103129-82-4Relevant articles and documents
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
Bánhegyi, Dorottya Fruzsina,Madarász, János,Pálovics, Emese,Szolcsányi, Dóra
, (2021/11/22)
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.
Enantioseparation of racemic amlodipine using immobilized ionic liquid by solid-phase extraction
Liu, Min,Liu, Zhong-Qian,Zhu, Hai,He, Chao-Hong,Wu, Ke-Jun
, p. 1062 - 1071 (2020/05/06)
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.
Method for preparing levamlodipine
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, (2020/10/14)
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.
Preparation method of levamlodipine benzenesulfonate (by machine translation)
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Paragraph 0089-0091; 0093-0094, (2020/07/24)
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)
Enantioseparation of chiral pharmaceuticals by vancomycin-bonded stationary phase and analysis of chiral recognition mechanism
Li, Jiaxi,Liu, Ruixia,Wang, Liyang,Liu, Xiaoling,Gao, Hongjie
, p. 236 - 247 (2019/02/01)
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.
Enantioselective potential of polysaccharide-based chiral stationary phases in supercritical fluid chromatography
Kucerova, Gabriela,Kalikova, Kveta,Tesarova, Eva
supporting information, p. 239 - 246 (2017/05/29)
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.
COMPOSITIONS AND METHODS FOR CYCLOFRUCTANS AS SEPARATION AGENTS
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Page/Page column 45-49; 59, (2010/12/31)
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.
METHOD OF PREPARING S-(-)-AMLODIPINE OR A SALT THEREOF AND AN INTERMEDIATE USED THEREIN
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Page/Page column 4, (2010/05/13)
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.
A novel chiral resolving reagent, bis((s)-mandelic acid)-3-nitrophthalate, for amlodipine racemate resolution: Scalable synthesis and resolution process
Lee, Hong Woo,Shin, Sung Jae,Yu, Hosung,Kang, Sung Kwon,Yoo, Choong Leol
experimental part, p. 1382 - 1386 (2010/04/22)
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.
METHOD OF PREPARING S-(-)-AMLODIPINE OR A SALT THEREOF AND AN INTERMEDIATE USED THEREIN
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Page/Page column 10, (2008/12/08)
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.