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WO2008026838A1 - Procédé d'élaboration d'amlodipine optiquement active - Google Patents

Procédé d'élaboration d'amlodipine optiquement active Download PDF

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Publication number
WO2008026838A1
WO2008026838A1 PCT/KR2007/003894 KR2007003894W WO2008026838A1 WO 2008026838 A1 WO2008026838 A1 WO 2008026838A1 KR 2007003894 W KR2007003894 W KR 2007003894W WO 2008026838 A1 WO2008026838 A1 WO 2008026838A1
Authority
WO
WIPO (PCT)
Prior art keywords
amlodipine
camphoric acid
racemic
preparing
chiral
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR2007/003894
Other languages
English (en)
Inventor
Il Suk Byun
Young Youn Kim
Wan Joo Kim
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chemtech Research Inc
Original Assignee
Chemtech Research Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chemtech Research Inc filed Critical Chemtech Research Inc
Priority to KR1020097000215A priority Critical patent/KR101088488B1/ko
Publication of WO2008026838A1 publication Critical patent/WO2008026838A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • 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
    • 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

Definitions

  • the present invention relates to a method for preparing an optically active amlodipine, i.e. S-amlodipine or R-amlodipine. More particularly, the present invention relates to a method for preparing S-amlodipine or R-amlodipine from racemic amlodipine using a chiral camphoric acid as an optical resolving agent.
  • an optically active amlodipine i.e. S-amlodipine or R-amlodipine. More particularly, the present invention relates to a method for preparing S-amlodipine or R-amlodipine from racemic amlodipine using a chiral camphoric acid as an optical resolving agent.
  • Amlodipine is a calcium channel blocker, and is widely used for the treatment of cardiovascular disorders, such as hypertension and angina, as disclosed in U. S. Patent No. 4,572,909.
  • Amlodipine has two enantiomers, i.e. S-amlodipine and R-amlodipine, and the S-amlodipine has more potent pharmacological activity as a calcium channel blocker, as described in J. Med. Chem., 29, 1696 (1986) and J. Med. Chem., 35, 3341 (1992).
  • the R-amlodipine is known as a potent inhibitor of smooth muscle cell migration despite its lack of calcium channel-blocking activity, as disclosed in U. S. Patent No. 6,080,761.
  • EP 0 331 315 B discloses a method of preparing S-amlodipine via the preparation of cin- chonidine salts as diastereomers using cinchonidine with a racemic azido acid compound having the following formula l(c), followed by a resolution of the intermediate diastereomers through crystallization and multi-step chemical reactions.
  • the preparation method disclosed in EP 0 331 315 B is also unsuitable to obtain the product in a high yield due to its multi-step reaction mechanism and the complexity of the reaction process.
  • the present inventors have explored the optically resolving effect of racemic amlodipine using a variety of different chiral organic acids as optical resolving agents. Unexpectedly, the present inventors discovered that chiral camphoric acid had an exceptionally high resolving effect and that the chiral camphoric acid used as an optical resolving agent was easily collected. Based on these unique findings, the present invention provides a method of preparing optically active amlodipine which is cost-effective and suitable for a high yield preparation process.
  • the present invention provides an efficient and economic method of preparing S-amlodipine or R-amlodipine via the resolution of racemic amlodipine, which is easily prepared and commercially available, using chiral camphoric acid as an optical resolving agent. Disclosure of Invention
  • the present invention provides a method of preparing S (-) amlodipine or R-amlodipine by optically resolving racemic amlodipine using as an optical resolving agent chiral camphoric acid that is easily collected while having excellent resolving efficacy.
  • a method of preparing optically active S(-)amlodipine or R-amlodipine including preparing a diastereomeric salt by reacting racemic amlodipine represented by the formula 2 with (IR, 3S)-camphoric acid or (IS, 3R)-camphoric acid represented by the formula 3, and hydrolyzing the diastereomeric salt:
  • the present invention provides a cost-effective method of preparing S-amlodipine or R-amlodipine in a high yield by optically resolving racemic amlodipine, which is easily prepared and commercially available, using chiral camphoric acid as an optical resolving agent. Best Mode for Carrying Out the Invention
  • the present invention provides a method of preparing optically active amlodipine by reacting racemic amlodipine with a chiral camphoric acid, (IR, 3S)-camphoric acid or (IS, 3R)-camphoric acid.
  • IR, 3S chiral camphoric acid
  • IS, 3R chiral camphoric acid
  • R-amlodipine can be easily prepared using (IS, 3R)-camphoric acid instead of (IR, 3S)-camphoric acid in Reaction Scheme 1.
  • the chiral camphoric acid is preferably used in an amount of not more than 2 equivalents, more preferably 0.2 to 1.0 equivalent, per mole of racemic amlodipine.
  • the obtained diastereomeric salt is (IR, 3S)-camphoric acid salt of S-amlodipine or
  • the process of hydrolyzing the salt of amlodipine and camphoric acid may be carried out using various well-known methods for preparing S-amlodipine from diastereomeric salts, for example, a conventional extraction process.
  • the obtained diastereomeric salts are extracted in an immiscible two-phase solvent of dichloromethane and a sodium hydroxide solution to obtain S-amlodipine and camphoric acid, which are dissolved in a dichloromethane layer and a sodium hydroxide solution layer, respectively.
  • These layers are acidified using hydrochloric acid and extracted using ethyl acetate, thereby easily collecting camphoric acid for recycling.
  • the optical purity of the resulting amlodipine can be easily determined by analysing N-Boc-amlodipine obtained by reacting the amlodipine with di-t-butyl pyrocarbonate using a Chiralcel OD column, as reported in J. Med. Chem., 35, 3341 (1992).
  • the present invention provides a method for preparing an optically active amlodipine using a chiral camphoric acid as an optical resolving agent that can be easily collected and has an excellent resolving efficacy.
  • the method according to the present invention is cost-effective and suitable to obtain the product in a high yield,

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Urology & Nephrology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Vascular Medicine (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

Procédé d'élaboration de S-amlodipine oru de R-amlodipine à partir d'amlodipine racémique, qui fait appel à de l'acide camphorique comme agent de résolution optique.
PCT/KR2007/003894 2006-08-30 2007-08-14 Procédé d'élaboration d'amlodipine optiquement active Ceased WO2008026838A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
KR1020097000215A KR101088488B1 (ko) 2006-08-30 2007-08-14 광학활성을 갖는 암로디핀의 제조방법

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2006-0082980 2006-08-30
KR20060082980 2006-08-30

Publications (1)

Publication Number Publication Date
WO2008026838A1 true WO2008026838A1 (fr) 2008-03-06

Family

ID=39136086

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2007/003894 Ceased WO2008026838A1 (fr) 2006-08-30 2007-08-14 Procédé d'élaboration d'amlodipine optiquement active

Country Status (2)

Country Link
KR (1) KR101088488B1 (fr)
WO (1) WO2008026838A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101805284A (zh) * 2010-04-19 2010-08-18 海南美兰史克制药有限公司 一种新方法的苯磺酸左旋氨氯地平化合物

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003035623A1 (fr) * 2001-10-24 2003-05-01 Sepracor, Inc. Procede de resolution de racemate d'amlodipine
US20030176706A1 (en) * 2002-03-18 2003-09-18 Joshi Rohini Ramesh Process for the preparation of [S(-) amlodipine - L (+)- hemitartarate]
WO2006043148A1 (fr) * 2004-10-20 2006-04-27 Emcure Pharmaceuticals Limited Procede de production d'un enantiomere d'amlodipine d'une haute purete optique

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE20117248U1 (de) 2001-10-24 2003-03-06 Reinhold, Klaus, 49525 Lengerich Vorrichtung zum Aufwickeln von Materialbahnen

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003035623A1 (fr) * 2001-10-24 2003-05-01 Sepracor, Inc. Procede de resolution de racemate d'amlodipine
US20030176706A1 (en) * 2002-03-18 2003-09-18 Joshi Rohini Ramesh Process for the preparation of [S(-) amlodipine - L (+)- hemitartarate]
WO2006043148A1 (fr) * 2004-10-20 2006-04-27 Emcure Pharmaceuticals Limited Procede de production d'un enantiomere d'amlodipine d'une haute purete optique

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101805284A (zh) * 2010-04-19 2010-08-18 海南美兰史克制药有限公司 一种新方法的苯磺酸左旋氨氯地平化合物

Also Published As

Publication number Publication date
KR101088488B1 (ko) 2011-11-30
KR20090026794A (ko) 2009-03-13

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