CN1263525A - 氨氯地平苯磺酸盐的制备方法 - Google Patents

氨氯地平苯磺酸盐的制备方法 Download PDF

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CN1263525A
CN1263525A CN99800509A CN99800509A CN1263525A CN 1263525 A CN1263525 A CN 1263525A CN 99800509 A CN99800509 A CN 99800509A CN 99800509 A CN99800509 A CN 99800509A CN 1263525 A CN1263525 A CN 1263525A
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amlodipine
water
salt
benzenesulphonate
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CN1122023C (zh
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M·洛斯托夫斯基
M·维克佐莱克
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Adamed Sp zoo
Adamed Pharma SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

本发明公开了一种氨氯地平苯磺酸盐的制备方法,其中氨氯地平与无机或有机酸形成的盐与碱金属苯磺酸盐在含水介质或在水－C1－2醇混合物中进行反应。氨氯地平苯磺酸盐用来制备具有钙通道阻断活性的药物,可用于治疗冠状动脉病变和动脉高压。

Description

氨氯地平苯磺酸盐的制备方法
本发明涉及氨氯地平苯磺酸盐，即式I所示的2-(2-氨基乙氧基甲基)-4-(2-氯苯基)-3-乙氧基羰基-5-甲氧基羰基-6-甲基-1，4-二氢吡啶单苯磺酸盐的制备方法。
氨氯地平是属于钙通道阻断剂族的现代药物。它对微动脉阻力和冠状动脉阻力呈现显著的选择性并具有特定的药物动力学性能：良好的生物可利用性、半衰期长、发生作用的起始和衰减缓慢以及长时间持续的药理反应、不存在与其它药物的任何明显相互作用。
由于氨氯地平的这些优点，它作为首选的药剂被成功的用于治疗动脉高压；它还成功的用于治疗冠状动脉病变，包括Prinzmetal心绞痛和其它循环系统疾病。
虽然氨氯地平以其游离碱的形态表现出生物活性，但它以与药理上可接受的酸的盐的形式被用在药物制剂中。
欧洲专利申请EP 089167公开了一系列药物可接受的氨氯地平的盐如盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、乙酸盐、马来酸盐、酒石酸盐、柠檬酸盐和其它盐。其中马来酸盐是最优选的盐。
欧洲专利申请EP 0244944公开了制备氨氯地平苯磺酸盐的方法，其中包括用苯磺酸或用苯磺酸铵盐在惰性有机溶剂中处理呈游离碱形式的氨氯地平。在其实施例(实施例I和V)中使用工业甲醇作为溶剂。
作为氨氯地平给药的已被接受的氨氯地平苯磺酸盐呈片剂和无菌水溶液形式。
氨氯地平苯磺酸盐表现出的一些物理性能使得它特别适用作药理上可接受的氨氯地平盐。无论是呈固体还是溶液形态，它都比其它盐稳定的多；它易溶于水(4.6mg/ml)但不吸湿。其饱和水溶液的pH为约6.6，较接近于血的pH7.4。最后，由于其极好的机械性能，易于被压制，形成性能良好的片剂，不会粘附到制片机的冲模上，等等。
然而，虽然氨氯地平苯磺酸盐极好地满足良好药物的要求，但其公知的制备方法却存在一些缺点。
EP 0244944的氨氯地平苯磺酸盐制备方法包括使氨氯地平游离碱与苯磺酸反应。该方法在醇中进行，因而，由于醇的易燃性可造成发生火灾的危险。其它的缺点是由于该反应利用了作为苛性、腐蚀性和毒性物质的游离苯磺酸。另外，由于其高吸水性，对该种酸在运输和操作过程中需要特殊的防护，其实际使用形态是含约90％酸和约10％水的稠密油状物质。
其可供选择替代的另一种方法也存在一些危险。虽然危险的苯磺酸已被其铵盐所替代，因而消除了与使用游离酸有关的危险和缺陷，但伴随氨氯地平苯磺酸盐的生成，形成氨气，它是有毒并危险的，因而必须另外将其吸收并脱活性。当然，与易燃的醇有关的火灾危险仍存在。
通过本发明的氨氯地平苯磺酸盐制备方法消除了以上讨论的危险和难题。
按照本发明的方法，氨氯地平的无机或有机酸盐(除苯磺酸盐外)与碱金属苯磺酸盐在含水介质中或在水-C1-C2醇混合物中进行反应。
氨氯地平盐优选选自乙酸盐、甲酸盐、氯代乙酸盐、氢溴酸盐、硝酸盐、盐酸盐、甲磺酸盐。特别优选盐酸盐、乙酸盐或甲酸盐。
碱金属苯磺酸盐包括苯磺酸锂、钠和钾。作为廉价、安全、稳定和市场上可得到的化学品，特别优选苯磺酸钠。
优选的水-醇混合物是水-乙醇混合物，其中含20至50％(V/V)乙醇，特别是1∶1的混合物。
本发明的方法可按以下方式实现，制备氨氯地平盐在水或水-醇混合物中的溶液或悬浮液，并优选在5-40℃强烈搅拌条件下以化学计量或者优选以苯磺酸钠/氨氯地平盐摩尔比为1∶1.15的量添加苯磺酸钠水溶液，该混合物被搅拌约10-60分钟，视具体情况而定被加热至40℃然后冷却至10℃。过滤所产生的氨氯地平苯磺酸盐沉淀物，用水洗涤两次，并干燥。如分离出的盐呈油状，还需添加一些氨氯地平苯磺酸盐晶体来加速结晶过程。如此获得的产物不含杂质。另外，也可通过向氨氯地平盐中添加固体苯磺酸钠来实现所述的方法。使反应物的添加次序相反，即向苯磺酸钠水溶液中添加氨氯地平盐也产生高纯度的产物。
以下提供非限定的实施例来说明本发明：
实施例1
向水(150ml)中添加氨氯地平盐酸盐(71.5g)，并在20℃搅拌该混合物15分钟。在10分钟内分批添加苯磺酸钠(33.3g)在200ml水中的溶液。添加作为晶种的少量氨氯地平苯磺酸盐晶体，并搅拌该混合物40分钟。然后冷却至10℃，并过滤生成的沉淀物。用蒸馏水(3×100ml)洗涤所述沉淀物并干燥。获得80.0g氨氯地平苯磺酸盐，mp＝201℃。产率：88％。
实施例2
在20℃搅拌条件下，向苯磺酸钠(4g)在水(20ml)中的溶液中，分批添加氨氯地平甲酸盐(9.1g)。在完成添加后，搅拌该混合物20分钟，然后冷却至5℃，并过滤产物沉淀物。用水(2×20ml)洗涤所述沉淀物并在真空中干燥。获得18.8g氨氯地平苯磺酸盐，mp＝201℃。产率：90％。
实施例3
在强烈搅拌条件下向氨氯地平氢溴酸盐(9.6g)在水(25ml)中的溶液中分批添加苯磺酸钠(4g)。在完成添加后，搅拌该混合物20分钟，然后冷却至5℃，按照实施例2的步骤，获得11.6g氨氯地平苯磺酸盐，mp＝201℃。
实施例4
在20℃搅拌条件下，向苯磺酸钠(4g)在水(10ml)中的溶液中，分批添加氨氯地平乙酸盐(9.3g)在20ml水-乙醇(1∶1)混合物中的溶液。在完成添加后，搅拌该混合物30分钟，然后冷却至5℃，添加一些氨氯地平苯磺酸盐晶体和另外10ml水。按照实施例2的步骤获得氨氯地平苯磺酸盐，产率为83％，mp＝201℃。
实施例5
以氨氯地平氯代乙酸盐(10.6g)和苯磺酸钠(4g)作为起始物，按照实施例1的步骤获得氨氯地平苯磺酸盐，产率为89％，mp＝201℃。
实施例6
以氨氯地平甲磺酸盐(10.6g)和苯磺酸钠(4g)作为起始物，按照实施例1的步骤获得氨氯地平苯磺酸盐，产率为81％，mp＝201℃。
实施例7
以氨氯地平硝酸盐(9.4g)和苯磺酸钠(4g)作为起始物，按照实施例1的步骤，获得氨氯地平苯磺酸盐，产率为83％，mp＝201℃。

Claims (6)

1.式I所示氨氯地平苯磺酸盐的制备方法，其特征在于氨氯地平与无机或有机酸形成的盐与碱金属苯磺酸盐在含水介质或在水-C1-2醇混合物中进行反应。
Figure A9980050900021
2.权利要求1的方法，其特征在于氨氯地平盐选自乙酸盐、甲酸盐、氯代乙酸盐、氢溴酸盐、硝酸盐、盐酸盐或甲磺酸盐，优选盐酸盐。
3.权利要求1-2中任一项的方法，其特征在于碱金属苯磺酸盐是苯磺酸钠。
4.权利要求1-3中任一项的方法，其特征在于所述反应在含20至50％乙醇的水-醇混合物，特别是1∶1混合物中进行。
5.权利要求1-4中任一项的方法，其特征在于所述反应在含水介质中进行。
6.权利要求1-5中任一项的方法，其特征在于所述反应在5-40℃的温度下进行。
CN99800509A 1998-04-09 1999-04-08 氨氯地平苯磺酸盐的制备方法 Expired - Fee Related CN1122023C (zh)

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DE (1) DE69926704D1 (zh)
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CN100391946C (zh) * 2006-05-26 2008-06-04 苏州东瑞制药有限公司 一种苯磺酸氨氯地平的制备方法
CN103044314A (zh) * 2013-01-06 2013-04-17 先声药业有限公司 马来酸氨氯地平的制备方法

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WO2002053541A1 (en) 2000-12-29 2002-07-11 Pfizer Limited Amide derivative of amlodipine
EP1309557B9 (en) 2000-12-29 2006-11-15 Pfizer Limited Amlodipine hemimaleate
GB2371862B (en) 2000-12-29 2004-07-14 Bioorg Bv Reference standards for determining the purity or stability of amlodipine maleate and processes therefor
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AT5874U1 (de) 2000-12-29 2003-01-27 Bioorg Bv Pharmazeutische zubereitungen enthaltend amlodipinmaleat
BR0116557A (pt) * 2000-12-29 2003-10-28 Pfizer Ltd Processo, processo para fabricação de um sal de maleato de amlodipina substancialmente livre de aspartato de amlodipina, processo para purificação, maleato de amlodipina, composição farmacêutica para tratar ou prevenir angina ou hipertenção, método para tratar hipertenção, angina ou ataque cardìaco, benzeno sulfonato de amlodipina, hidrocloreto de amlodipina e uso de maleato de amlodipina substancialmente livre de aspartato de amlodipina
EP1309556B1 (en) 2000-12-29 2004-11-24 Pfizer Limited Amlodipine fumarate
GB2372036B (en) 2000-12-29 2004-05-19 Bioorg Bv Aspartate derivative of amlodipine
DE50112189D1 (de) * 2001-01-09 2007-04-26 Siegfried Generics Int Ag Salze von Amlodipin-Mesylat
EP1435954B1 (en) 2001-07-06 2010-01-13 LEK Pharmaceuticals D.D. A PROCESS FOR THE PREPARATION OF HIGHlLY PUREAMLODIPINE BENZENESULFONATE
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US6828339B2 (en) * 2001-11-21 2004-12-07 Synthon Bv Amlodipine salt forms and processes for preparing them
KR100538641B1 (ko) 2002-07-30 2005-12-22 씨제이 주식회사 암로디핀의 유기산염
KR100462304B1 (ko) 2002-07-30 2004-12-17 씨제이 주식회사 암로디핀의 유기산염
KR100496436B1 (ko) 2002-07-30 2005-06-20 씨제이 주식회사 암로디핀의 유기산염
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PL236001B1 (pl) 2012-12-21 2020-11-30 Adamed Spolka Z Ograniczona Odpowiedzialnoscia Złożona kompozycja farmaceutyczna zawierająca kandesartan cyleksetylu oraz amlodypinę, sposób jej wytwarzania oraz jednostkowa postać dawkowania zawierająca tę kompozycję

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Publication number Priority date Publication date Assignee Title
CN100391946C (zh) * 2006-05-26 2008-06-04 苏州东瑞制药有限公司 一种苯磺酸氨氯地平的制备方法
CN103044314A (zh) * 2013-01-06 2013-04-17 先声药业有限公司 马来酸氨氯地平的制备方法

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PL325757A1 (en) 1999-10-11
WO1999052873A1 (en) 1999-10-21
ATE302187T1 (de) 2005-09-15
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SK282736B6 (sk) 2002-11-06
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EP0993447A1 (en) 2000-04-19
CZ295311B6 (cs) 2005-07-13
DE69926704D1 (de) 2005-09-22
UA57091C2 (uk) 2003-06-16
ES2245823T3 (es) 2006-01-16
KR20010013297A (ko) 2001-02-26
RU2177000C2 (ru) 2001-12-20
AU3061399A (en) 1999-11-01
PL189666B1 (pl) 2005-09-30
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