CN1100038C - 氨氯地平对映体的拆分 - Google Patents
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- 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
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Abstract
本发明提供一个可行的拆分消旋氨氯地平的两个(R)-(+)-和(S)-(-)-对映体的方法，拆分用的手性试剂是酒石酸，拆分用的手性助剂是六氘代二甲基亚砜(DMSO-d6)。
Description
本发明提供一个可行的拆分消旋氨氯地平的两个(R)-(+)-和(S)-(-)-对映体的方法，拆分用的手性试剂是酒石酸，拆分用的手性助剂是六氘代二甲基亚砜(DMSO-d6)。
1.背景
(S)-(-)-氨氯地平和它的盐是长效钙通道拮抗剂，对于治疗高血压和心绞痛是有效的。(R)-(+)-氨氯地平也显示了治疗或防止动脉硬化的活性。
辉瑞公司(Pfizer)发明了一个氨氯地平对映体的拆分可行方法(WO95/25722)，其光学纯度和收率都非常高。该方法的关键是同时应用二甲基亚砜(DMSO)及手性试剂酒石酸。
本发明指出六氘代二甲基亚砜(DMSO-d6)是一种比DMSO还好的手性助剂，其光学纯度可达100％e.e.，并且收率也相当高。
2.发明
本发明提供了一个可行的拆分消旋氨氯地平的方法，拆分用的手性试剂是L-酒石酸或D-酒石酸，拆分用的手性助剂是六氘代二甲基亚砜(DMSO-d6)，氨氯地平和酒石酸的摩尔比大约是1∶0.25，发生的沉淀是(S)-(-)-氨氯地平-半-D-酒石酸-单-DMSO-d6配合物或(R)-(+)-氨氯地平-半-L-酒石酸-单-DMSO-d6配合物。
拆分氨氯地平的过程是，在手性助剂六氘代二甲基亚砜(DMSO-d6)或含DMSO-d6的有机溶剂中分别溶解氨氯地平和酒石酸，然后搅拌混合，氨氯地平同D-或L-酒石酸反应，结合一个DMSO-d6的(S)-(-)-氨氯地平的D-酒石酸盐，或结合一个DMSO-d6的(R)-(+)-氨氯地平的L-酒石酸盐而分别沉淀，用于沉淀物的分离方法有过滤，离心分离或移注。沉淀物的进一步处理可以得到(R)-(+)-氨氯地平或(S)-(-)-氨氯地平。
除去沉淀物后的母液可以用0.25当量相反极性的酒石酸(如首先用的是L-酒石酸，现在则用D-酒石酸)处理，相反极性的氨氯地平及其酒石酸和DMSO-d6配合物可生成沉淀。
拆分的溶剂是亚砜、酮、醇、醚、酰胺、酯、氯代烃、水、腈和烃。常见的溶剂是DMSO-d6、DMSO、丙酮、甲乙酮、异丙醇、乙醚、四氢呋喃、N，N’-二甲基甲酰胺、N，N’-二甲基丙撑脲、乙酸乙酯、氯仿、二氯甲烷、1，2-二氯乙烷、1，1，1-三氯乙烷、乙腈和甲苯。
其中使用的某一溶剂的最大数量是变化的，一个技术熟练的人能够确定这一适当的比例。但DMSO-d6/氨氯地平≥1(摩尔比)。
用于酒石酸盐重结晶的溶剂是醇类，例如：甲醇。
由氨氯地平的盐制备氨氯地平所用的碱类是金属的氢氧化物、氧化物、碳酸盐和酰胺盐。氢氧化钠是最方便的。
结晶的沉淀物组成分别是(S)-(-)-氨氯地平-半-D-酒石酸-单-DMSO-d6和(R)-(+)-氨氯地平-半-L-酒石酸-单-DMSO-d6配合物。
3.关于实施例
在以下实施例中，样品的光学纯度由手性HPLC测定。用于分离的HPLC条件如下：手性柱Ultron ES-OVM，Ovomucoid-15cm，流速0.3ml/min，检测波长360nm，流动相磷酸氢二钠缓冲溶液(20mM，PH7)/乙氰＝80/20。样品溶于乙氰/水＝50/50中，浓度为0.3mg/ml。
实施例1 由(R，S)-氨氯地平制备(S)-(-)-氨氯地平-半-D-酒石酸-单-DMSO-d6配合物和(R)-(+)-氨氯地平-半-D-酒石酸-单-DMSO-d6配合物5g(R，S)-氨氯地平溶于22.9g的DMSO-d6中，然后加入含0.458g D-酒石酸(0.25摩尔当量)溶于22.9g的DMSO-d6溶液并同时搅拌，在一分钟内开始沉淀，室温下搅拌过夜。过滤后，再用20ml丙酮洗涤，沉淀物在50℃下真空干燥过夜，得2.36g(理论收率的68％)(S)-(-)-氨氯地平-半-D-酒石酸-单-DMSO-d6配合物，m.p.158-160℃，(发现：C 50.81％，H(D)7.09％，N 4.84％，C20H25N2O5Cl·0.5[C4H6O6]·C2D6OS的计算值：C 50.74％，H(D)7.04％，N 4.90％)，光学纯度99.9％d.e.(手性HPLC)。
0.44g L-酒石酸(0.25摩尔当量)加入过滤液中，室温下搅拌过夜。过滤再用20ml丙酮洗涤，沉淀物在50℃下真空干燥过夜，得2.0g(理论收率的55％)(R)-(+)-氨氯地平-半-L-酒石酸-单-DMSO-d6配合物，m.p.158-160℃，(发现：C 50.67％，H(D)6.95％，N 4.90％，C20H25N2O5Cl·0.5[C4H6O6]·C2D6OS的计算值：C 50.74％，H(D)7.04％，N 4.93％)，光学纯度99.5％d.e.(手性HPLC)。
实施例2 由(S)-(-)-氨氯地平-半-D-酒石酸-单-DMSO-d6配合物制备(S)-(-)-氨氯地平 5g(S)-(-)-氨氯地平-半-D-酒石酸-单-DMSO-d6配合物和56ml 2N NaOH水溶液与56ml CH2Cl2一起搅拌40分钟。用水洗涤分离后的有机溶液蒸除CH2Cl2，加入己烷并搅拌使其结晶。过滤后的固体经50℃真空过夜干燥得3.20g(理论收率的88％)(S)-(-)-氨氯地平，m.p.107-110℃，(发现：C 58.69％，H 6.09％，N 6.84％；C20H25N2O5Cl的计算值：C 58.75％，H 6.16％，N 6.85％)，[α]D 25-32.6°(C＝1，MeOH)，光学纯度99.9％e.e.(手性HPLC)。
实施例3 由(R)-(+)-氨氯地平-半-L-酒石酸-单-DMSO-d6配合物制备(R)-(+)-氨氯地平5g(R)-(+)-氨氯地平-半-L-酒石酸-单-DMSO-d6配合物和56ml 2N NaOH水溶液与56ml CH2Cl2一起搅拌40分钟。用水洗涤分离后的有机溶液蒸除CH2Cl2，加入己烷并搅拌使其结晶。过滤后的固体经50℃真空过夜干燥得3.31g(理论收率的91％)(R)-(+)-氨氯地平，m.p.107-110℃，(发现：C 58.41％，H 6.05％，N 6.62％；C20H25N2O5Cl的计算值：C 58.75％，H 6.16％，N 6.85％)，[α]D 25+32.6°(C＝1，MeOH)，光学纯度99.5％e.e.(手性HPLC)。
实施例4 由(R，S)-氨氯地平制备(S)-(-)-氨氯地平-半-D-酒石酸-单-DMSO-d6配合物和(R)-(+)-氨氯地平-半-D-酒石酸-单-DMSO-d6配合物用实施例1的方法，但DMSO-d6用混合溶剂代替，并且DMSO-d6/氨氯地平≥1(摩尔比)。V溶剂/(VDMSO-d6+V溶剂)以百分比表示，(VDMSO-d6+V溶剂)/M＝4～18，其中V，溶剂体积，单位ml；M，氨氯地平质量，单位g。按实施例2-3处理配合物给出(S)-(-)-氨氯地平和(R)-(+)-氨氯地平
表
*测试方法为手性HPLC。
| 溶剂 | 溶剂体积％ | (S)-(-)-对映体％e.e.* | (R)-(+)-对映体e.e.* |
| 甲乙酮 | 2 | 99.0 | 98.7 |
| 甲苯 | 2 | 92.0 | 91.7 |
| 异丙醇 | 5 | 92.6 | 92.4 |
| 水 | 10 | 98.5 | 98.4 |
| 二甲基甲酰胺 | 10 | 98.3 | 98.1 |
| 四氢呋喃 | 33 | 98.6 | 98.5 |
| 乙酸乙酯 | 50 | 99.2 | 99.1 |
| 二氯甲烷 | 50 | 100 | 99.8 |
| 二乙基亚砜 | 50 | 98.1 | 98.4 |
| 二乙基亚砜 | 72 | 91.1 | 90.5 |
| 二甲基亚砜 | 90 | 94.5 | 94.1 |
| 丙酮 | 50 | 99.2 | 99.0 |
| 丙酮 | 70 | 95.7 | 96.1 |
| 丙酮 | 90 | 95.4 | 95.7 |
| 丙酮 | 97 | 96.8 | 96.5 |
| 丙酮 | 99 | 95.4 | 95.1 |
实施例5 苯磺酸(S)-(-)-氨氯地平的制备5g(S)-(-)-氨氯地平置120ml水中，然后加入1.4g苯磺酸并搅拌，在氮气保护下加热至60℃。溶解后，停止搅拌并冷却至室温，结晶过夜。过滤后，再经20ml水洗涤，苯磺酸(S)-(-)-氨氯地平在50℃下真空干燥过夜，得6.2g(理论收率的90％)，(发现：C 54.85％，H 5.15％，N 5.58％；C20H25N2O5Cl的计算值：C 54.72％，H 5.14％，N 5.34％)，[α]D 25-24.9°(C＝1，MeOH)，光学纯度99.9％e.e.(手性HPLC)。
Claims (3)
1.一种从混合物中分离出氨氯地平的(R)-(+)-和(S)-(-)-异构体的方法。其特征在于：包含下述反应，即在手性助剂六氘代二甲基亚砜(DMSO-d6)或含DMSO-d6的有机溶剂中，异构体的混合物同拆分手性试剂D-或L-酒石酸反应，结合一个DMSO-d6的(S)-(-)-氨氯地平的D-酒石酸盐，或结合一个DMSO-d6的(R)-(+)-氨氯地平的L-酒石酸盐而分别沉淀，其中氨氯地平与酒石酸的摩尔比约等于0.25。
2.根据权利要求1所述的方法，其特征在于：在DMSO-d6/氨氯地平≥1(摩尔比)条件下，所述用含DMSO-d6的有机溶剂是可以使含DMSO-d6配合物发生沉淀差异的溶剂，这些溶剂是水、亚砜类、酮类、酰胺类、酯类、氯代烃以及烃类化合物。
3.根据述任一权利要求所述的方法，其特征在于：沉淀的配合物是(S)-(-)-氨氯地平-半-D-酒石酸-单-DMSO-d6配合物或(R)-(+)-氨氯地平-半-L-酒石酸-单-DMSO-d6配合物。
Priority Applications (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN00102701A CN1100038C (zh) | 2000-02-21 | 2000-02-21 | 氨氯地平对映体的拆分 |
| PCT/CN2000/000538 WO2001060799A1 (fr) | 2000-02-21 | 2000-12-08 | Resolution d'enantiomeres d'amlidipine |
| US10/203,615 US6646131B2 (en) | 2000-02-21 | 2000-12-08 | Resolution of the enantiomers of amlodipine |
| CA002416062A CA2416062C (en) | 2000-02-21 | 2000-12-08 | Resolution of the enantiomers of amlodipine |
| AU2001218494A AU2001218494B2 (en) | 2000-02-21 | 2000-12-08 | Resolution of the enantiomers of amlodipine |
| DE60027476T DE60027476T2 (de) | 2000-02-21 | 2000-12-08 | Enantiomerentrennung von amlodipin |
| EP00981132A EP1258477B1 (en) | 2000-02-21 | 2000-12-08 | Resolution of the enantiomers of amlodipine |
| AU1849401A AU1849401A (en) | 2000-02-21 | 2000-12-08 | Resolution of the enantiomers of amlodipine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN00102701A CN1100038C (zh) | 2000-02-21 | 2000-02-21 | 氨氯地平对映体的拆分 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1267669A CN1267669A (zh) | 2000-09-27 |
| CN1100038C true CN1100038C (zh) | 2003-01-29 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN00102701A Expired - Fee Related CN1100038C (zh) | 2000-02-21 | 2000-02-21 | 氨氯地平对映体的拆分 |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US6646131B2 (zh) |
| EP (1) | EP1258477B1 (zh) |
| CN (1) | CN1100038C (zh) |
| AU (2) | AU1849401A (zh) |
| CA (1) | CA2416062C (zh) |
| DE (1) | DE60027476T2 (zh) |
| WO (1) | WO2001060799A1 (zh) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005054196A1 (fr) * | 2003-12-05 | 2005-06-16 | Shijiazhuang Pharmaceutical Group Ouyi Pharma. Co., Ltd. | Methode de separation enantiomere d'une amlodipine active optique |
| WO2011097860A1 (zh) | 2010-02-09 | 2011-08-18 | 施慧达药业集团(吉林)有限公司 | 一种左旋氨氯地平或其可药用盐和β受体阻滞剂的药物组合物及其应用 |
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| KR20040062575A (ko) | 2001-10-24 | 2004-07-07 | 세프라코 아이엔시. | 암로디핀 라셈체의 분리 방법 |
| CN1152013C (zh) * | 2001-11-22 | 2004-06-02 | 张喜田 | 一类左旋氨氯地平盐的水合物及其制剂 |
| KR100476636B1 (ko) | 2002-09-11 | 2005-03-17 | 한림제약(주) | 엘-(+)-타르트레이트를 이용한 에스-(-)-암로디핀의 제조방법 |
| WO2006043148A1 (en) * | 2004-10-20 | 2006-04-27 | Emcure Pharmaceuticals Limited | Process for producing enantiomer of amlodipine in high optical purity |
| WO2006059886A1 (en) * | 2004-12-02 | 2006-06-08 | Sk Chemicals, Co., Ltd. | Optical resolution method of amlodipine |
| KR101235116B1 (ko) * | 2005-10-17 | 2013-02-20 | 에스케이케미칼주식회사 | 광학활성 암로디핀 겐티세이트 염의 제조방법 |
| CN100436417C (zh) * | 2006-04-11 | 2008-11-26 | 石药集团中奇制药技术（石家庄）有限公司 | 一种光学活性氨氯地平的拆分方法 |
| KR100828883B1 (ko) * | 2006-10-27 | 2008-05-09 | 씨제이제일제당 (주) | 라세믹 암로디핀으로부터 ｓ-(-)-암로디핀의 분리방법 |
| US20090247750A1 (en) * | 2008-03-28 | 2009-10-01 | Biocryst Pharmaceuticals, Inc. | Process for preparing nucleoside analogs |
| CN104151229B (zh) * | 2014-07-30 | 2015-04-22 | 施慧达药业集团(吉林)有限公司 | 一种(S)-(-)-氨氯地平-半-D-酒石酸-单-DMSO-d6配合物的制备方法 |
| ES2886067T3 (es) | 2016-10-07 | 2021-12-16 | Silvergate Pharmaceuticals Inc | Formulaciones de amlodipina |
| JP7456933B2 (ja) | 2018-04-11 | 2024-03-27 | シルバーゲイト ファーマシューティカルズ，インク． | アムロジピン製剤 |
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| CN111100064B (zh) * | 2020-01-08 | 2024-01-02 | 湖南理工学院 | 一种从废液中富集、回收和拆分碱性手性药物氨氯地平的方法 |
| CN111777547B (zh) * | 2020-07-17 | 2021-10-08 | 江西施美药业股份有限公司 | 一种诱导析晶拆分左旋氨氯地平的方法 |
| CN112079770B (zh) * | 2020-10-05 | 2024-01-02 | 湖南理工学院 | 用于高效手性拆分及母液原位再生的循环萃取和非对映体结晶耦合新方法 |
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| CN1144523A (zh) * | 1994-03-24 | 1997-03-05 | 辉瑞研究与发展公司 | 由阿罗地平的非对映的酒石酸盐分离其对映体 |
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| GB8804630D0 (en) * | 1988-02-27 | 1988-03-30 | Pfizer Ltd | Preparation of r-& s-amlodipine |
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- 2000-02-21 CN CN00102701A patent/CN1100038C/zh not_active Expired - Fee Related
- 2000-12-08 US US10/203,615 patent/US6646131B2/en not_active Expired - Fee Related
- 2000-12-08 EP EP00981132A patent/EP1258477B1/en not_active Expired - Lifetime
- 2000-12-08 AU AU1849401A patent/AU1849401A/xx active Pending
- 2000-12-08 CA CA002416062A patent/CA2416062C/en not_active Expired - Fee Related
- 2000-12-08 DE DE60027476T patent/DE60027476T2/de not_active Expired - Fee Related
- 2000-12-08 WO PCT/CN2000/000538 patent/WO2001060799A1/zh active IP Right Grant
- 2000-12-08 AU AU2001218494A patent/AU2001218494B2/en not_active Ceased
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| EP0331354A2 (en) * | 1988-02-29 | 1989-09-06 | Nihon Taisanbin Kogyo Kabushiki Kaisha | Information reading apparatus |
| CN1144523A (zh) * | 1994-03-24 | 1997-03-05 | 辉瑞研究与发展公司 | 由阿罗地平的非对映的酒石酸盐分离其对映体 |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2005054196A1 (fr) * | 2003-12-05 | 2005-06-16 | Shijiazhuang Pharmaceutical Group Ouyi Pharma. Co., Ltd. | Methode de separation enantiomere d'une amlodipine active optique |
| US7678921B2 (en) | 2003-12-05 | 2010-03-16 | Shijiazhuang Pharmaceutical Group Ouyl Pharma. Co., Ltd. | Method for the enantiomoeric separation of optical active amlodipine |
| WO2011097860A1 (zh) | 2010-02-09 | 2011-08-18 | 施慧达药业集团(吉林)有限公司 | 一种左旋氨氯地平或其可药用盐和β受体阻滞剂的药物组合物及其应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1258477A4 (en) | 2003-04-02 |
| CN1267669A (zh) | 2000-09-27 |
| WO2001060799A1 (fr) | 2001-08-23 |
| US20030028031A1 (en) | 2003-02-06 |
| EP1258477A1 (en) | 2002-11-20 |
| DE60027476T2 (de) | 2006-12-07 |
| CA2416062A1 (en) | 2002-11-06 |
| AU2001218494B2 (en) | 2006-09-28 |
| DE60027476D1 (de) | 2006-05-24 |
| AU1849401A (en) | 2001-08-27 |
| EP1258477B1 (en) | 2006-04-19 |
| CA2416062C (en) | 2009-02-17 |
| US6646131B2 (en) | 2003-11-11 |
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