- Enantiomeric separation of racemic amlodipine by sequential fractional crystallization through formation of diastereomeric salt solvates and co-crystals of solvate-like compounds with specific structure — A tandem resolution
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A new resolution method of racemic amlodipine has been developed. The racemic compound is reacted in a suitable solvent with 0.25-mol equivalent of (R,R)-tartaric acid. After the decomposition of the diastereomeric salt, the remaining racemic fraction is precipitated with half-equivalent of fumaric acid, and the pure amlodipine enantiomer is obtained. A quarter equivalent of the same resolving agent, (R,R)-tartaric acid has been also added to the mother liquor to obtain the other enantiomer. The advantage of this method is that both of the enantiomers of amlodipine could be obtained with high enantiomeric excess with the same resolving agent. The racemic excess can also be isolated and re-resolved. Achiral reagents (urea and thiourea) have been added to the resolving agent. These neutral additives are incorporated as co-crystals in the structure of the diastereomeric salts. The used solvate-former solvents and achiral additives are structurally similar, and their presence can enable the fractional separation of the diastereomers. In addition, the racemate, the enantiomers, and some intermediate salts with high diastereomeric excess obtained in the resolution process of amlodipine have been also subjected to thermal (DSC, TG/DTA-EGA-MS, and -FTIR), analytical (FTIR spectroscopic), and structural (XRD) comparisons, which indicate that the key-intermediate crystalline diastereomeric salts—as solvates and co-crystals—inherit a kind of structural similarity from their related additives—solvents (DMF, DMAA, and DMSO) or (thio)ureas, respectively.
- Bánhegyi, Dorottya Fruzsina,Madarász, János,Pálovics, Emese,Szolcsányi, Dóra
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- Method for preparing levamlodipine
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The invention provides a method for preparing levamlodipine and belongs to the technical field of medicine synthesis. The method provided by the invention comprises the following steps: concentratingamlodipine resolution mother liquor to be dry, then mixing with an oxidizing agent and a first solvent, and carrying out an oxidation reaction to obtain 2-((2-aminoethoxy)methyl)-4-(2-chlorphenyl)-6-methyl-3,5-pyridine ethyl methyl diformate, wherein the oxidizing agent is an achiral reagent; mixing the 2-((2-aminoethoxy)methyl)-4-(2-chlorphenyl)-6-methyl-3,5-pyridine ethyl methyl diformate, a reducing agent and a second solvent, and carrying out a reduction reaction to obtain an amlodipine racemate; and mixing the amlodipine racemate, a resolution reagent and a third solvent, and carrying outresolution treatment to obtain levamlodipine. According to the method provided by the invention, the amlodipine in the amlodipine resolution mother liquor can be effectively recycled and converted into high-value levamlodipine.
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- Enantioseparation of racemic amlodipine using immobilized ionic liquid by solid-phase extraction
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In this paper, a novel l-glutamate based immobilized chiral ionic liquid (SBA-IL (Glu)) was prepared by chemical bonding method and applied as a solid sorbent for chiral separation of amlodipine. The performance of SBA-IL (Glu) was investigated for the absorption of (S)-amlodipine and separation of amlodipine enantiomer. The static experiment showed that equilibrium adsorption was achieved within 80 minutes, and the saturation adsorptions capacity was 12 mg/g. The complex was then packed in a glass chromatographic column for the separation of amlodipine and the enantiomeric excess (%ee) of (S)-amlodipine reached 24.67%. The immobilized ionic liquids exhibit good reusability, and the separation efficiency remains 18.24% after reused five times, which allows potential scale-up for the chiral separation of amlodipine.
- Liu, Min,Liu, Zhong-Qian,Zhu, Hai,He, Chao-Hong,Wu, Ke-Jun
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p. 1062 - 1071
(2020/05/06)
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- Preparation method of levamlodipine benzenesulfonate (by machine translation)
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The invention belongs to the technical field of drug synthesis and provides a production method of levamlodipine benzenesulfonate, which comprises the following steps: (R, S)-amlodipine is reacted with a resolving agent. The method is simple and convenient to operate, does not need special equipment, and has a better industrial application prospect. (by machine translation)
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Paragraph 0089-0091; 0093-0094
(2020/07/24)
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- Enantioseparation of chiral pharmaceuticals by vancomycin-bonded stationary phase and analysis of chiral recognition mechanism
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The drug chirality is attracting increasing attention because of different biological activities, metabolic pathways, and toxicities of chiral enantiomers. The chiral separation has been a great challenge. Optimized high-performance liquid chromatography (HPLC) methods based on vancomycin chiral stationary phase (CSP) were developed for the enantioseparation of propranolol, atenolol, metoprolol, venlafaxine, fluoxetine, and amlodipine. The retention and enantioseparation properties of these analytes were investigated in the variety of mobile phase additives, flow rate, and column temperature. As a result, the optimal chromatographic condition was achieved using methanol as a main mobile phase with triethylamine (TEA) and glacial acetic acid (HOAc) added as modifiers in a volume ratio of 0.01% at a flow rate of 0.3?mL/minute and at a column temperature of 5°C. The thermodynamic parameters (eg, ΔH, ΔΔH, and ΔΔS) from linear van 't Hoff plots revealed that the retention of investigated pharmaceuticals on vancomycin CSP was an exothermic process. The nonlinear behavior of lnk′ against 1/T for propranolol, atenolol, and metoprolol suggested the presence of multiple binding mechanisms for these analytes on CSP with variation of temperature. The simulated interaction processes between vancomycin and pharmaceutical enantiomers using molecular docking technique and binding energy calculations indicated that the calculated magnitudes of steady combination energy (ΔG) coincided with experimental elution order for most of these enantiomers.
- Li, Jiaxi,Liu, Ruixia,Wang, Liyang,Liu, Xiaoling,Gao, Hongjie
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p. 236 - 247
(2019/02/01)
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- Enantioselective potential of polysaccharide-based chiral stationary phases in supercritical fluid chromatography
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The enantioselective potential of two polysaccharide-based chiral stationary phases for analysis of chiral structurally diverse biologically active compounds was evaluated in supercritical fluid chromatography using a set of 52 analytes. The chiral selectors immobilized on 2.5?μm silica particles were tris-(3,5-dimethylphenylcarmabate) derivatives of cellulose or amylose. The influence of the polysaccharide backbone, different organic modifiers, and different mobile phase additives on retention and enantioseparation was monitored. Conditions for fast baseline enantioseparation were found for the majority of the compounds. The success rate of baseline and partial enantioseparation with cellulose-based chiral stationary phase was 51.9% and 15.4%, respectively. Using amylose-based chiral stationary phase we obtained 76.9% of baseline enantioseparations and 9.6% of partial enantioseparations of the tested compounds. The best results on cellulose-based chiral stationary phase were achieved particularly with propane-2-ol and a mixture of isopropylamine and trifluoroacetic acid as organic modifier and additive to CO2, respectively. Methanol and basic additive isopropylamine were preferred on amylose-based chiral stationary phase. The complementary enantioselectivity of the cellulose- and amylose-based chiral stationary phases allows separation of the majority of the tested structurally different compounds. Separation systems were found to be directly applicable for analyses of biologically active compounds of interest.
- Kucerova, Gabriela,Kalikova, Kveta,Tesarova, Eva
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supporting information
p. 239 - 246
(2017/05/29)
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- COMPOSITIONS AND METHODS FOR CYCLOFRUCTANS AS SEPARATION AGENTS
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The present invention relates to derivatized cyclofructan compounds, compositions comprising derivatized cyclofructan compounds, and methods of using compositions comprising derivatized cyclofructan compounds for chromatographic separations of chemical species, including enantiomers. Said compositions may comprise a solid support and/or polymers comprising derivatized cyclofructan compounds.
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Page/Page column 45-49; 59
(2010/12/31)
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- METHOD OF PREPARING S-(-)-AMLODIPINE OR A SALT THEREOF AND AN INTERMEDIATE USED THEREIN
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The present invention provides a novel method for preparing S-(?)-amlodipine having a high optical purity or a salt thereof and an intermediate used therein.
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Page/Page column 4
(2010/05/13)
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- A novel chiral resolving reagent, bis((s)-mandelic acid)-3-nitrophthalate, for amlodipine racemate resolution: Scalable synthesis and resolution process
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A novel bis((S)-mandelic acid)-3-nitrophthalate (1), a chiral resolving reagent for the separation of (S)-(-)-isomers of amlodipine from the racemate thereof, is designed and synthesized. A simple three-step pilot-scale preparation of 1, along with the optimization of a resolution process on the racemate amlodipine, is reported.
- Lee, Hong Woo,Shin, Sung Jae,Yu, Hosung,Kang, Sung Kwon,Yoo, Choong Leol
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experimental part
p. 1382 - 1386
(2010/04/22)
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- METHOD OF PREPARING S-(-)-AMLODIPINE OR A SALT THEREOF AND AN INTERMEDIATE USED THEREIN
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The present invention provides a novel method for preparing S-(-)-amlodipine having a high optical purity or a salt thereof and an intermediate used therein.
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Page/Page column 10
(2008/12/08)
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- METHOD FOR THE SEPARATION OF S-(-)-AMLODIPINE FROM RACEMIC AMLODIPINE
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Disclosed is a method for the separation of S-(-)-amlodipine from a racemic amlodipine. Featuring the use of inexpensive L-tartaric acid as an optical resolution agent and DMAC as a solvent, the separation method allows the resolution of S-(-)-amlodipine from racemic amlodipine at high yield and to a satisfactory enantiomeric excess and thus is economically favorable and applicable to the mass production of the optical isomer.
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Page/Page column 5; 7; 8
(2008/12/05)
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- Process for Producing Enantiomer of Amlodipine in High Optical Purity
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The present invention relates to a process for preparation of optically pure (S)-amlodipine-L-hemitartrate DMF solvate comprising the steps of treating (R,S) amlodipine base with L-tartaric acid in the presence of dimethyl formamide and a co-solvent. The invention also relates to a process for converting (R) or (S)-amlopidine-L-hemitartrate DMF solvate into their besylates without isolating free chiral amlopidine base after solution.
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Page/Page column 7
(2008/12/04)
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- (S)-(-)-AMLODIPINE CAMSYLATE OR HYDRATE THEREOF AND PHARMACEUTICAL COMPOSITION COMPRISING SAME
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This invention relates to (S)-(-)-amlodipine camsylate or a hydrate thereof having good photostability and high solubility, and a pharmaceutical composition comprising same, which can be efficiently used in treating cardiovascular diseases.
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Page/Page column 7
(2008/06/13)
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- Method for the enantiomoeric separation of optical active amlodipine
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The present invention relates to the preparation of the (S)-(?)-amlodipine and (R)-(+)-amlodipine by means of enantiomoeric separation of racemic amlodipine mixture, in which, L- or D-tartaric acid is used as resolution agent, and organic solvent containing 2-butone is used as solvent. The 2-butone used in the present invention has the advantage of low boiling point, low toxicity, litter pollution, and the method is suitable for large-scaled production.
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Page/Page column 2
(2008/06/13)
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- COMPOSITIONS COMPRISING (S)-AMLODIPINE AND AN ANGIOTENSIN RECEPTOR BLOCKER AND METHODS OF THEIR USE
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A pharmaceutical composition comprising enantiomerically pure (S)-amlodipine, an ARB and optional other active agents, and methods of treating, preventing and managing cardiovascular diseases and disorders, and symptoms thereof, using the composition, are disclosed.
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Page/Page column 33
(2008/06/13)
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- COMBINATION OF (S)-AMLODIPINE AND AN ACE INHIBITOR, AND METHODS FOR REDUCING HYPERTENSION
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The present invention generally relates to pharmaceutical compositions comprising optically pure (S)-amlodipine and an ACE inhibitor. In a preferred embodiment the (S)--amlodipine is (S)-amlodipine-L-malate, or a polymorph, pseudopolymorph or solvate thereof. In a preferred embodiment, the ACE inhibitor is ramipril. The pharmaceutical compositions of the invention are useful in the treatment of hypertension. The present invention also relates to a method of treating a patient suffering from hypertension or a cardiac disorder, comprising co-administering a therapeutically effective amount of optically pure (S)-amlodipine and an ACE inhibitor. In a preferred embodiment the (S)--amlodipine is (S)-amlodipine-L-malate, or a polymorph, pseudopolymorph or solvate thereof. In a preferred embodiment, the ACE inhibitor is ramipril.
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Page/Page column 71
(2010/02/13)
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- COMBINATION OF (S)-AMLODIPINE AND A BETA-BLOCKER, AND METHODS FOR REDUCING HYPERTENSION
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One aspect of the present invention relates to pharmaceutical compositions comprising optically pure (S)-amlodipine and a beta-blocker. In a preferred embodiment, the beta-blocker is atenolol or bisprolol. Another aspect of the present invention relates to pharmaceutical compositions consisting essentially of at least one pharmaceutically acceptable carrier, optically pure (S)-amlodipine and a beta-blocker. In a preferred embodiment, the beta-blocker is atenolol or bisoprolol. The pharmaceutical compositions of the invention are useful, e.g., in the treatment of hypertension. In addition, the present invention also relates to a method of treating a patient suffering from hypertension or a related cardiac disorder, comprising co-administering to a patient in need thereof a therapeutically effective amount of optically pure (S)-amlodipine and a beta-blocker. In certain embodiments of the compositions and methods, said optically pure (S)-amlodipine is optically pure (S)-amlodipine malate, or a polymorph, pseudopolymorph or solvate thereof.
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Page/Page column 93-94; sheet 1/7; figure 1; sheet 3/7; figure 3
(2010/02/14)
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- COMBINATIONS COMPRISING (S)- AMLODIPINE AND A HMG-CoA REDUCTASE INHIBITOR OR CHOLESTEROL ABSORPOTION INHIBITOR OR BOTH, AND METHODS FOR REDUCING HYPERTENSION
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One aspect of the present invention relates to pharmaceutical compositions comprising optically pure (S)-amlodipine and a HMG-CoA reductase inhibitor. In a preferred embodiment, the HMG-CoA reductase inhibitor is lovastatin. Another aspect of the present
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Page/Page column 95-96
(2010/02/14)
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- PROCESSES FOR THE PREPARATION OF S-(-)-AMLODIPINE
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The present invention provides a process for the preparation of S-(-)-amlodipine from (R,S)-amlodipine in industrial-scale using L-(+)-tartaric acid, which is much cheaper than D-(-)-tartaric acid.
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- Process for the preparation of S(-)-amlodipine-L(+)-hemitartrate
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The present invention relates to a process for the preparation of [S(-) amlodipine-L(+)-hemi tartrate] from RS amlodipine base using L(+) tartaric acid in the presence of an organic solvent such as dimethyl sulfoxide.
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Page/Page column 4
(2008/06/13)
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- Resolution of the enantiomers of amlodipine
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The invitation provides an efficient method for the resolution of (R)-(+)-(formula (I)) and (S)-(?)(formula (II))-enantiomers of amlodipine, where the chiral reagent for resolution is tartaric acid and the chiral auxiliary reagent for resolution is deuterated dimethyl sulphoxide (DMSO-d6).
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- Separation of the enantiomers of amlodipine via their diastereomeric tartrates
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A method for the separation of R-(+)- and S-(-)-isomers of amlodipine (I) from mixtures thereof, which comprises the reaction of the mixture of isomers with either L- or D-tartaric acid in an organic solvent containing sufficient dimethyl sulphoxide (DMSO) for the precipitation of, respectively, a DMSO solvate of an L-tartrate salt of R-(+)-amlodipine, or a DMSO solvate of a D-tartrate salt of S-(-)-amlodipine. STR1
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- Determination of the absolute configuration of the active amlodipine enantiomer as (-)-S: A correction
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The active (-) enantiomer of amlodipine was originally reported to have R configuration. This does not concur with other 1,4-dihydropyridines with known absolute configuration. This configuration has now been determined by X-ray structural analysis using (1S)-camphanic acid and (S)-2-methoxy-2- phenylethanol as chiral probes. Both determinations gave the S configuration for the amlodipine (-) enantiomer with the greater Ca-antagonistic activity.
- Goldmann,Stoltefuss,Born
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p. 3341 - 3344
(2007/10/02)
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