JP5226000B2 - ラセミアムロジピンからのs−(−)−アムロジピンの分離方法 - Google Patents
ラセミアムロジピンからのs−(−)−アムロジピンの分離方法 Download PDFInfo
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- JP5226000B2 JP5226000B2 JP2009534499A JP2009534499A JP5226000B2 JP 5226000 B2 JP5226000 B2 JP 5226000B2 JP 2009534499 A JP2009534499 A JP 2009534499A JP 2009534499 A JP2009534499 A JP 2009534499A JP 5226000 B2 JP5226000 B2 JP 5226000B2
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- Prior art keywords
- amlodipine
- racemic
- dmac
- separating
- tartrate
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hospice & Palliative Care (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Epidemiology (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
1)ジメチルアセトアミド(DMAC)溶媒内でラセミアムロジピンとL−酒石酸とを反応させた後、生成された沈殿物[R−(+)−アムロジピン−ヘミ−L−タルトレート−DMAC溶媒和物]を除去する段階と、
2)前記1)段階で得た濾液に塩化メチレンとn−ヘキサンを添加してS−(−)−アムロジピン−ヘミ−L−タルトレート−DMAC溶媒和物を得る段階と、
3)前記S−(−)−アムロジピン−ヘミ−L−タルトレート−DMAC溶媒和物をメタノールで精製した後、塩基処理する段階とを含む、ラセミアムロジピンからのS−(−)−アムロジピンの分離方法を提供する。
1.(R,S)−アムロジピンからのS−(−)−アムロジピン−ヘミ−L− タルトレート−DMAC溶媒和物の製造
(R,S)−アムロジピン10g(24.26mmol)をジメチルアセトアミド(DMAC)50mLに加えて溶かした後、L−酒石酸3.8g(1.0モル当量)を添加した。前記混合物を5℃に冷却し、2時間攪拌した。生成された固体を濾過させて除去し、得られた濾液に30mLの塩化メチレンと250mLのn−ヘキサンを加えて12時間攪拌した。生成された固体を濾過し、30mLのn−ヘキサンで洗浄した後、50℃で真空乾燥させてS−(−)−アムロジピン−ヘミ−L−タルトレート−DMAC溶媒和物を得た。
−融点:136〜140℃、
−キラルHPLC:98.9%ee、
−1H-NMR(CD3OD) : 7.39(d,1H) 7.25(d,1H) 7.10(t,1H) 7.08(t,1H) 5.41(s,1H) 4.77(d,1H) 4.69(d,1H) 4.36(s,1H) 4.05(m,2H) 3.78(t,2H) 3.58(s,3H) 3.22(m,2H) 3.05(s, DMAC) 2.92(s,DMAC) 2.34(s,3H) 2.08(s,DMAC) 1.16(t,3H)。
段階1で製造したS−(−)−アムロジピン−ヘミ−L−タルトレート−DMAC溶媒和物5.5gを100mLのメタノールに加えて溶かした後、6時間加熱還流した。常温に冷却して得られた沈殿物を濾過し、これを33mLの塩化メチレンに加えて溶かした後、2NのNaOH溶液33mLを加えて40分間攪拌した。層分離して有機層を得た後、蒸留水で洗浄し、有機層を濃縮して得たオイル相に5mLの塩化メチレンと50mLの5−ヘキサンを徐々に加えて4時間攪拌した。生成された沈殿物を濾過し、30mLのn−ヘキサンで洗浄した後、50℃で真空乾燥させてS−(−)−アムロジピンを得た。
−融点:108〜110℃、
−キラルHPLC:99%ee、
−1H-NMR(CD3OD) : 7.40(d,1H) 7.36(d,1H) 7.24(t,1H) 7.09(m,1H) 5.40(s,1H) 4.72(d,1H) 4.59(d,1H) 4.03(m,2H) 3.57(s,3H) 2.88(t,2H) 2.32(s,3H) 1.14(t,3H)。
Claims (7)
- 1)ジメチルアセトアミド(DMAC)溶媒内でラセミアムロジピンとL−酒石酸とを反応させた後、生成された沈殿物[R−(+)−アムロジピン−ヘミ−L−タルトレート−DMAC溶媒和物]を除去する段階と、
2)前記1)段階で得た濾液に塩化メチレンとn−ヘキサンを添加してS−(−)−アムロジピン−ヘミ−L−タルトレート−DMAC溶媒和物を得る段階と、
3)前記S−(−)−アムロジピン−ヘミ−L−タルトレート−DMAC溶媒和物をメタノールで精製した後、塩基処理する段階とを含むことを特徴とする、ラセミアムロジピンからのS−(−)−アムロジピンの分離方法。 - 前記ジメチルアセトアミド(DMAC)溶媒は、ラセミアムロジピンg当り3〜10倍量(mL)を使用することを特徴とする、請求項1に記載のラセミアムロジピンからのS−(−)−アムロジピンの分離方法。
- 前記L−酒石酸は、ラセミアムロジピン1モル当り0.25〜1.0モルを使用することを特徴とする、請求項1に記載のラセミアムロジピンからのS−(−)−アムロジピンの分離方法。
- 前記2)段階で、塩化メチレンとn−ヘキサンはそれぞれラセミアムロジピンの1〜3倍量(mL)と10〜30倍量を使用することを特徴とする、請求項1に記載のラセミアムロジピンからのS−(−)−アムロジピンの分離方法。
- 前記3)段階で、塩基はアルカリ金属またはアルカリ土金属の水酸化物、水和物、酸化物、炭酸塩、重炭酸塩およびアミドよりなる群から選ばれることを特徴とする、請求項1に記載のラセミアムロジピンからのS−(−)−アムロジピンの分離方法。
- 前記塩基はアルカリ金属またはアルカリ土金属の水酸化物であることを特徴とする、請求項5に記載のラセミアムロジピンからのS−(−)−アムロジピンの分離方法。
- 前記塩基は水酸化ナトリウムであることを特徴とする、請求項6に記載のラセミアムロジピンからのS−(−)−アムロジピンの分離方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR10-2006-0105107 | 2006-10-27 | ||
KR1020060105107A KR100828883B1 (ko) | 2006-10-27 | 2006-10-27 | 라세믹 암로디핀으로부터 s-(-)-암로디핀의 분리방법 |
PCT/KR2007/005330 WO2008051056A1 (en) | 2006-10-27 | 2007-10-26 | Method for the separation of s-(-)-amlodipine from racemic amlodipine |
Publications (2)
Publication Number | Publication Date |
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JP2010507654A JP2010507654A (ja) | 2010-03-11 |
JP5226000B2 true JP5226000B2 (ja) | 2013-07-03 |
Family
ID=39324794
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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JP2009534499A Expired - Fee Related JP5226000B2 (ja) | 2006-10-27 | 2007-10-26 | ラセミアムロジピンからのs−(−)−アムロジピンの分離方法 |
Country Status (6)
Country | Link |
---|---|
US (1) | US8436188B2 (ja) |
EP (1) | EP2077993B1 (ja) |
JP (1) | JP5226000B2 (ja) |
KR (1) | KR100828883B1 (ja) |
CN (1) | CN101528697B (ja) |
WO (1) | WO2008051056A1 (ja) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
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US9602777B2 (en) | 2008-04-25 | 2017-03-21 | Roche Diagnostics Hematology, Inc. | Systems and methods for analyzing body fluids |
KR101125123B1 (ko) * | 2008-12-04 | 2012-03-16 | 화일약품주식회사 | 높은 광학적 순도의 s-(-)-암로디핀을 제조하는 방법 및 그 중간생성 화합물 |
KR101705535B1 (ko) * | 2009-04-01 | 2017-02-28 | 주식회사 씨트리 | 광학활성을 갖는 1-(3-히드록시페닐)에틸아민의 제조방법 |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8804630D0 (en) | 1988-02-27 | 1988-03-30 | Pfizer Ltd | Preparation of r-& s-amlodipine |
US6057344A (en) * | 1991-11-26 | 2000-05-02 | Sepracor, Inc. | Methods for treating hypertension, and angina using optically pure (-) amlodipine |
CA2124445A1 (en) * | 1991-11-26 | 1993-06-10 | James W. Young | Methods and compositions for treating hypertension, angina and other disorders using optically pure (-) amlodipine |
GB9317773D0 (en) * | 1993-08-26 | 1993-10-13 | Pfizer Ltd | Therapeutic compound |
GB9405833D0 (en) * | 1994-03-24 | 1994-05-11 | Pfizer Ltd | Separation of the enantiomers of amlodipine |
CN1100038C (zh) * | 2000-02-21 | 2003-01-29 | 张喜田 | 氨氯地平对映体的拆分 |
IL161448A0 (en) * | 2001-10-24 | 2004-09-27 | Sepracor Inc | Method of resolving amlodipine racemate |
DE10228103A1 (de) | 2002-06-24 | 2004-01-15 | Bayer Cropscience Ag | Fungizide Wirkstoffkombinationen |
KR100476636B1 (ko) * | 2002-09-11 | 2005-03-17 | 한림제약(주) | 엘-(+)-타르트레이트를 이용한 에스-(-)-암로디핀의 제조방법 |
EP1769092A4 (en) | 2004-06-29 | 2008-08-06 | Europ Nickel Plc | IMPROVED LIXIVIATION OF BASE METALS |
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 |
-
2006
- 2006-10-27 KR KR1020060105107A patent/KR100828883B1/ko not_active IP Right Cessation
-
2007
- 2007-10-26 WO PCT/KR2007/005330 patent/WO2008051056A1/en active Application Filing
- 2007-10-26 EP EP07833638A patent/EP2077993B1/en not_active Not-in-force
- 2007-10-26 US US12/447,306 patent/US8436188B2/en not_active Expired - Fee Related
- 2007-10-26 JP JP2009534499A patent/JP5226000B2/ja not_active Expired - Fee Related
- 2007-10-26 CN CN2007800397866A patent/CN101528697B/zh not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
US8436188B2 (en) | 2013-05-07 |
CN101528697A (zh) | 2009-09-09 |
EP2077993A1 (en) | 2009-07-15 |
JP2010507654A (ja) | 2010-03-11 |
WO2008051056A1 (en) | 2008-05-02 |
KR100828883B1 (ko) | 2008-05-09 |
US20100069445A1 (en) | 2010-03-18 |
EP2077993B1 (en) | 2013-01-16 |
CN101528697B (zh) | 2013-02-13 |
EP2077993A4 (en) | 2010-07-14 |
KR20080037874A (ko) | 2008-05-02 |
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