- Access to Optically Enriched α-Aryloxycarboxylic Esters via Carbene-Catalyzed Dynamic Kinetic Resolution and Transesterification
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Optically active α-aryloxycarboxylic acids and their derivatives are important functional molecules. Disclosed here is a carbene-catalyzed dynamic kinetic resolution and transesterification reaction for access to this class of molecules with up to 99% yields and 99:1 er values. Addition of a chiral carbene catalyst to the ester substrate leads to two diastereomeric azolium ester intermediates that can quickly epimerize to each other and thus allows for effective dynamic kinetic resolution to be realized. The optically enriched ester products from our reaction can be quickly transformed to chiral herbicides and other bioactive molecules.
- Liu, Bin,Song, Runjiang,Xu, Jun,Majhi, Pankaj Kumar,Yang, Xing,Yang, Song,Jin, Zhichao,Chi, Yonggui Robin
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supporting information
p. 3335 - 3338
(2020/04/30)
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- Alkali-sensitive ring opening cucurbituril and application thereof
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The invention discloses alkali-sensitive ring opening cucurbituril. A structural formula of the alkali-sensitive ring opening cucurbituril is shown. The alkali-sensitive ring opening cucurbituril hasthe advantages that the alkali-sensitive ring opening cucurbituril can be used as a supermolecular medicine carrier and is provided with large ring cryptand with inner cavities, the ring rigidity of large rings can be reduced by means of ring opening, and accordingly the alkali-sensitive ring opening cucurbituril is extremely high in host-guest bonding capacity; the alkali-sensitive ring opening cucurbituril is excellent in alkali sensitivity, contains carboxylic acid groups and can be used as the medicine carrier to be widely applied to medicine delivery paths, and the water solubility and the stability of insoluble medicines can be greatly improved; the alkali-sensitive ring opening cucurbituril can be used as an alkali-sensitive carrier, medicines can be released in alkaline environments such as small intestines in human bodies, accordingly, effects of releasing the medicines in a sustained and controlled manner can be realized, and irritation of the medicines on gastric mucosas canbe prevented.
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Paragraph 0017; 0018
(2018/08/04)
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- Highly Enantioselective Hydrogenation of Amides via Dynamic Kinetic Resolution Under Low Pressure and Room Temperature
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High-throughput screening and lab-scale optimization were combined to develop the catalytic system trans-RuCl2((S,S)-skewphos)((R,R)-dpen), 2-PrONa, and 2-PrOH. This system hydrogenates functionalized α-phenoxy and related amides at room temperature under 4 atm H2 pressure to give chiral alcohols with up to 99% yield and in greater than 99% enantiomeric excess via dynamic kinetic resolution.
- Rasu, Loorthuraja,John, Jeremy M.,Stephenson, Elanna,Endean, Riley,Kalapugama, Suneth,Clément, Roxanne,Bergens, Steven H.
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supporting information
p. 3065 - 3071
(2017/03/11)
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- A 2 - (4-methoxyphenoxy) process for industrial production of sodium propionate
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The invention relates to the technical field of a preparation method of a compound, and especially relates to an industrial production method of a sweetness inhibitor 2-(4-methoxyphenoxy)sodium propionate. The method comprises the following steps: taking methoxyphenol and methyl 2-chloropropionate as raw materials, under the effect of sodium hydroxide and a catalyst, taking water as a solvent, reacting for 6-24 hours at the temperature of 60-90 DEG C to obtain the product 2-(4-methoxyphenoxy)propionic acid; placing the 2-(4-methoxyphenoxy)propionic acid and sodium hydroxide in ethanol, heating, and reacting to obtain 2-(4-methoxyphenoxy)sodium propionate. According to the invention, water is taken as a solvent, the impurity in the generated product can be effectively removed, the synthesis and purification treatment processes are simple, the purity of the product is high, and the industrial production method is suitable for industrial production of 2-(4-methoxyphenoxy)sodium propionate.
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Paragraph 0029; 0030
(2016/10/07)
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- Optimization of benzoxazole-based inhibitors of Cryptosporidium parvum inosine 5′-monophosphate dehydrogenase
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Cryptosporidium parvum is an enteric protozoan parasite that has emerged as a major cause of diarrhea, malnutrition, and gastroenteritis and poses a potential bioterrorism threat. C. parvum synthesizes guanine nucleotides from host adenosine in a streamlined pathway that relies on inosine 5′-monophosphate dehydrogenase (IMPDH). We have previously identified several parasite-selective C. parvum IMPDH (CpIMPDH) inhibitors by high-throughput screening. In this paper, we report the structure-activity relationship (SAR) for a series of benzoxazole derivatives with many compounds demonstrating CpIMPDH IC50 values in the nanomolar range and >500-fold selectivity over human IMPDH (hIMPDH). Unlike previously reported CpIMPDH inhibitors, these compounds are competitive inhibitors versus NAD +. The SAR study reveals that pyridine and other small heteroaromatic substituents are required at the 2-position of the benzoxazole for potent inhibitory activity. In addition, several other SAR conclusions are highlighted with regard to the benzoxazole and the amide portion of the inhibitor, including preferred stereochemistry. An X-ray crystal structure of a representative E·IMP·inhibitor complex is also presented. Overall, the secondary amine derivative 15a demonstrated excellent CpIMPDH inhibitory activity (IC 50 = 0.5 ± 0.1 nM) and moderate stability (t1/2 = 44 min) in mouse liver microsomes. Compound 73, the racemic version of 15a, also displayed superb antiparasitic activity in a Toxoplasma gondii strain that relies on CpIMPDH (EC50 = 20 ± 20 nM), and selectivity versus a wild-type T. gondii strain (200-fold). No toxicity was observed (LD 50 > 50 μM) against a panel of four mammalian cells lines.
- Gorla, Suresh Kumar,Kavitha, Mandapati,Zhang, Minjia,Chin, James En Wai,Liu, Xiaoping,Striepen, Boris,Makowska-Grzyska, Magdalena,Kim, Youngchang,Joachimiak, Andrzej,Hedstrom, Lizbeth,Cuny, Gregory D.
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p. 4028 - 4043
(2013/06/27)
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- Design, synthesis, and pharmacological effects of structurally simple ligands for MT1 and MT2 melatonin receptors
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A series of phenoxyalkyl and phenylthioalkyl amides were prepared as melatoninergic ligands. Modulation of affinity of the newly synthesized compound by applying SARs around the terminal amide moiety, the alkyl chain, and the methoxy group on the aromatic ring provides compounds with nanomolar affinity for both melatonin receptor subtypes. Affinity towards MT1 and MT2 receptors were modulated also exploiting chirality. The investigation of intrinsic activity revealed that all the tested compounds behave as full or partial agonists.
- Carocci, Alessia,Catalano, Alessia,Lovece, Angelo,Lentini, Giovanni,Duranti, Andrea,Lucini, Valeria,Pannacci, Marilou,Scaglione, Francesco,Franchini, Carlo
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experimental part
p. 6496 - 6511
(2010/10/02)
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- A great improvement of the enantioselectivity of lipase-catalyzed hydrolysis and esterification using co-solvents as an additive
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Addition of co-solvents such as tetrahydrofuran resulted in a great improvement of the enantioselectivity of lipase-catalyzed hydrolysis of butyl 2-(4-substituted phenoxy)propanoates in an aqueous buffer solution. On the other hand, lipase lyophilized from an aqueous solution containing the co-solvents catalyzed highly enantioselective esterification of 2-(4-substituted phenoxy)propionic acids, 2-(4-isobutylphenyl)propionic acid (ibuprofen), and 2-(6-methoxy-2-naph-thyl)propionic acid (naproxen) in an organic solvent. An increase in the E value up to two orders of magnitude was observed for some substrates. The origin of the enantioselectivity enhancement caused by the co-solvent addition was mainly attributed to a significant deceleration in the initial reaction rate for the incorrectly binding enantiomer, as compared with that for the correctly binding enantiomer. From the results of FT-1R, CD, and ESR spectra, the co-solvent addition was also found to bring about a partial destruction of the tertiary structure of lipase.
- Nishigaki, Tomohiro,Yasufuku, Yoshitaka,Murakami, Sayuri,Ebara, Yasuhito,Ueji, Shin-Ichi
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experimental part
p. 617 - 622
(2009/04/11)
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- Chlorination of 2-phenoxypropanoic acid with NCP in aqueous acetic acid: Using a novel ortho-para relationship and the para/meta ratio of substituent effects for mechanism elucidation
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(Graph Presented) Rate constants were measured for the oxidative chlorodehydrogenation of (R,S)-2-phenoxypropanoic acid and nine ortho-, ten para- and five meta-substituted derivatives using (R,S)-1-chloro-3-methyl-2,6- diphenylpiperidin-4-one (NCP) as chlorinating agent. The kinetics was run in 50% (v/v) aqueous acetic acid acidified with perchloric acid under pseudo-first-order conditions with respect to NCP at temperature intervals of 5 K between 298 and 318 K, except at the highest temperature for the meta derivatives. The dependence of rate constants on temperature was analyzed in terms of the isokinetic relationship (IKR). For the 20 reactions studied at five different temperatures, tne isokinetic temperature was estimated to be 382 K, which suggests the preferential involvement of water molecules in the rate-determining step. The dependence of rate constants on meta and para substitution was analyzed using the tetralinear extension of the Hammett equation. The parameter λ for the para/meta ratio of polar substituent effects was estimated to be 0.926, and its electrostatic modeling suggests the formation of an activated complex bearing an electric charge near the oxygen atom belonging to the phenoxy group. A new approach is introduced for examining the effect of ortho substituents on reaction rates. Using IKR-determined values of activation enthalpies for a set of nine pairs of substrates with a given substituent, a linear correlation is found between activation enthalpies of ortho and para derivatives. The correlation is interpreted in terms of the selectivity of the reactant toward para- or ortho-monosubstituted substrates, the slope of which being related to the ortho effect. This slope is thought to be approximated by the ratio of polar substituent effects from ortho and para positions in benzene derivatives. Using the electrostatic theory of through-space interactions and a dipole length of 0.153 nm, this ratio was calculated at various positions of a charged reaction center along the benzene C1-C4 axis, being about 2.5 near the ring and decreasing steeply with increasing distance until reaching a minimum value of -0.565 at 1.3 nm beyond the aromatic ring. Activation enthalpies and entropies were estimated for substrates bearing the isoselective substituent in either ortho and para positions, being demonstrated that they are much different from the values for the parent substrate. The electrophilic attack on the phenolic oxygen atom by the protonated chlorinating agent is proposed as the rate-determining step, this step being followed by the fast rearrangement of the intermediate thus formed, leading to products containing chlorine in the aromatic ring.
- Segurado, Manuel A. P.,Reis, Joao Carlos R.,De Oliveira, Jaime D. Gomes,Kabilan, Senthamaraikannan,Shanthi, Manohar
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p. 5327 - 5336
(2008/02/07)
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- TRIAZOLE, OXADIAZOLE AND THIADIAZOLE DERIVATIVE AS PPAR MODULATORS FOR THE TREATMENT OF DIABETES
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The present invention is directed to compounds represented by the following structural formula, Formula (I): wherein: (a) X is selected from the group consisting of a single bond, O, S, S(O)2 and N; (b) U is an aliphatic linker; (c) Y is selected from the group consisting of O, C, S, NH and a single bond; (d) W is N, O or S; (e) E is C(R3)(R4)A or A and wherein; (f) A is selected from the group consisting of carboxyl, tetrazole, C1-C6 alkylnitrile, carboxamide, sulfonamide and acylsufonamide. The other substituents are defined in the claims; the compounds are modulators of peroxisome proleferator activated receptors (PPARs) and are useful for the treatment of diabetes and other metabolic disorders.
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Page/Page column 82
(2008/06/13)
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- Microbial deracemization of α-substituted carboxylic acids: Substrate specificity and mechanistic investigation
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A new enzymatic method for the preparation of optically active α-substituted carboxylic acids is reported. This technique is called deracemization reaction, which provides us with a route to obtain the enantiomerically pure compounds, theoretically in 100% yield starting from the racemic mixture. This means that the synthesis of a racemate is almost equal to the synthesis of the optically active compound, and this concept is entirely different from the commonly accepted one in the asymmetric synthesis. Using the growing cell system of Nocardia diaphanozonaria JCM3208, racemates of 2-aryl- and 2-aryloxypropanoic acid are deracemized smoothly and (R)-form-enriched products are recovered in high chemical yield (>50%). In addition, using optically active starting compounds and deuterated derivatives as well as inhibitors, we have disclosed the fact that a new type of enzyme takes part in this biotransformation, and that the reaction proceeds probably via the same mechanism as that in rat liver.
- Kato, Dai-Ichiro,Mitsuda, Satoshi,Ohta, Hiromichi
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p. 7234 - 7242
(2007/10/03)
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- Electrochemically-induced spirolactonization of α-(methoxyphenoxy)alkanoic acids into quinone ketals
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Anodic oxidation of two series of α-(2)- and α-(4-methoxyphenoxy)alkanoic acids were studied both at the analytical and preparative scales in order to delineate mechanistic aspects of electrochemically induced spirolactonization and to develop synthetically useful orthoquinone bis- and monoketals. Although α-monomethylated carboxylic acids and acetic acid derivatives do not undergo any spiroannulation, α-dimethylated carboxylic acids furnished spirolactones in high yields. A gem-dimethyl effect is invoked to explain these differences in cyclization capacity. Electrooxidation conditions can be selected to furnish either quinone spirolactone bis- or monoketals. Chemoselective monohydrolysis of bisketals can also be accomplished in a stepwise fashion to furnish the corresponding spirolactone monoketals, but the ortho compound unfortunately dimerized in situ via a Diels-Alder process. An ECEC pathway is proposed to rationalize the observed spirolactonizations on the basis of cyclic voltammetry analyses.
- Deffieux, Denis,Fabre, Isabelle,Courseille, Christian,Quideau, Stephane
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p. 4458 - 4465
(2007/10/03)
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- Kinetics and mechanism of thermal gas-phase elimination of α-substituted carboxylic acids: Role of relative basicity of α-substituents and acidity of incipient proton
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2-Phenoxypropanoic acid together with five of its aryl derivatives, its phenylthio and its N-phenylamino analogues were pyrolyzed at 494-566 K. The reactions were homogeneous, polar and free from catalytic and radical pathways, and obeyed a first-order rate equation. The limits of the Arrhenius log A (s-1) and E (kJ mol-1) values obtained for these reactions averaged 11.98 ± 1.71 and 158.1 ± 17.4, respectively. Analysis of the pyrolysates showed the elimination products to be carbon monoxide, acetaldehyde and the corresponding phenol, thiophenol or aniline compounds. The pyrolysis of 2-phenoxy- and 2-(N-phenylamino)-1-propanol was also investigated over the temperature range 638-792 K. The kinetic results and products analysis lend support to a reaction pathway involving a five-membered cyclic polar transition state. Copyright
- Al-Awadi, Nouria A.,Kaul, Kamini,El-Dusouqui, Osman M. E.
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p. 499 - 504
(2007/10/03)
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- (R)- and (S)-3-Hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone as chiral auxiliaries for the asymmetric synthesis of α-hydroxy acids
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Rac-α-bromo acids, rac-4, have been converted into(R)- or(S)-α-hydroxy acids, (R)- or (S)-9 by DCC-induced esterification with the chiral auxiliaries (R)or (S)-1, followed by reaction with sodium p-methoxyphenoxide in the presence of tetra-n-hexylammonium iodide, conditions of dynamic kinetic resolution, to give quite diastereoselectively the (αR,3S)- or (αS,3R)-α-(p-methoxyphenoxy) esters, 7, which were then oxidized with eerie ammonium nitrate and hydrolyzed under controlled acid conditions.
- Camps, Pelayo,Perez, Francesc,Soldevilla, Nuria
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p. 1877 - 1894
(2007/10/03)
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- Process for the preparation of optically active 2-(4-methoxyphenoxy) propionic acid
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A process for the preparation of optically active 2-(4-methoxyphenoxy)propionic acid of at least 75 percent enantiomeric excess of the desired optical isomer comprised of contacting 2-chloropropionic acid or a lower alkyl ester or an alkali metal salt thereof, having an optical purity greater than 85 percent of the opposite configuration, with from 3 to 10 molar equivalents of 4-methoxyphenol in an aqueous base.
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- [(Isopropylideneamino)oxy]-ethyl-2-[[6-chloroquinoxalinyl)oxy]phenoxy]propionate postemergent herbicide
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The oxime ester compound [(isopropylideneamino)oxy]-ethyl-2-[[(6-chloroquinoxalinyl)oxy]phenoxy]propionate, processes for the preparation thereof, herbicidal compositions containing said compound and methods of use of the composition.
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