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CN1196679C - 无定形阿托伐斯汀钙的制备方法 - Google Patents

无定形阿托伐斯汀钙的制备方法 Download PDF

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CN1196679C
CN1196679C CNB008080275A CN00808027A CN1196679C CN 1196679 C CN1196679 C CN 1196679C CN B008080275 A CNB008080275 A CN B008080275A CN 00808027 A CN00808027 A CN 00808027A CN 1196679 C CN1196679 C CN 1196679C
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atorvastatin calcium
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CN1351493A (zh
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Y·库马
R·K·萨普
S·M·D·库马
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or 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 to ring carbon atoms
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Abstract

本发明涉及一种制备无定形阿托伐斯汀钙和其水合物的方法，包括：(a)将结晶阿托伐斯汀溶于非羟基溶剂；(b)加入非极性烃反溶剂或将溶解的阿托伐斯汀加到非极性反溶剂中，以沉淀出阿托伐斯汀钙；和(c)通过过滤除去溶剂，得到无定形阿托伐斯汀钙。

Description

无定形阿托伐斯汀钙的制备方法
发明领域
本发明涉及无定形阿托伐斯汀钙(atorvastatin calcium)的制备方法。
发明背景
阿托伐斯汀的化学名是[R-(R*，R*)]-2-(4-氟-苯基)-β-二羟基-5-(1-甲乙基)-3-苯基-4-[(苯基氨基)羰基]-1H-吡咯-1-庚酸。阿托伐斯汀钙是一种合成的HMG-CoA还原酶抑制剂，它用来治疗高血脂症和高胆固醇血症，该两者都是动脉硬化和冠心病的危险因素。业已合成了阿托伐斯汀的开环的二羟基羧酸、内酯和各种盐形式。
美国专利5,273,995揭示了开环酸形式的R-形式对胆固醇的生物合成有出乎意料的抑制作用。阿托伐斯汀的钙盐形式，即下式1的[R-(R*，R*)]-2-(4-氟-苯基)-β，δ-二羟基-5-(1-甲乙基)-3-苯基-4-[(苯基氨基)羰基]-1H-吡咯-1-庚酸钙盐(2∶1)更适合制剂，并业已推荐用作药物。
美国专利5,003,080；5,097,045；5,103,024；5,124,482；5,149,837；5,248,793；5,280,126；5,342,952(在此并入供参考)揭示了制备阿托伐斯汀的各种方法和关键的中间体。
用上述美国专利揭示的方法制备的阿托伐斯汀钙不全都是无定形的阿托伐斯汀，而是其晶体和无定形形式的混合物，它们具有不合适的过滤和干燥特性，不适合用于大规模生产。
PCT申请，WO 97/03959，揭示了阿托伐斯汀新颖的晶体形式(称为形式I、II和形式IV)和它们的制备方法，所述的形式提供了较有利的过滤和干燥特性。
PCT申请WO 97/03960揭示了将阿托伐斯汀的晶体形式转化为无定形形式的过程。它揭示的方法包括使晶体形式-I的阿托伐斯汀溶于非羟基溶剂，如四氢呋喃或四氢呋喃和甲苯的混合物中。该方法涉及在高温(约90℃)和高真空(约5mm)下用投资大的设备来完全除去溶剂。物质在高温下暴露数天会使产品分解。这使该方法非常不适合大规模操作。制造规模下慢慢除去溶剂使该方法成本高，产出低。
发明概述
本发明的一个目的是提供产生无定形阿托伐斯汀的有效方法，它消除了现有技术中的问题并便于商业规模操作。
因此，本发明提供了制备无定形形式的阿托伐斯汀钙的方法，它包括使结晶的阿托伐斯汀溶于非羟基溶剂(non-hydroxylic solvent)，加入合适的非极性烃溶剂，通过溶剂沉淀、分离和干燥产品从其溶液中回收阿托伐斯汀。
一般来说，可通过本技术领域已知的任何标准方法，如过滤、离心或倾析来分离产物。典型的是，当使用本发明方法范围里的任何溶剂时，该产品可通过过滤来分离。
与现有技术相比，本发明的主要优点是：
i.不需要用干燥技术除去溶剂。
ii.对改进的过滤耗费的时间更少。
iii.易于大规模操作
iv.再生的无定形产物具有可接受水平的残留溶剂。
本发明因此提供了新颖的制备无定形阿托伐斯汀钙和其水合物的方法，它包括：
(a)将晶体阿托伐烯烃钙溶于非羟基溶剂；
(b)加入非极性烃反溶剂(anti-solvent)来沉淀出物质；和
(c)通过过滤除去溶剂得到无定形的阿托伐斯汀钙。
非羟基溶剂选自能溶解晶体阿托伐斯汀的溶剂组，包括四氢呋喃。合适的非极性烃溶剂选自正己烷、正庚烷、环己烷、己烷馏分(fraction)、庚烷馏分之类。在本发明优选的技术方案中，非羟基溶剂是四氢呋喃，反溶剂是正己烷、环己烷或正庚烷。
一般来说，结晶阿托伐斯汀钙以约15％w/v到约40％w/v的浓度，优选的是以约25％w/v到约15％w/v的浓度在室温下溶于非羟基溶剂，如四氢呋喃，在0℃到50℃，优选的是20℃到25℃下加入非极性烃，优选的是正己烷、环己烷或正庚烷。在室温下通过过滤回收产物。用真空吸滤过滤器(nutsche)过滤或离心过滤来进行快速和平稳的过滤。优选的是，大规模制备中使用真空吸滤过滤。滤得的物质为半干粉末在真空塔盘干燥器、塔盘干燥器、流化床干燥器或旋转真空干燥器里进一步干燥，来除去表面溶剂，得到无定形物质。优选的是，物质在约20℃到约80℃下在真空塔盘干燥器里干燥6到24小时。最好是在约50℃到约60℃下干燥12小时。
反溶剂的用量根据在非羟基溶剂里的溶液而定，是加入的结晶阿托伐斯汀钙的5-50倍。优选的是，反溶剂的用量是加入的结晶阿托伐斯汀用量的约20倍到约40倍，使其总的浓度为约5％w/v到约2.5％w/v。
根据本发明方法制备的无定形阿托伐斯汀钙可由其x-射线粉末衍射图(图2)来表征。X-射线粉末衍射图(图2)显示没有峰值，所述的峰值是结晶阿托伐斯汀钙的特征(图1)，因此，显示了产物的无定形性质。
附图简述
图1是结晶阿托伐斯汀钙的衍射图。水平轴代表2θ，垂直轴代表峰强度。
图2是无定形阿托伐斯汀钙的衍射图。水平轴代表2θ，垂直轴代表峰强度。
本发明通过下列非限制本发明权利要求书范围的实施例进行阐述。
发明详述
实施例1
[R-(R*，R*)]-2-(4-氟-苯基)-β，δ-二羟基-5-(1-甲乙基)-3-苯基-4-[(苯基氨基)羰基]-1H-吡咯-1-庚酸半钙盐(无定形阿托伐斯汀钙)。
方法A
在室温搅拌下将结晶阿托伐斯汀钙(10kg)溶于四氢呋喃(30升)。在氮气氛下将这样得到的澄清溶液慢慢加到环己烷(350升)中。在20-25℃温度下激烈搅拌。离心沉淀出的产物，在约60℃下真空干燥12小时。得到无定形形式的阿托伐斯汀(9.5kg)，其残留的溶剂水平为0.01％w/w四氢呋喃和0.6％w/w环己烷。X-射线粉末衍射图(图2)显示了产物的无定形性质。
方法B
在室温搅拌下将结晶阿托伐斯汀钙(10kg)溶于四氢呋喃(30升)。在20-25℃激烈搅拌下，向阿托伐斯汀的澄清溶液中加入环己烷(350升)。沉淀出的物质进一步搅拌30分钟，经离心过滤。在约60℃下将产物干燥12小时。得到无定形形式的阿托伐斯汀(9.6kg)，其残留溶剂水平为0.01％w/w四氢呋喃和0.7％w/w环己烷。X-射线粉末衍射图显示了产物的无定形性质。
实施例2
[R-(R*，R*)]-2-(4-氟-苯基)-β，δ-二羟基-5-(1-甲乙基)-3-苯基-4-[(苯基氨基)羰基]-1H-吡咯-1-庚酸半钙盐(无定形阿托伐斯汀钙)
重复实施例1的方法，将结晶阿托伐斯汀钙(10kg)溶于四氢呋喃(30升)，用正己烷代替环己烷，得到无定形阿托伐斯汀(9.5kg)。X-射线衍射图证实了产物的无定形性质。
实施例3
[R-(R*，R*)]-2-(4-氟-苯基)-β，δ-二羟基-5-(1-甲乙基)-3-苯基-4-[(苯基氨基)羰基]-1H-吡咯-1-庚酸半钙盐(无定形阿托伐斯汀钙)
重复实施例1的方法，将结晶阿托伐斯汀钙(10kg)溶于四氢呋喃(30升)，用正庚烷代替环己烷，得到无定形阿托伐斯汀(9.6kg)。X-射线结晶衍射图检测证实了产物的无定形性质。
虽然本发明已就特定的技术方案进行了描述，但某些修饰和等同物对本技术领域的人员来说是很明显的，它们也在本发明的范围里。

Claims (6)

1.一种制备无定形阿托伐斯汀钙的方法，包括：
(a)将结晶阿托伐斯汀钙溶于非羟基溶剂；
(b)加入非极性烃的不良溶剂，或将溶解的阿托伐斯汀加到非极性不良溶剂中，以沉淀出阿托伐斯汀钙；
(c)通过过滤除去溶剂，得到无定形的阿托伐斯汀钙。
2.根据权利要求1所述的方法，其中非羟基溶剂是四氢呋喃，不良溶剂选自非极性烃溶剂，包括正己烷、环己烷或正庚烷。
3.根据权利要求1所述的方法，其中非羟基溶剂是四氢呋喃，不良溶剂是正己烷。
4.根据权利要求1所述的方法，其中非羟基溶剂是四氢呋喃，不良溶剂是环己烷。
5.根据权利要求1所述的方法，其中非羟基溶剂是四氢呋喃，不良溶剂是正庚烷。
6.根据权利要求1所述的方法，其中所述的无定形阿托伐斯汀钙通过过滤分离。
CNB008080275A 1999-05-25 2000-01-06 无定形阿托伐斯汀钙的制备方法 Expired - Fee Related CN1196679C (zh)

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Families Citing this family (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7411075B1 (en) 2000-11-16 2008-08-12 Teva Pharmaceutical Industries Ltd. Polymorphic form of atorvastatin calcium
SI20425A (sl) * 1999-12-10 2001-06-30 LEK tovarna farmacevtskih in kemi�nih izdelkov d.d. Priprava amorfnega atorvastatina
US7501450B2 (en) 2000-11-30 2009-03-10 Teva Pharaceutical Industries Ltd. Crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms
IL156055A0 (en) 2000-11-30 2003-12-23 Teva Pharma Novel crystal forms of atorvastatin hemi calcium and processes for their preparation as well as novel processes for preparing other forms
WO2002057228A1 (en) * 2001-01-17 2002-07-25 Biocon India Limited Atorvastatin calcium
SI20814A (sl) * 2001-01-23 2002-08-31 LEK, tovarna farmacevtskih in kemi�nih izdelkov, d.d. Priprava amorfnega atorvastatina
IN190564B (zh) * 2001-04-11 2003-08-09 Cadila Heathcare Ltd
EP3009423A3 (en) * 2001-06-29 2016-12-28 Warner-Lambert Company LLC Crystalline forms of [r-(r*,r*)]-2-(4-fluorophenyl)-beta, delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-phenylamino)carbonyl]-1h-pyrrole-1-heptanoic acid calcium salt (2:1) (atorvastatin)
CA2456095C (en) * 2001-08-31 2010-05-11 Morepen Laboratories Ltd. An improved process for the preparation of amorphous atorvastatin calcium salt (2:1)
UA77990C2 (en) * 2001-12-12 2007-02-15 Crystalline calcium salt of (2:1) [r-(r*,r*)]-2-(4-fluorophenyl)-?,?-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrroleheptanic acid
CZ296967B6 (cs) * 2002-02-01 2006-08-16 Zentiva, A.S. Zpusob výroby amorfní formy hemivápenaté soli (3R,5R) 7-[3-fenyl-4-fenylkarbamoyl-2-(4-fluorfenyl)-5-isopropylpyrrol-1-yl]-3,5-dihydroxyheptanové kyseliny (atorvastatinu)
ITMI20020907A1 (it) * 2002-04-29 2003-10-29 Chemi Spa Processo di preparazione della forma amorfa del sale di calcio della atorvastatina
AU2002356423A1 (en) * 2002-05-28 2003-12-12 Cadila Healthcare Limited Process for the preparation of amorphous atorvastatin calcium
US8367848B2 (en) 2003-04-11 2013-02-05 Lek Pharmaceuticals D.D. Process for the preparation of amorphous calcium salt of atorvastatin
AU2004234057A1 (en) * 2003-04-29 2004-11-11 Akzo Nobel N.V. Antisolvent solidification process
US7790197B2 (en) 2003-06-09 2010-09-07 Warner-Lambert Company Llc Pharmaceutical compositions of atorvastatin
US20050271717A1 (en) 2003-06-12 2005-12-08 Alfred Berchielli Pharmaceutical compositions of atorvastatin
US7655692B2 (en) 2003-06-12 2010-02-02 Pfizer Inc. Process for forming amorphous atorvastatin
CA2456430A1 (en) * 2004-01-28 2005-07-28 Brantford Chemicals Inc. Improved process for the preparation of amorphous atorvastatin calcium
CZ298382B6 (cs) * 2004-03-10 2007-09-12 Zentiva, A. S. Zpusob prípravy amorfní formy hemivápenaté soli atorvastatinu a její stabilizace
PL1727795T3 (pl) 2004-03-17 2012-06-29 Ranbaxy Laboratories Ltd Sposób wytwarzania soli wapniowej atorwastatyny w formie bezpostaciowej
US7241800B2 (en) * 2004-03-17 2007-07-10 Mai De Ltd. Anhydrous amorphous form of fluvastatin sodium
KR100829268B1 (ko) * 2004-04-16 2008-05-13 화이자 프로덕츠 인코포레이티드 비정질 아토바스타틴 칼슘의 제조 방법
ES2739493T3 (es) 2004-05-05 2020-01-31 Pfizer Prod Inc Formas de sal de de atorvastatina con benetamina
CA2833770A1 (en) * 2004-07-16 2006-01-26 Lek Pharmaceuticals D.D Oxidative degradation products of atorvastatin calcium
BRPI0513422A (pt) 2004-07-20 2008-05-06 Warner Lambert Co formas de sais cálcio do ácido (r-(r*))-2-(4- fluorfenil)-(beta), (sigma)-diidróxi-5-(1-metiletil) -3-fenil-4-((fenilamino) carbonil)-1h-pirrol-1-heptanóico (2:1)
CA2578722C (en) 2004-08-27 2010-02-02 Biocon Limited Process for atorvastatin calcium amorphous
US20060106230A1 (en) * 2004-10-18 2006-05-18 Michael Pinchasov Processes for preparing amorphous atorvastatin hemi-calcium
CA2585836A1 (en) * 2004-10-28 2006-05-04 Warner-Lambert Company Llc Process for forming amorphous atorvastatin
WO2006048888A1 (en) * 2004-11-01 2006-05-11 Jubilant Organosys Limited Novel process for the preparation of amorphous atorvastatin calcium salt
CA2588216A1 (en) 2004-11-22 2006-05-26 Dexcel Pharma Technologies Ltd. Stable atorvastatin formulations
WO2007052296A2 (en) * 2005-08-23 2007-05-10 Kopran Research Laboratories Ltd A process of preparing amorphous atorvastatin calcium
US20090216029A1 (en) * 2005-09-16 2009-08-27 Yatendra Kumar Process for the production of atorvastatin calcium in amorphous form
CA2547216A1 (en) 2005-09-21 2007-03-21 Renuka D. Reddy Process for annealing amorphous atorvastatin
PT1957452E (pt) 2005-11-21 2010-05-25 Warner Lambert Co Novas formas de ácido [r-(r*,r*)]-2-(4-fluorofenil)-b,b--di-hidroxi-5-(1-metiletil)-3-fenil-4-[(fenilamino)-carbonil]-1h-pirrole-1-heptanóico magnésico
EP1810667A1 (en) 2006-01-20 2007-07-25 KRKA, tovarna zdravil, d.d., Novo mesto Pharmaceutical composition comprising amorphous atorvastatin
WO2008053312A2 (en) * 2006-11-02 2008-05-08 Cadila Pharmaceuticals Limited Process for preparing amorphous atorvastatin hemi calcium salt and its intermediate
US7834195B2 (en) 2007-01-24 2010-11-16 Apotex Pharmachem Inc. Atorvastatin calcium propylene glycol solvates
AU2008281640A1 (en) * 2007-07-27 2009-02-05 Cipla Limited Pharmaceutical compositions and process for making them
EP2075246A1 (en) 2007-12-27 2009-07-01 M. J. Institute of Research A process for preparation of amorphous form of atorvastatin hemi-calcium salt
CN101684090B (zh) * 2008-09-27 2012-12-05 广东东阳光药业有限公司 一种制备无定形阿托伐他汀钙的方法
US8115015B2 (en) 2009-01-26 2012-02-14 Cadila Healthcare Limited Process for the preparation of amorphous atorvastatin calcium
CZ201039A3 (cs) 2010-01-19 2011-07-27 Zentiva, K. S Zpusob prumyslové výroby amorfní formy hemivápenaté soli (3R,5R) 7-[3-fenyl-4-fenylkarbamoyl-2-(4-fluorfenyl)-5-isopropylpyrrol-1-yl]-3,5-dihydroxyheptanové kyseliny (atorvastatinu) s vysokým specifickým povrchem a jeho použití v lékové forme
HUP1000299A2 (hu) 2010-06-08 2012-02-28 Nanoform Cardiovascular Therapeutics Ltd Nanostrukturált Atorvastatint, gyógyszerészetileg elfogadott sóit és kokristályait tartalmazó készítmény és eljárás elõállításukra
US10138206B2 (en) * 2014-10-09 2018-11-27 Glenmark Pharmaceuticals Limited Amorphous form of lomitapide mesylate

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
YU44680B (en) * 1982-07-30 1990-12-31 Glaxo Lab Ltd Process for obtaining very pure amorphous form of cephuroxim axetile
US5124482A (en) 1988-02-22 1992-06-23 Warner-Lambert Company Process for trans-6-(2-substituted-pyrrol-1-yl)alkyl)pyran-2-one inhibitors of cholesterol synthesis
US5149837A (en) 1988-02-22 1992-09-22 Warner-Lambert Company Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
US5097045A (en) 1989-02-01 1992-03-17 Warner-Lambert Company Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
US5245047A (en) 1988-02-22 1993-09-14 Warner-Lambert Company Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
US5003080A (en) 1988-02-22 1991-03-26 Warner-Lambert Company Process for trans-6-(2-(substituted-pyrrol-1-yl)alkyl)pryan-2-one inhibitors of cholesterol synthesis
FI94339C (fi) 1989-07-21 1995-08-25 Warner Lambert Co Menetelmä farmaseuttisesti käyttökelpoisen /R-(R*,R*)/-2-(4-fluorifenyyli)- , -dihydroksi-5-(1-metyylietyyli)-3-fenyyli-4-/(fenyyliamino)karbonyyli/-1H-pyrroli-1-heptaanihapon ja sen farmaseuttisesti hyväksyttävien suolojen valmistamiseksi
US5103024A (en) 1990-10-17 1992-04-07 Warner-Lambert Company Process for the synthesis of (4r-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate
US5248793A (en) 1990-10-17 1993-09-28 Warner-Lambert Company Process for the synthesis of (4R-cis)-1,1-dimethylethyl 6-iodomethyl or 6-(phenyl-substituted)sulfonyloxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate
US5298627A (en) 1993-03-03 1994-03-29 Warner-Lambert Company Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
PL193479B1 (pl) * 1995-07-17 2007-02-28 Warner Lambert Co Formy krystaliczne hydratu atorwastatyny, kompozycja farmaceutyczna zawierająca formę krystaliczną I hydratu atorwastatyny oraz jej zastosowanie
HRP960312B1 (en) 1995-07-17 2001-10-31 Warner Lambert Co NOVEL PROCESS FOR THE PRODUCTION OF AMORPHOUS /R-(R*, R*)/-2-(4-FLUOROPHENYL)-"beta", "delta"-DIHYDROXY-5-PHENYL-4-/(PHENYLAMINO)CARBONYL/-1H-PYRROLE -1-HEPTANOIC ACID CALCIUM SALT (2 : 1)
HRP960313B1 (en) * 1995-07-17 2002-08-31 Warner Lambert Co Form iii crystalline (r- (r*, r*)-2- (4-fluorophenyl) -beta-delta-hydroxy-5-(1-methylethyl) -3-phenyl-4- ((phenylamino) carbonyl -1h-pyrrole-1-heptanoic acid calcium salt (2:1)
SI20425A (sl) * 1999-12-10 2001-06-30 LEK tovarna farmacevtskih in kemi�nih izdelkov d.d. Priprava amorfnega atorvastatina

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PT1185264E (pt) 2007-07-10
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