- Catalytic asymmetric synthesis of the alkaloid (+)-myrtine
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A new protocol for the asymmetric synthesis of trans-2,6-disubstituted-4- piperidones has been developed using a catalytic enantioselective conjugate addition reaction in combination with a diastereoselective lithiation- substitution sequence; an efficient synthesis of (+)-myrtine has been achieved via this route.
- Pizzuti, Maria Gabriella,Minnaard, Adriaan J.,Feringa, Ben L.
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- Synthesis of Aminoethyl-Substituted Piperidine Derivatives as σ1 Receptor Ligands with Antiproliferative Properties
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A series of novel σ1 receptor ligands with a 4-(2-aminoethyl)piperidine scaffold was prepared and biologically evaluated. The underlying concept of our project was the improvement of the lipophilic ligand efficiency of previously synthesized potent σ1 ligands. The key steps of the synthesis comprise the conjugate addition of phenylboronic acid at dihydropyridin-4(1H)-ones 7, homologation of the ketones 8 and introduction of diverse amino moieties and piperidine N-substituents. 1-Methylpiperidines showed particular high σ1 receptor affinity and selectivity over the σ2 subtype, whilst piperidines with a proton, a tosyl moiety or an ethyl moiety exhibited considerably lower σ1 affinity. Molecular dynamics simulations with per-residue binding free energy deconvolution demonstrated that different interactions of the basic piperidine-N-atom and its substituents (or the cyclohexane ring) with the lipophilic binding pocket consisting of Leu105, Thr181, Leu182, Ala185, Leu186, Thr202 and Tyr206 are responsible for the different σ1 receptor affinities. Recorded logD7.4 and calculated clogP values of 4a and 18a indicate low lipophilicity and thus high lipophilic ligand efficiency. Piperidine 4a inhibited the growth of human non-small cell lung cancer cells A427 to a similar extent as the σ1 antagonist haloperidol. 1-Methylpiperidines 20a, 21a and 22a showed stronger antiproliferative effects on androgen negative human prostate cancer cells DU145 than the σ1 ligands NE100 and S1RA.
- Catapano, Carlo V.,Civenni, Gianluca,Holtschulte, Catharina,Laurini, Erik,Marson, Domenico,Pricl, Sabrina,Schepmann, Dirk,B?rgel, Frederik,Wünsch, Bernhard,Westph?linger, Stefanie
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- Synthesis of 5-Acyl-4-methylene-1,2,3,4-Tetrahydropyridines
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Several approaches to monocyclic N-protected 4-methylene-1,2,3,4-Tetrahydropyridines are reported. N-Boc-4-methylenepiperidin-3-one was found to be unstable and its enol triflate was not easily accessible. However, N-protected 2,3-dihydropyridin-4-ones ar
- Longshaw, Alistair I,Thomas, Eric J
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- Preparation method of tert-butyl 4-oxo-3,4-dihydropyridine-1(2H)-carboxylate
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The invention discloses a preparation method of tert-butyl 4-oxo-3,4-dihydropyridine-1(2H)-carboxylate, which comprises the steps of dissolving tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate in a solvent, adding alkali, and reacting to obtain tert-butyl 4-oxo-3,4-dihydropyridine-1(2H)-carboxylate. According to the preparation method of tert-butyl 4-oxo-3,4-dihydropyridine-1(2H)-carboxylate provided by the invention, the used raw materials such as tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate, lithium bromide and lithium carbonate are wide in source, cheap and easily available, and tert-butyl 4-oxo-3,4-dihydropyridine-1(2H)-carboxylate can be quickly and efficiently obtained by only one-step reaction.
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Paragraph 0034-0046
(2021/01/29)
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- Design, Synthesis, and Pharmacological Characterization of a Neutral, Non-Prodrug Thrombin Inhibitor with Good Oral Pharmacokinetics
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Despite extensive research on small molecule thrombin inhibitors for oral application in the past decades, only a single double prodrug with very modest oral bioavailability has reached human therapy as a marketed drug. We have undertaken major efforts to identify neutral, non-prodrug inhibitors. Using a holistic analysis of all available internal data, we were able to build computational models and apply these for the selection of a lead series with the highest possibility of achieving oral bioavailability. In our design, we relied on protein structure knowledge to address potency and identified a small window of favorable physicochemical properties to balance absorption and metabolic stability. Protein structure information on the pregnane X receptor helped in overcoming a persistent cytochrome P450 3A4 induction problem. The selected compound series was optimized to a highly potent, neutral, non-prodrug thrombin inhibitor by designing, synthesizing, and testing derivatives. The resulting optimized compound, BAY1217224, has reached first clinical trials, which have confirmed the desired pharmacokinetic properties.
- Hillisch, Alexander,Gericke, Kersten M.,Allerheiligen, Swen,Roehrig, Susanne,Schaefer, Martina,Tersteegen, Adrian,Schulz, Simone,Lienau, Philip,Gnoth, Mark,Puetter, Vera,Hillig, Roman C.,Heitmeier, Stefan
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supporting information
p. 12574 - 12594
(2020/11/13)
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- Synthesis method of 4-oxy-3,4-dihydro-2H-pyridine-1-tert-butyl formate
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The invention relates to a synthesis method of 4-oxy-3,4-dihydro-2H-pyridine-1-tert-butyl formate, which mainly solves the technical problems that the cost is high and the environment is polluted due to the use of a noble metal reagent in the existing synthesis method, and severe reaction conditions are not easy to control. The synthesis method comprises the following steps: taking N-tert-butyloxycarboryl-4-piperidone as the raw material to react with iodine in the presence of sodium methoxide, so as to obtain 3-hydroxy-4,4-dimethoxy-piperidine-1-tert-butyl formate; allowing the 3-hydroxy-4,4-dimethoxy-piperidine-1-tert-butyl formate to react with an activating group to obtain 3-activating group-4,4-dimethoxy-piperidine-1-tert-butyl formate; under the action of alkali, carrying out an eliminating reaction to obtain 4,4-dimethoxy-3,4-dihydro-2H-pyridine-1-tert-butyl formate; and finally, removing a protecting group to obtain 4-oxy-3,4-dihydro-2H-pyridine-1-tert-butyl formate. This type compound is an important drug compound structure modification small molecule in the research field of new drug.
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- Catalytic Allylic Oxidation of Cyclic Enamides and 3,4-Dihydro-2H-Pyrans by TBHP
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Allylic oxidation of heteroatom substituted cyclic alkenes by tert-butyl hydroperoxide (70% TBHP in water) using catalytic dirhodium caprolactamate [Rh2(cap)4] forms enone products with a variety of 2-substituted cyclic enamides and 3,4-dihyro-2H-pyrans. These reactions occur under mild reaction conditions, are operationally convenient to execute, and are effective for product formation with as low as 0.25 mol% catalyst loading. With heteroatom stabilization of the intermediate allylic free radical two sites for oxidative product formation are possible, and the selectivity of the oxidative process varies with the heteroatom when R = H. Cyclic enamides produce 4-piperidones in good yields when R = alkyl or aryl, but oxidation of 2H-pyrans also gives alkyl cleavage products. Alternative catalysts for TBHP oxidations show comparable selectivities but give lower product yields.
- Yu, Yang,Humeidi, Ranad,Alleyn, James R.,Doyle, Michael P.
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supporting information
p. 8506 - 8513
(2017/08/23)
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- Copper-catalyzed asymmetric 1,4-addition of alkenyl alanes to N-substituted-2-3-dehydro-4-piperidones
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Readily available vinyl alanes are used in the Cu-catalyzed asymmetric conjugate addition reaction to N-substituted-2-3-dehydro-4-piperidones. The enhanced reactivity of recently developed and easily prepared phosphine amine ligands in combination with inexpensive Cu(II)naphtenate (CuNp) allows the introduction of a great variety of alkenyl, alkyl, and aryl aluminums in high enantioselectivity.
- Mueller, Daniel,Alexakis, Alexandre
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supporting information; experimental part
p. 1842 - 1845
(2012/06/18)
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- Synthesis of cyclic enones via direct palladium-catalyzed aerobic dehydrogenation of ketones
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α,β-Unsaturated carbonyl compounds are versatile intermediates in the synthesis of pharmaceuticals and biologically active compounds. Here, we report the discovery and application of Pd(DMSO)2(TFA)2 as a catalyst for direct dehydrogenation of cyclohexanones and other cyclic ketones to the corresponding enones, using O2 as the oxidant. The substrate scope includes heterocyclic ketones and several natural-product precursors.
- Diao, Tianning,Stahl, Shannon S.
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supporting information; experimental part
p. 14566 - 14569
(2011/10/17)
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- Allylic Oxidations Catalyzed by Dirhodium Catalysts under Aqueous Conditions
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The present invention relates to compositions and methods for achieving the efficient allylic oxidation of organic molecules, especially olefins and steroids, under aqueous conditions. The invention concerns the use of dirhodium (II,II) “paddlewheel complexes, and in particular, dirhodium carboximate and tert-butyl hydroperoxide as catalysts for the reaction. The use of aqueous conditions is particularly advantageous in the allylic oxidation of 7-keto steroids, which could not be effectively oxidized using anhydrous methods, and in extending allylic oxidation to enamides and enol ethers.
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Page/Page column 24
(2009/04/24)
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- Catalytic enantioselective conjugate addition of dialkylzinc reagents to N-substituted-2,3-dehydro-4-piperidones
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The first, highly enantioselective, copper/phosphoramidite-catalyzed conjugate addition of dialkylzinc reagents to N-substituted 2,3-dehydro-4- piperidones is described. The Royal Society of Chemistry 2005.
- Sebesta, Radovan,Pizzuti, Maria Gabriella,Boersma, Arnold J.,Minnaard, Adriaan J.,Feringa, Ben L.
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p. 1711 - 1713
(2007/10/03)
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- SEROTONERGIC BENZOFURANS
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The present invention provides serotonergic benzofurans of Formula (I): where A, R, R, R, R, and R are as described in the specification.
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Page/Page column 31
(2010/02/04)
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