- Fully automated high yield synthesis of (R)- and (S)-[11C]verapamil for measuring P-glycoprotein function with positron emission tomography
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Racemic (±) verapamil is a well characterized substrate for P-glycoprotein (P-gp). However, the in vivo pharmacokinetics and pharmacodynamics of both enantiomers are reported to be different. In the preparation of evaluation studies of both enantiomers in animals and humans, the purpose of the present study was to optimize and automate the synthesis of (R)- and (S)- [11C]verapamil. (R)- and (S)-[11C]verapamil were prepared from (R)- and (S)-desmethyl-verapamil, respectively, by methylation with no-carrier added [11C]methyliodide or [11C]methyltriflate. Different conditions of the methylation reaction were studied: reaction time, temperature, base and solvent, and chemical form of the precursor using either the hydrochloric acid salt or the free base of the starting material. After optimization, the synthesis was fully automated using home-made modules and performed according to GMP guidelines. Optimal yields of 60-70% for the methylation reaction were obtained using 1.5 mg of the free base of (R)- or (S)-desmethyl-verapamil in 0.5ml of acetonitrile at 50°C for 5min with [11C]methyltriflate as methylating agent. Under the same reaction conditions, but with a reaction temperature of 100°C, the radiochemical yield starting with [11C]methyliodide as methylation reagent was 40%. The specific activity of (R)- and (S)-[11C]verapamil was > 20 GBq/μmol and the radiochemical purity was > 99% for both methods. The total synthesis time was 45 min. The automated high yield synthesis of (R)- and (S)-[11C]verapamil provides the means for evaluating both enantiomers as in vivo tracers of P-gp function. Copyright
- Luurtsema, Gert,Windhorst, Albert D.,Mooijer, Martien P.J.,Herscheid, Jacobus D.M.,Lammertsma, Adriaan A.,Franssen, Eric J.F.
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- In-situ and one-step preparation of protein film in capillary column for open tubular capillary electrochromatography enantioseparation
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In this work, the phase-transitioned BSA (PTB) film using the mild and fast fabrication process adhered to the capillary inner wall uniformly, and the fabricated PTB film-coated capillary column was applied to realize open tubular capillary electrochromatography (OT-CEC) enantioseparation. The enantioseparation ability of PTB film-coated capillary was evaluated with eight pairs of chiral analytes including drugs and neurotransmitters, all achieving good resolution and symmetrical peak shape. For three consecutive runs, the relative standard deviations (RSD) of migration time for intra-day, inter-day, and column-to-column repeatability were in the range of 0.3%–3.5%, 0.2%–4.9% and 2.1%–7.7%, respectively. Moreover, the PTB film-coated capillary column ran continuously over 300 times with high separation efficiency. Therefore, the coating method based on BSA self-assembly supramolecular film can be extended to the preparation of other proteinaceous capillary columns.
- Li, Ling,Xue, Xuqi,Zhang, Huige,Lv, Wenjuan,Qi, Shengda,Du, Hongying,Manyande, Anne,Chen, Hongli
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supporting information
p. 2139 - 2142
(2021/04/07)
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- Enantioselective synthesis of nitriles containing a quaternary carbon center by michael reactions of silyl ketene imines with 1-acrylpyrazoles
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The enantioselective construction of quaternary carbon centers is a marked challenge in asymmetric catalysis research. It is extremely difficult when a chiral catalyst can not distinguish the facial selectivity of the substrate through bond interactions. Here we realized an enantioselective Michael reaction of silyl ketene imines to 1-acrylpyrazoles using a chiral N,N′-dioxide-Co(II) complex. The protocol is highly efficient for the construction of nitrile-, aryl-, and dialkyl-bearing carbon centers and has been successful applied in the divergent synthesis of pharmaceuticals and natural products. The through-space dispersion interactions between unbound silyl ketene imines and the 1-acrylpyrazole-bonded catalyst play a key role in facilitating the reactivity and the enantioselectivity of this process.
- Chen, Long,Pu, Maoping,Li, Shiyang,Sang, Xinpeng,Liu, Xiaohua,Wu, Yun-Dong,Feng, Xiaoming
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p. 19091 - 19098
(2021/11/22)
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- Method for asymmetric catalytic synthesis of gamma-cyanoamide compound and chiral drug using gamma-cyanoamide compound
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The invention relates to a method for asymmetric catalytic synthesis of a gamma-cyanoamide compound and a chiral drug using the gamma-cyanoamide compound. The method specifically comprises the following step: with silicon group-protected allene ketimine and alpha,beta-unsaturated pyrazolecarboxamide as raw materials, a complex formed by chiral amine oxide and cobalt trifluoromethanesulfonate as a catalyst, water as an additive, and trichloromethane as a solvent, conducting reacting for 2 to 48 hours at 0 to -60 DEG C so as to obtain the chiral gamma-cyanopyrazolecarboxamide compound which is high in property and good in substrate universality. A plurality of chiral natural products or drug molecules such as verapamil, Sporochnol A and key intermediates for synthesizing Epilarene, Aphanorphine and Ammoglutethimide can be obtained by performing some simple conversion on the catalytic product, namely the gamma-cyanopyrazolecarboxamide compound.
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- A Concise and Modular Three-Step Synthesis of (S)-Verapamil using an Enantioselective Rhodium-Catalyzed Allylic Alkylation Reaction
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A concise and modular asymmetric synthesis of the calcium channel blocker (S)-verapamil is described. This approach employs an enantioselective rhodium-catalyzed allylic alkylation reaction between an α-isopropyl-substituted benzylic nitrile and allyl benzoate to construct the challenging acyclic quaternary stereocenter. The terminal olefin then serves as a convenient synthetic handle for a hydroamination to introduce the phenethylamine moiety, furnishing (S)-verapamil in three steps and 55% overall yield, thus providing the most efficient synthesis of this important pharmaceutical reported to date. Furthermore, given the modular nature of the synthesis, it can be readily modified to prepare structurally related bioactive agents.
- Evans, P. Andrew,Tom, Mai-Jan,Turnbull, Ben W. H.
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p. 2185 - 2189
(2020/08/26)
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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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- Nucleophile-catalyzed asymmetric acylations of silyl ketene imines: Application to the enantioselective synthesis of verapamil
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All-carbon quaternary stereocenters are generated with good enantioselectivity through a nucleophile-catalyzed acylation reaction of silyl ketene imines (see scheme, TBS = tert-butyldimethylsilyl). The method is applied to the first catalytic asymmetric synthesis of the drug verapamil.
- Mermerian, Ara H.,Fu, Gregory C.
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p. 949 - 952
(2007/10/03)
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- Enzyme-mediated synthesis of (S)- And (R)-verapamil
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A lipase-mediated synthesis of (S)- And (R)-verapamil is described. The key steps of the synthetic sequence are the enantioselective acetylation, mediated by Lipase PS, of allylic alcohol (Z)-(±)-2, affording the acetate derivative (Z,R)-(-)-3 (ee 92%) and the Ireland-Claisen rearrangement of this latter and of its enantiomer (Z,S)-(+)-3 (ee 92%) to afford acid derivatives (E,R)-(-)-4 (ee 94%) and (E,S)-(+)-4 (ee 93%), precursors of (S)- and (R)-verapamil, respectively.
- Brenna, Elisabetta,Fuganti, Claudio,Grasselli, Piero,Serra, Stefano
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p. 1349 - 1357
(2007/10/03)
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- Maltooligosaccharides as chiral selectors for the separation of pharmaceuticals by capillary electrophoresis
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Complexation between the linear maltodextrin oligosaccharides and certain enantiomeric compounds of pharmaceutical interest in buffered solutions can lead to an analytically desirable chiral recognition. Different maltodextrins were assessed in their capacity to cause enantiomeric separations under various conditions of capillary electrophoresis. The mechanism of chiral recognition has been probed through electrophoretic mobility and selectivity measurements for different buffer solutions and organic solvent additives. A differential interaction of chiral solutes with the maltodextrin helical entities emerges as the basis of such enantioselectivity. This notion is further supported by 1H- and 13C-NMR experiments. Optimized separations of simendan, ibuprofen, warfarin, and ketoprofen enantiomers are demonstrated together with a chiral determination of ibuprofen in a blood serum sample at the therapeutic level.
- Soini, Helena,Stefansson, Morgan,Rlekkola, Marja-Lllsa,Novotny, Mllos V.
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p. 3477 - 3484
(2007/10/02)
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