 (en) 2003-08-07
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CZ20023176A3 (cs) 2003-02-12
SI1272489T1 (en) 2004-02-29
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