CN1157374C - 非晶形阿托伐他汀钙的制备方法 - Google Patents

非晶形阿托伐他汀钙的制备方法 Download PDF

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CN1157374C
CN1157374C CNB008144583A CN00814458A CN1157374C CN 1157374 C CN1157374 C CN 1157374C CN B008144583 A CNB008144583 A CN B008144583A CN 00814458 A CN00814458 A CN 00814458A CN 1157374 C CN1157374 C CN 1157374C
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atorvastatin calcium
amorphous atorvastatin
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Z·戈里弗
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P·考特纳吉
J·巴考茨
G·斯米格
L·巴拉茨
I·多曼
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Z·拉德凯
P·塞雷斯
Z·圣特克拉里
F·巴瑟
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G·维里克兹科纳多纳斯
K·纳吉
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    • C07D207/00Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
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Abstract

本发明涉及一种从有机溶剂中通过粗阿托伐他汀的重结晶而制备非晶形阿托伐他汀钙的方法,该方法包括在加热条件下,在包含2-4个碳原子的低级链烷醇或这样链烷醇的混合物中,溶解粗非晶形阿托伐他汀钙,和在冷却之后分离沉淀的非晶形阿托伐他汀钙。已知获得的阿托伐他汀钙是用于治疗高脂血症和高胆固醇血症的有价值的试剂。

Description

非晶形阿托伐他汀钙的制备方法
发明领域
本发明涉及用于制备阿托伐他汀(atorvastatin)钙的改进新方法。
发明背景
具有INN阿托伐他汀的[R-(Rx,Rx)]-2-(4-氟苯基)-β,δ-二羟基-5-[1-甲基-乙基]-3-苯基-4-[(苯基氨基)-羰基]-1H-吡咯-1-庚酸的钙盐是3-羟基-3-甲基谷氨酰胺辅酶A还原酶的抑制剂。由于此效果,阿托伐他汀是有价值的脂质和胆固醇水平降低剂,用于治疗高脂血症和高胆固醇血症。阿托伐他汀首先描述在US5,273,995中。在此US专利说明书中,没有公开产物的结晶形式。阿托伐他汀和用于合成的关键中间体的制备在现有技术中,描述在几处(如US5,003,080、US5,097,045、US5,103,024、US5,124,482、US5,149,837、US5,155,251、US5,216,174、US5,245,047、US5,248,793、US5,280,126、US5,397,792和US5,342,952)。
以确定的结晶形态的阿托伐他汀钙首先描述在WO97/03958中。
在现有技术中,公开了四种阿托伐他汀钙的不同多晶形物。WO97/03958涉及阿托伐他汀钙的结晶形态III。根据此公开的PCT申请,通过允许包含结晶形态II的阿托伐他汀钙,在95%的水分含量下静置11天,而制备结晶形态III。
在WO97/03959中,要求和公开了阿托伐他汀钙的结晶形态I,II和IV。
根据此公开PCT申请的实施例,结晶形态I可以采用两种方式制备。根据一种工艺,通过以结晶形态I为种子而获得产物。根据另一种工艺,在水和甲醇的17∶3体积/体积混合物中,在40℃下,将非晶形和结晶形态I的阿托伐他汀钙混合物搅拌17小时。
根据WO97/03959的实施例,通过在20倍量的甲醇和水3∶2体积混合物中,悬浮非晶形和结晶形态I的阿托伐他汀钙的混合物,交搅拌悬浮液3天,而制备结晶形态II。
从阿托伐他汀内酯制备结晶形态IV。根据WO97/03959的实施例,在65-70℃下,将在阿托伐他汀钙盐形成过程中获得的含水混合物加热至少5分钟,然后将混合物冷却到55-65℃。将沉淀的晶体过滤,在甲醇中在55-60℃下搅拌,将悬浮液冷却到25-30℃,最后通过过滤分离结晶形态IV。
与结晶形态相比,非晶形阿托伐他汀显示许多优点。根据现有技术,与结晶形态相比[Konno T.,《药物化学公告》(Chem.Pharm.Bull.),38,2003-2007(1990)],非晶形阿托伐他汀钙具有可变的溶解特性,和在一些情况下获得可变的生物可利用性。在一些治疗指征中,某些生物可利用性特征比其它一些更优选。基于此原因,需要能够制备非晶形阿托伐他汀钙的方法。
在WO97/03960中,公开了一种从结晶形态I开始,制备非晶形阿托伐他汀钙的新方法。根据此公开国际申请的主权利要求,将结晶形态I的阿托伐他汀钙溶于无羟基溶剂,随后除去溶剂以得到非晶形阿托伐他汀。从属权利要求保护四氢呋喃自身或四氢呋喃和甲苯的混合物作为无羟基溶剂的用途。根据实施例,将结晶形态I溶于约四倍量的四氢呋喃和甲苯的3∶2混合物中,随后通过特殊的干燥技术除去溶剂。在专门为此目的制造的设备中,在如下条件下进行干燥:首先在35℃,和然后在85℃、在真空中、6-8mmHg下进行4天。
在WO97/03960中公开的方法的缺点在于从确定的结晶形态,即从结晶形态I制备非晶形阿托伐他汀。此多晶形物的制备公开于WO97/03959。根据此参考文献的教导,此方法复杂和仅可以在困难的条件下重复。在20页14-19行有如下陈述:
“可以根据经验确定结晶形态I的阿托伐他汀形成的精确条件,和仅可以给出可适用于实施的许多方法。”
发明内容
本发明的目的是消除已知步骤的缺点,和提供用于高纯度和均匀非晶形阿托伐他汀钙的简单而经济可行的制备方法。
上述目的由本发明的如下方法解决。
根据本发明,提供一种从有机溶剂通过粗阿托伐他汀的重结晶而制备非晶形阿托伐他汀钙的方法,该方法包括在加热条件下,在包含2-4个碳原子的低级链烷醇或这样链烷醇的混合物中,溶解粗阿托伐他汀钙,和在冷却之后分离沉淀的非晶形阿托伐他汀钙。
已经令人惊奇地发现,从包含2-4个碳原子的低级链烷醇或两种或多种这样链烷醇的混合物,通过重结晶粗阿托伐他汀钙,以简单而可重复的方式获得均匀非晶形的阿托伐他汀钙。根据WO97/03960的教导公开的是无羟基溶剂专门适用于非晶形阿托伐他汀的制备,上述认识是如此更加令人惊奇的。
根据本发明的方法,乙醇、正丙醇、异丙醇、正丁醇或支链丁醇可用作包含2-4个碳原子的链烷醇。优选使用异丙醇或乙醇,或异丙醇和乙醇的混合物。此方法也可通过使用两种或多种链烷醇的混合物而进行。
作为起始原料,人们可优选使用粗阿托伐他汀钙(根据US5,273,995制备的产物)。
附图简述
图1是本发明非晶形阿托伐他汀产品的X射线粉末衍射图。
图2是结晶形阿托伐他汀的X射线粉末衍射图。
根据本发明方法的优选实施形式,人们可按如下方式进行:
在加热条件下,有利地在溶剂的沸点下,将起始原料溶于包含2-4个碳原子的链烷醇中。人们可优选通过过滤溶液,允许滤液冷却到室温和允许悬浮液在冷却状态下静置而进行。将沉淀的非晶形阿托伐他汀钙通过过滤或离心分离,采用用于重结晶的包含2-4个碳原子的冷链烷醇洗涤,最后在真空下干燥。人们也可通过过滤热溶液到沸腾的C2-4链烷醇中,然后按上述方式进行而操作。
本发明的方法可以在较短的时间内进行。根据起始原料的数量,反应时间等于几小时。
本发明的方法具有如下优点:
-该方法以简单而可重复的方式提供均匀高纯度非晶形产物,从制药工业观点来看,此产物具有有利的性能。
-从粗阿托伐他汀获得非晶形阿托伐他汀钙,它可容易地制备,而不是从偶然可得的结晶形态I制备。
-消除了溶剂的蒸发和痕量溶剂的间接脱除。在冷却温热溶液时,通过沉淀的非晶形产物的过滤,以简单的方式分离所需的产物。
-由于上述优点,此方法可在短时间内,通过使用简单的设备进行。
-此方法非常适于工业规模生产。
-用于此方法的溶剂对环境无害。
本发明的更详细情况可在如下实施例中找到,而不是将保护范围限制到该实施例。
具体实施方式
实施例1
将120ml的2-丙醇中的2.74g(2.37毫摩尔)根据US专利No.5,273,995实施例10制备的粗阿托伐他汀钙加热到沸腾,直到材料进入溶液中。将因此获得的热溶液过滤到20ml沸腾的2-丙醇中,使其冷却到室温。将异丙醇悬浮液在4℃下静置4小时。将沉淀的非晶形产物过滤出,以冷异丙醇(4℃)洗涤,在室温下、真空中、55Pa下干燥。获得2.50g均匀非晶形阿托伐他汀钙。收率9 1.2%。
设备:PHILIPS-PW1820粉末衍射仪
辐射:Cu Kα(λ∶1,54190埃)
单色仪:石墨
激光电压:40kV
阳极电流:30mA
样品:平滑表面,厚度0.5mm。
X射线结构(X射线衍射)的测量基于点阵原子的电子的衍射和干扰。表征结晶材料的有序,点阵结构由X射线图的反射(最大干扰)显示。由于它们的无序结构,非晶形材料在衍射图中并不显示尖峰,它们仅由平的曲线表征。使用X射线衍射,因此人们可以毫不含糊地检验材料的结晶态或非晶态。
实施例2
在20cm3的乙醇中,将2.00g(1.73毫摩尔)非晶形阿托伐他汀钙盐加热到沸腾,直到材料进入溶液中(大约1分钟)。将获得的热溶液过滤到沸腾的100cm3的2-丙醇中并使其冷却到室温,同时非晶形阿托伐他汀钙盐开始沉淀。将获得的悬浮液在4℃下静置4小时,然后过滤,以5cm3的2-丙醇(4℃)洗涤,并在室温、真空中、55Pa下干燥。因此获得1.74g(87%)非晶形阿托伐他汀钙盐。

Claims (4)

1.一种从有机溶剂通过粗阿托伐他汀的重结晶而制备非晶形阿托伐他汀钙的方法,该方法包括在加热条件下,在包含2-4个碳原子的低级链烷醇或这样链烷醇的混合物中,溶解粗阿托伐他汀钙,并在冷却之后分离沉淀的非晶形阿托伐他汀钙。
2.权利要求1的方法,它包括使用异丙醇或乙醇,或异丙醇和乙醇的混合物作为包含2-4个碳原子的链烷醇。
3.权利要求1或2的方法,它包括在溶剂的沸点下,在2-丙醇中或在乙醇中,溶解起始原料。
4.根据权利要求1或2的方法,它包括冷却溶液,和通过过滤或离心来分离沉淀的非晶形阿托伐他汀钙。
CNB008144583A 1999-10-18 2000-10-17 非晶形阿托伐他汀钙的制备方法 Expired - Fee Related CN1157374C (zh)

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HU9903634A HU226640B1 (en) 1999-10-18 1999-10-18 Process for producing amorphous atorvastatin calcium salt
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HU226640B1 (en) 2009-05-28
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UA72777C2 (en) 2005-04-15
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HRP20020334B1 (en) 2007-12-31
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HUP9903634A3 (en) 2002-01-28
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