CN103108863A - 低醚杂质的阿托伐他汀的制备 - Google Patents
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Abstract
本发明涉及一种通过浓缩步骤的方式来制备杂质(3)和(4)的水平降低的阿托伐他汀的方法。
Description
技术领域
本发明涉及一种用于制备阿托伐他汀的方法。
背景技术
阿托伐他汀([R-(R*，R*)]-2-(4-氟苯基)-β，δ-二羟基-5-(1-甲基乙基)-3-苯基-4-[(苯氨基)羰基1]-1H-吡咯-1-庚酸半钙盐，(2))是可用作酶3-羟基-3-甲基戊二酰-辅酶A还原酶(HMG-CoA还原酶)的抑制剂的药物成分，因而可用作降血脂剂和降血胆固醇制剂。
阿托伐他汀的制备是众所周知的，最常用的方法是基于作为叔丁酯((1)；R1＝-C(CH3)3)的羧酸官能团以及作为丙酮化合物((1)；R2＝R3＝-CH3)的二醇官能团的保护/脱保护。这在WO 2008/129562及其中所列的多个参考文献中已有描述。
就任何活性药物中间体而言，最终产品中杂质的严格控制对于阿托伐他汀来说都是至关重要的。上述利用羧酸官能团的叔丁酯保护的一般反应顺序已得到广泛的研究。叔丁酯官能团的独特的化学特性产生独特的杂质光谱，不论是化学结构方面还是相对量的方面。在上述文献中给出了多种溶液用于降低杂质的量。然而，所有这些溶液均只适用于叔丁酯的保护策略。
近年来，WO 2009/019561中公开了另一种保护形式，即用于羧酸基保护的异丙基((1)；R1＝-CH(CH3)2)的使用。在现有技术的脱保护条件下，与叔丁酯官能团相比该基团化学反应性的差异导致需要不同溶液的杂质分布的差异。
发明详述
在本发明的第一方面，通过下列步骤实现由通式(1)的化合物制备式(2)的阿托伐他汀半钙盐，其中R1＝-CH(CH3)2，并且R2和R3独立地选自由乙基、甲基和丙基组成的组，或其中R2和R3形成环戊亚基或环己亚基环，
(a)用酸处理通式(1)的所述化合物在第一溶剂中的溶液；
(b)用碱金属氢氧化物处理步骤(a)所得到的混合物；
(c)用钙盐或氢氧化钙处理经洗涤的在步骤(b)所得到的混合物。
合适的第一溶剂包括乙腈、醇、环醚(例如二氧六环和四氢呋喃)和酮(例如丙酮)及其混合物。第一溶剂可以是醇，例如乙醇、异丙醇、甲醇和丙醇。步骤(a)中所用的酸可以是无机酸，例如氢溴酸、氢氯酸、硝酸、磷酸或硫酸。加入步骤(b)的碱金属氢氧化物的量使得混合物的pH升至介于11和13之间的值，优选介于11.5和12.5之间。合适的碱金属氢氧化物为氢氧化锂、氢氧化钾和氢氧化钠。步骤(c)中使用的钙盐可以是乙酸钙。为了促进结晶，加入钙盐之前，可以加入阿托伐他汀半钙盐晶形I的晶种。
步骤(c)之后阿托伐他汀半钙盐沉淀并且可以通过过滤、离心或本领域技术人员已知的其他技术而分离。任选地，在水环境(优选在水中)中通过再成浆使所得到的产物进一步纯化，随后分离并干燥晶体。
在上述工艺期间，形成杂质(3)和/或(4)。
不幸的是，其中存在于最终产品的这些杂质的量可能高达0.2％，鉴于USP和/或European Pharmacopoeia(Ph.Eur.)要求，这是不想要的。令人惊讶的是，已发现可以通过浓缩步骤(a)中得到的混合物而显著降低杂质的量。当所述浓缩在5min到8h的时间段内在10℃到30℃的温度下进行时，得到最好的结果。温度可以保持低于25℃。在浓缩过程中第一醇的加入量进一步改善了工艺，从而允计更长的浓缩时间。通过应用上述手段，得到杂质(3)和/或(4)的水平低至0.0001％到0.05％的阿托伐他汀半钙盐的晶形I。浓缩时间为1到4小时，例如2到3.5小时。
业已发现，在特定的情况下可能有利的是，可以在过程步骤(b)和(c)之间进行使用第二溶剂的洗涤步骤。所述第二溶剂可以是醚(例如二丁基醚、二乙基醚、甲基醚、甲基叔丁基醚)或酯(例如乙酸乙酯或乙酸异丙酯)或烃(例如甲苯或石油醚)。
在本发明的第二方面，公开了一种组合物，其包含阿托伐他汀半钙盐和0.0001重量％到0.05重量％的通式(3)的化合物和/或0.0001重量％到0.05重量％的通式(4)的化合物。本发明第二方面的组合物中存在的少量杂质是前所未有的，将产生纯度增大的活性药物成分，有利的是其在治疗期间将产生更少的副作用。
实施例
实施例1
由2-((4R，6R)-6-(2-(3-(苯氨羰基)-5-(4-氟苯基)-2-异丙基-4-苯基-1H-吡咯-1-基)乙基)-2，2-二甲基-1，3-二氧六环-4-基)乙酸异丙酯((1)；R1＝-CH(CH3)2，R2和R3＝-CH3)制备阿托伐他汀钙
将2-((4R，6R)-6-(2-(3-(苯氨羰基)-5-(4-氟苯基)-2-异丙基-4-苯基-1H-吡咯-1-基)乙基)-2，2-二甲基-1，3-二氧六环-4-基)乙酸异丙酯(20g，31mmol)加入600mL甲醇中。混合物在33-35℃下搅拌直到得到透明的溶液。将溶液冷却到26-28℃。然后在约15min内加入21mL 2.2N的HCl水溶液。使反应混合物在26-28℃下搅拌7h。在2h内使混合物在真空和约27-29℃下浓缩至其原始体积的约50％。浓缩之后，将反应混合物搅拌30min。HPLC分析表明起始物料减少至小于0.05％。在1h内向该混合物加入147mL 0.6N的NaOH水溶液，同时保持温度低于30℃。pH为约12。搅拌4h之后，透明的溶液在真空和27-29℃下浓缩直至得到淤浆。然后加入200mL水和100mL甲基叔丁基醚。发生相分离。用2.0g活性炭处理水相。过滤掉碳之后，用5％的乙酸水溶液将pH调至8.7。加热反应混合物加热直到45-50℃，并加入40mL水。接着，加入2.0g阿托伐他汀钙多晶型物I的种子，随后加入3.2g乙酸钙在100mL水中的溶液。将混合物加热到55-58℃，并保持在该温度30min。将淤浆冷却到40-45℃并搅拌3h。通过过滤分离出固体并在200mL水中再次成浆。将淤浆加热到40℃，搅拌1h之后过滤。白色固体在50-55℃下干燥。重量为18.0g。杂质：醚(3)：0.04％；缩酮(4)：0.05％。对比例2(在40-45℃下浓缩)
由2-((4R，6R)-6-(2-(3-(苯氨羰基)-5-(4-氟苯基)-2-异丙基-4-苯基-1H-吡咯-1-基)乙基)-2，2-二甲基-1，3-二氧六环-4-基)乙酸异丙酯((1)‘R1＝-CH(CH3)2，R2和R3＝-CH3)制备阿托伐他汀钙
将2-((4R，6R)-6-(2-(3-(苯氨羰基)-5-(4-氟苯基)-2-异丙基-4-苯基-1H-吡咯-1-基)乙基)-2，2-二甲基-1，3-二氧六环-4-基)乙酸异丙酯(30g，31mmol)加入450mL甲醇中。混合物在33-35℃下搅拌直到得到透明的溶液，然后冷却到26-28℃。在15min内加入HCl水溶液(2.2N，36mL)并在26-28℃下搅拌2h。在4h内使混合物在真空和40-45℃下浓缩(大约蒸馏掉200mL)，随后加入200mL甲醇。当HPLC分析表明起始物料减少至小于0.05％时，将反应混合物搅拌1h。在1h内向该混合物加入207mL 0.6N的NaOH水溶液，同时保持温度低于30℃。pH为约12。搅拌2h之后，透明的溶液在真空和27-29℃下浓缩直至得到淤浆。加入水(300mL)和甲基叔丁基醚(180mL)。发生相分离。用3.0g活性炭处理水相。过滤掉碳之后，用5％的乙酸水溶液将pH调至9.0。将反应混合物加热至45-50℃，并加入60mL水。接着，加入3.0g阿托伐他汀钙多晶型物I的种子，随后在1h内加入6.0g乙酸钙在150mL水中的溶液。将混合物加热到55-58℃，并保持在该温度30min。将淤浆冷却到40-45℃并搅拌3h。通过过滤分离出固体并在450mL水中再次成浆。将淤浆加热到40℃，搅拌1h之后过滤。白色固体在50-55℃的真空下干燥。重量为22.8g。杂质：醚(3)：0.73％；缩酮(4)：0.02％。对比例3(无浓缩)
由2-((4R，6R)-6-(2-(3-(苯氨羰基)-5-(4-氟苯基)-2-异丙基-4-苯基-1H-吡咯-1-基)乙基)-2，2-二甲基-1，3-二氧六环-4-基)乙酸异丙酯((1）；R1＝-CH(CH3)2，R2和R3＝-CH3)制备阿托伐他汀钙
将2-（(4R，6R)-6-(2-(3-(苯氨羰基)-5-(4-氟苯基)-2-异丙基-4-苯基-1H-吡咯-1-基)乙基)-2，2-二甲基-1，3-二氧六环-4-基)乙酸异丙酯(30g，31mmol)加入450mL甲醇中。混合物在33-35℃下搅拌直到得到透明的溶液，随后冷却到26-28℃。当HPLC分析表明起始物料减少至小于0.2％时，在15min内加入36mL 2.2N的HCl水溶液，并将所得到的反应混合物在26-28℃下搅拌2h。在1h内向该混合物加入207mL 0.6N的NaOH水溶液，同时保持温度低于30℃。pH为约12。搅拌2h之后，透明的溶液在真空和27-29℃下浓缩直至得到淤浆。然后加入300mL水和180mL甲基叔丁基醚。发生相分离。接着，用乙酸乙酯/环己烷的混合物(240mL乙酸乙酯和240mL环己烷，50/50)来萃取水层。发生相分离。之后用3.0g活性炭处理水相。过滤掉碳之后，溶液的pH为约8.5。加热反应混合物直到45-50℃，并加入60mL水。加入3.0g阿托伐他汀钙多晶型物I的种子，随后在1h内加入6.0g乙酸钙在150mL水中的溶液。将混合物加热到55-58℃，并保持在该温度30min。将淤浆冷却到40-45℃并搅拌3h。通过过滤分离出固体并在400mL水中再次成浆。将淤浆加热到40℃，搅拌1h之后过滤。白色固体在50-55℃下干燥。重量为23.6g。杂质：醚(3)：0.16％；缩酮(4)：0.15％。
实施例4
由2-((4R，6R)-6-(2-(3-(苯氨羰基)-5-(4-氟苯基)-2-异丙基-4-苯基-1H-吡咯-1-基)乙基)-2，2-二甲基-1，3-二氧六环-4-基)乙酸异丙酯((1)；R1＝-CH(CH3)2，R2和R3＝-CH3)制备阿托伐他汀钙
将2-（(4R，6R)-6-(2-(3-(苯氨羰基)-5-(4-氟苯基)-2-异丙基-4-苯基-1H-吡咯-1-基)乙基)-2，2-二甲基-1，3-二氧六环-4-基)乙酸异丙酯(75kg，117mol)加入1125L甲醇中。混合物在35-37℃下搅拌直到透明。将溶液冷却到25-27℃。加入HCl水溶液(由19kg浓HCl和64L水制成)，并使反应混合物在25-27℃下搅拌2h。接着，在3.5h内使混合物在真空和20-22℃下浓缩至其原始体积的约50％。加入甲醇(825L)，并使混合物搅拌45min。HPLC分析表明起始物料减少至小于0.03％。向该混合物加入NaOH水溶液(由15kgNaOH和560L水制成)，同时保持温度低于30℃，以得到12.2的pH。溶液在25-27℃下搅拌2h，保持pH不小于12。在5h内使反应混合物在真空和20-22℃的温度下浓缩至约900L。接着，加入750L水和450L甲基叔丁基醚并搅拌15分钟。放置反应混合物，发生相分离。再次加入450L甲基叔丁基醚并搅拌15分钟。放置反应混合物，发生相分离。将水层加热到35-37℃之后，加入7.5kg活性炭，随后搅拌30min。通过经水/甲醇(135L水/15L 甲醇)洗涤的Hyflo床和碳/hyflo床来过滤反应混合物。所得到的溶液在真空下浓缩，随后加入150L水和37.5L甲基叔丁基醚。温度增大到45-47℃，并用乙酸水溶液(3L乙酸在60L水中)将pH调至8.6-8.8。加热反应混合物直到47-50℃之后，加入7.5kg阿托伐他汀钙多晶型物I的种子，随后在1h内加入14.5kg乙酸钙在375L水中的溶液。将混合物加热到55-58℃，并保持在该温度30min。然后将淤浆冷却到40-45℃并搅拌3h。通过离心分离出固体，所得到的湿饼在40-45℃的1125L水中再次成浆。搅拌1h之后，通过离心分离出固体并在50-55℃的真空下干燥。重量为63.5kg。如果需要，材料可以研磨、共混和/或微粉化。杂质：醚(3)：0.05％；缩酮(4)：未检测到。
实施例5(较长的浓缩时间)
由2-((4R，6R)-6-(2-(3-(苯氨羰基)-5-(4-氟苯基)-2-异丙基-4-苯基-1H-吡咯-1-基)乙基)-2，2-二甲基-1，3-二氧六环-4-基)乙酸异丙酯((1)’R1＝-CH(CH3)2，R2和R3＝-CH3)制备阿托伐他汀钙
将2-((4R，6R)-6-(2-(3-(苯氨羰基)-5-(4-氟苯基)-2-异丙基-4-苯基-1H-吡咯-1-基)乙基)-2，2-二甲基-1，3-二氧六环-4-基)乙酸异丙酯(90kg，141mol)加入1350L甲醇中。混合物在35-37℃下搅拌直到透明。将溶液冷却到25-27℃。加入HCl水溶液(由22.8kg浓HCl和77L水制成)。使混合物在25-27℃下搅拌2h。然后在约16h内使混合物在真空和29-30℃下浓缩至其原始体积的约30％。加入825L甲醇，并使混合物在5h内在真空和29-30℃下继续浓缩至其原始体积的约40％。向该混合物加入900L甲醇，之后加入620L 0.6N的NaOH水溶液，同时保持温度低于30℃，以得到不小于12的pH(实际温度为26℃且pH为12.4)。溶液在25-27℃下搅拌2h，保持pH不小于12。在8h内使反应混合物在真空和29-30℃下浓缩(蒸馏掉约900L)。接着，加入810L水和540L甲基叔丁基醚并搅拌15分钟。放置反应混合物，发生相分离。将水层加热到35-37℃之后，加入5.0kg活性炭并搅拌30min。通过经水/甲醇(80L水/10L甲醇)洗涤的Hyflo床和碳/hyflo床来过滤反应混合物。向该溶液加入22L乙酸乙酯并搅拌1h。如果pH不是8.0-8.5，则加入5L乙酸乙酯并继续搅拌1h或更长。加热反应混合物至47-50℃之后，加入9.0kg阿托伐他汀钙多晶型物I的种子，随后在1h内加入14.0kg乙酸钙在270L水中的溶液。将混合物加热到55-58℃，并保持在该温度30min。然后将淤浆冷却到40-45℃并搅拌3h。通过离心分离出固体，所得到的湿饼在40-45℃的900L水中再次成浆。搅拌1h之后，通过离心分离出固体并在50-55℃的真空下干燥。重量为75.9kg。如果需要，材料可以研磨、共混和/或微粉化。杂质：醚(3)：0.16％；缩酮(4)：未检测到。
N.D.＝未检测到
Claims (7)
1.一种用于由通式(1)的化合物来制备式(2)的阿托伐他汀半钙盐的方法，其中R1＝-CH(CH3)2，并且R2和R3独立地选自由乙基、甲基和丙基组成的组，或其中R2和R3形成环戊亚基或环己亚基环，所述方法包括下列步骤：
(a)用酸处理通式(1)的所述化合物在第一溶剂中的溶液；
(b)用碱金属氢氧化物处理步骤(a)所得到的所述混合物；
(c)用钙盐或氢氧化钙处理经洗涤的在步骤(b)所得到的所述混合物，所述方法的特征在于，步骤(a)所得到的所述混合物在5min到8h的时间段内在10℃到30℃的温度下进行浓缩。
2.如权利要求1所述的方法，其中，R2和R3均为甲基。
3.如权利要求1或2中任意一项所述的方法，其中，所述第一溶剂是醇。
4.如权利要求1至3中任意一项所述的方法，其中，所述第一溶剂是甲醇。
5.如权利要求1至4中任意一项所述的方法，其中，在步骤(c)之前用第二溶剂洗涤步骤(b)之后得到的所述混合物。
6.如权利要求5所述的方法，其中，所述第二溶剂是醚。
7.一种组合物，其包含阿托伐他汀半钙盐和0.0001重量％到0.05重量％的通式(3)的化合物和/或0.0001重量％到0.05重量％的通式(4)的化合物。
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Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003068739A1 (en) * | 2002-02-01 | 2003-08-21 | Zentiva A.S. | Method of manufacturing an amorphous form of the hemi-calcium salt of (3r, 5r) 7- 3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl!-3, 5-dihydroxyheptanoic acid (atorvastatin) |
| CN1487921A (zh) * | 2001-01-23 | 2004-04-07 | ������ҩ�뻯ѧ��˾ | 非结晶阿托伐他汀钙的制备 |
| WO2006011155A1 (en) * | 2004-07-26 | 2006-02-02 | Apollo International Limited | One pot process for amorphous atorvastain calcium |
| WO2006048893A2 (en) * | 2004-11-05 | 2006-05-11 | Morepen Laboratories Limited | A process for synthesis of large particle size statin compounds |
| CN1946688A (zh) * | 2004-03-17 | 2007-04-11 | 兰贝克赛实验室有限公司 | 阿托伐他汀半钙的晶型 |
| CN1980890A (zh) * | 2004-05-31 | 2007-06-13 | 兰贝克赛实验室有限公司 | 阿托伐他汀的制备方法 |
| WO2008129562A2 (en) * | 2007-04-20 | 2008-10-30 | Morepen Laboratories Limited | An improved process for the preparation of stable amorphous atorvastatin hemi calcium and their salts thereof |
| TW200848406A (en) * | 2006-12-19 | 2008-12-16 | Pfizer Prod Inc | Novel process for the synthesis of [R-(R*,R*)]-2-(4-fluorophenyl)-β, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid or a pharmaceutically acceptable salt thereof |
| WO2009019561A2 (en) * | 2007-08-03 | 2009-02-12 | Pfizer Products Inc. | Process for preparing chiral compounds |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6777552B2 (en) * | 2001-08-16 | 2004-08-17 | Teva Pharmaceutical Industries, Ltd. | Processes for preparing calcium salt forms of statins |
| PT1341785E (pt) * | 2000-11-16 | 2009-01-16 | Teva Pharma | Hidrólise de ésteres de ácidos r(r*,r*)-2-(4-fluorofenil)-beta,delta-di-hidroxi-5-(1-metiletil)-3-fenil-4-[(fenilamino)-carbonil]-1h-pirrole-1-heptanóico com hidróxido de cálcio |
-
2011
- 2011-04-18 US US13/642,005 patent/US20130041162A1/en not_active Abandoned
- 2011-04-18 WO PCT/EP2011/056103 patent/WO2011131605A1/en active Application Filing
- 2011-04-18 EP EP11714776.9A patent/EP2560951B1/en active Active
- 2011-04-18 SI SI201130926A patent/SI2560951T1/sl unknown
- 2011-04-18 HU HUE11714776A patent/HUE030160T2/en unknown
- 2011-04-18 CN CN201180020007.4A patent/CN103108863B/zh active Active
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1487921A (zh) * | 2001-01-23 | 2004-04-07 | ������ҩ�뻯ѧ��˾ | 非结晶阿托伐他汀钙的制备 |
| WO2003068739A1 (en) * | 2002-02-01 | 2003-08-21 | Zentiva A.S. | Method of manufacturing an amorphous form of the hemi-calcium salt of (3r, 5r) 7- 3-phenyl-4-phenylcarbamoyl-2-(4-fluorophenyl)-5-isopropyl-pyrrol-1-yl!-3, 5-dihydroxyheptanoic acid (atorvastatin) |
| CN1946688A (zh) * | 2004-03-17 | 2007-04-11 | 兰贝克赛实验室有限公司 | 阿托伐他汀半钙的晶型 |
| CN1980890A (zh) * | 2004-05-31 | 2007-06-13 | 兰贝克赛实验室有限公司 | 阿托伐他汀的制备方法 |
| WO2006011155A1 (en) * | 2004-07-26 | 2006-02-02 | Apollo International Limited | One pot process for amorphous atorvastain calcium |
| WO2006048893A2 (en) * | 2004-11-05 | 2006-05-11 | Morepen Laboratories Limited | A process for synthesis of large particle size statin compounds |
| TW200848406A (en) * | 2006-12-19 | 2008-12-16 | Pfizer Prod Inc | Novel process for the synthesis of [R-(R*,R*)]-2-(4-fluorophenyl)-β, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid or a pharmaceutically acceptable salt thereof |
| WO2008129562A2 (en) * | 2007-04-20 | 2008-10-30 | Morepen Laboratories Limited | An improved process for the preparation of stable amorphous atorvastatin hemi calcium and their salts thereof |
| WO2009019561A2 (en) * | 2007-08-03 | 2009-02-12 | Pfizer Products Inc. | Process for preparing chiral compounds |
Non-Patent Citations (3)
| Title |
|---|
| JEONG-SOO KIM,等: "Physicochemical properties and oral bioavailability of amorphous atorvastatin hemi-calcium using spray-drying and SAS process", 《INTERNATIONAL JOURNAL OF PHARMACEUTICS》 * |
| 张海霞,等: "反溶剂沉淀法制备阿托伐他汀钙微粉", 《化工学报》 * |
| 徐颂: "阿托伐他汀钙合成路线", 《中国新药杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109232355A (zh) * | 2018-10-09 | 2019-01-18 | 河南师范大学 | 一种有效去除阿托伐他汀钙粗品中杂质阿托伐他汀缩合物的方法 |
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