- 2-(Halogenated Phenyl) acetamides and propanamides as potent TRPV1 antagonists
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A series consisting of 117 2-(halogenated phenyl) acetamide and propanamide analogs were investigated as TRPV1 antagonists. The structure–activity analysis targeting their three pharmacophoric regions indicated that halogenated phenyl A-region analogs exhibited a broad functional profile ranging from agonism to antagonism. Among the compounds, antagonists 28 and 92 exhibited potent antagonism toward capsaicin for hTRPV1 with Ki[CAP] = 2.6 and 6.9 nM, respectively. Further, antagonist 92 displayed promising analgesic activity in vivo in both phases of the formalin mouse pain model. A molecular modeling study of 92 indicated that the two fluoro groups in the A-region made hydrophobic interactions with the receptor.
- Ann, Jihyae,Bahrenberg, Gregor,Blumberg, Peter M.,Choi, Sun,Christoph, Thomas,Do, Nayeon,Frank-Foltyn, Robert,Ha, Heejin,Jeong, Jin Ju,Kang, Jin Mi,Kim, Changhoon,Kwon, Sun Ok,Lee, Jeewoo,Lee, Sunho,Lesch, Bernhard,Stockhausen, Hannelore,Vu, Thi Ngoc Lan,Yoon, Sanghee
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- Harnessing Applied Potential: Selective β-Hydrocarboxylation of Substituted Olefins
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The construction of carboxylic acid compounds in a selective fashion from low value materials such as alkenes remains a long-standing challenge to synthetic chemists. In particular, β-addition to styrenes is underdeveloped. Herein we report a new electrosynthetic approach to the selective hydrocarboxylation of alkenes that overcomes the limitations of current transition metal and photochemical approaches. The reported method allows unprecedented direct access to carboxylic acids derived from β,β-trisubstituted alkenes, in a highly regioselective manner.
- Alkayal, Anas,Buckley, Benjamin R.,Malkov, Andrei V.,Montanaro, Stephanie,Tabas, Volodymyr,Wright, Iain A.
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supporting information
(2020/02/13)
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- Deracemizing α-Branched Carboxylic Acids by Catalytic Asymmetric Protonation of Bis-Silyl Ketene Acetals with Water or Methanol
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We report a highly enantioselective catalytic protonation of bis-silyl ketene acetals. Our method delivers α-branched carboxylic acids, including nonsteroidal anti-inflammatory arylpropionic acids such as Ibuprofen, in high enantiomeric purity and high yields. The process can be incorporated in an overall deracemization of α-branched carboxylic acids, involving a double deprotonation and silylation followed by the catalytic asymmetric protonation.
- Mandrelli, Francesca,Blond, Aurélie,James, Thomas,Kim, Hyejin,List, Benjamin
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p. 11479 - 11482
(2019/07/18)
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- AZABICYCLO AND DIAZEPINE DERIVATIVES FOR TREATING OCULAR DISORDERS
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The present invention provides in one aspect azabicycio and diazepine derivatives useful as modulators of muscarinic receptors. In another aspect, the present invention provides pharmaceutical compositions for treating ocular diseases, the compositions comprising at least one muscarinic receptor modulator. Formulae (I) & (II):
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Page/Page column 64
(2019/05/22)
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- New Strategy for Forging Contiguous Quaternary Carbon Centers via H 2 O 2 -Mediated Ring Contraction
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Stereospecific construction of contiguous quaternary carbon centers constitutes a major challenge in natural product synthesis. A general protocol that enables stereospecific construction of all stereoisomers of such a moiety remains elusive. In this article, we will discuss the oxidative ring contraction of all-substituted cyclic α-formyl ketones mediated by H 2 O 2, which provides a facile access to the stereospecific construction of contiguous quaternary carbon centers.
- Hu, Jiadong,Yu, Xin,Xie, Weiqing
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p. 2517 - 2524
(2017/09/28)
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- Enantioselective Decarboxylative Cyanation Employing Cooperative Photoredox Catalysis and Copper Catalysis
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The merger of photoredox catalysis with asymmetric copper catalysis have been realized to convert achiral carboxylic acids into enantiomerically enriched alkyl nitriles. Under mild reaction conditions, the reaction exhibits broad substrate scope, high yields and high enantioselectivities. Furthermore, the reaction can be scaled up to synthesize key chiral intermediates to bioactive compounds.
- Wang, Dinghai,Zhu, Na,Chen, Pinhong,Lin, Zhenyang,Liu, Guosheng
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supporting information
p. 15632 - 15635
(2017/11/14)
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- Asymmetric Hydrogenation of α-Substituted Acrylic Acids Catalyzed by a Ruthenocenyl Phosphino-oxazoline-Ruthenium Complex
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Asymmetric hydrogenation of various α-substituted acrylic acids was carried out using RuPHOX-Ru as a chiral catalyst under 5 bar H2, affording the corresponding chiral α-substituted propanic acids in up to 99% yield and 99.9% ee. The reaction could be performed on a gram-scale with a relatively low catalyst loading (up to 5000 S/C), and the resulting product (97%, 99.3% ee) can be used as a key intermediate to construct bioactive chiral molecules. The asymmetric protocol was successfully applied to an asymmetric synthesis of dihydroartemisinic acid, a key intermediate required for the industrial synthesis of the antimalarial drug artemisinin.
- Li, Jing,Shen, Jiefeng,Xia, Chao,Wang, Yanzhao,Liu, Delong,Zhang, Wanbin
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p. 2122 - 2125
(2016/06/01)
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- Ferrocenyl chiral bisphosphorus ligands for highly enantioselective asymmetric hydrogenation via noncovalent ion pair interaction
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A new class of ferrocenyl chiral bisphosphorus ligand, Wudaphos, was developed, and exhibits excellent ee and activity (ee up to 99%, TON up to 20000) for the asymmetric hydrogenation of both 2-aryl and 2-alkyl acrylic acids through ion pair noncovalent interaction under base free and mild reaction conditions. Well-known anti-inflammatory drugs such as naproxen and ibuprofen together with the intermediate for the preparation of Roche ester and some bioactive compounds were also efficiently obtained with excellent ee. Control experiments were conducted and revealed that the ion pair noncovalent interaction and chain length played important roles.
- Chen, Caiyou,Wang, Heng,Zhang, Zhefan,Jin, Shicheng,Wen, Songwei,Ji, Jianjian,Chung, Lung Wa,Dong, Xiu-Qin,Zhang, Xumu
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p. 6669 - 6673
(2016/10/31)
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- Chiral diphosphine ligand in asymmetric hydrogenation thereof and related application of the catalyst in the reaction (by machine translation)
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The invention discloses a chiral diphosphine ligand based on ferrocene skeleton in asymmetric hydrogenation thereof and related application of the catalyst in the reaction. This kind of novel chiral diphosphine ligand has as the general formula I The structure of the shown, wherein R 1 can be is methyl, phenyl, tert-butyl, hydroxy, etc.. R 2 can be ethyl, phenyl, cyclohexyl, methyl phenyl, tert-butyl, 3,5-dimethyl phenyl, 3,5-di-tert-butyl phenyl, 3,5-di-tert-butyl-4-methoxybenzene, 2,6-dimethoxyphenyl, 2,6-dimethyl phenyl, anthryl. At the same time, two phosphine atom bridged between the can is phenyl, naphthyl, alkyl or the like. At the same time, this invention has disclosed this kind of novel chiral diphosphine ligand synthesis and in preparation of chiral pharmaceutical ibuprofen and a naproxen, and the like. (by machine translation)
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Paragraph 0104; 0108; 0109
(2016/10/09)
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- Oxidative rearrangement of malondialdehyde: Substrate scope and mechanistic insights
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A novel oxidative rearrangement of malondialdehyde was described. Under the effect of H2O2, malondialdehyde smoothly transferred to carboxylic acid with C-C bond cleavage in good to excellent yields. Mechanistic studies showed that this reaction proceeded via the formation of a 1,2-dioxolane intermediate, followed by concert C-C, O-O, C-H bond cleavage and a hydride shift.
- Yu, Xin,Liu, Zheng,Xia, Zilei,Shen, Zhigao,Pan, Xixian,Zhang, Hui,Xie, Weiqing
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p. 53397 - 53401
(2015/01/16)
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- LORCASERIN HYDROCHLORIDE
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The present invention relates to amorphous lorcaserin hydrochloride; amorphous solid dispersion comprising lorcaserin hydrochloride and one or more pharmaceutically acceptable carries; processes for preparation thereof; pharmaceutical compositions comprising amorphous lorcaserin hydrochloride and one or more pharmaceutically acceptable carries.
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- Nickel-catalyzed reductive carboxylation of styrenes using CO2
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A nickel-catalyzed reductive carboxylation of styrenes using CO2 has been developed. The reaction proceeds under mild conditions using diethylzinc as the reductant. Preliminary data suggests the mechanism involves two discrete nickel-mediated catalytic cycles, the first involving a catalyzed hydrozincation of the alkene followed by a second, slower nickel-catalyzed carboxylation of the in situ formed organozinc reagent. Importantly, the catalyst system is very robust and will fixate CO2 in good yield even if exposed to only an equimolar amount introduced into the headspace above the reaction. Copyright
- Williams, Catherine M.,Johnson, Jeffrey B.,Rovis, Tomislav
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supporting information; experimental part
p. 14936 - 14937
(2009/03/12)
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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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- Enantioselective hydrolysis of various racemic α-substituted arylacetonitriles using Rhodococcus sp. CGMCC 0497
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The enantioselective hydrolysis of 17 racemic α-substituted arylacetonitriles by Rhodococcus sp. CGMCC 0497 is described. The corresponding (R)-amides and (S)-acids were obtained with excellent enantiomeric excess in most cases. The effect of steric and electronic factors on the outcome of the reactions are discussed here. The results prove that nitrile-converting enzymes are efficient tools for the synthesis of sterically unencumbered chiral α-arylpropionic acids and amides.
- Wu, Zhong-Liu,Li, Zu-Yi
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p. 3305 - 3312
(2007/10/03)
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- Enantioselective synthesis of α-methyl carboxylic acids using a DiTOX chiral auxiliary
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Five α-methyl carboxylic acids have been prepared with high e.e.s using 1,3-dithiane 1-oxide (DiTOX) units as the stereocontrolling elements and sources of chirality.
- Page, Philip C. Bulman,McKenzie, Michael J.,Allin, Steven M.,Klair, Sukhbinder S.
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p. 13149 - 13164
(2007/10/03)
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- Enantioselective synthesis of α-arylpropanoic acids
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A range of (+)-α-arylpropanoic acids has been prepared in high enantiomeric excesses using 1,3-dithiane 1-oxide (DiTOX) units as the stereocontrolling elements and sources of chirality.
- Page, Philip C.,McKenzie, Michael J.,Buckle, Derek R.
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p. 2673 - 2676
(2007/10/02)
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- Presynaptic cholinergic modulators as potent cognition enhancers and analgesic drugs. 1. Tropic and 2-phenylpropionic acid esters
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Previous studies have shown that (R)-(+)-hyoscyamine has analgesic activity as a consequence of increased ACh release following antagonism of central muscarinic autoreceptors. Since the enhancement of central cholinergic transmission could be beneficial for cognitive disorders, we manipulated (R)-(+)-hyoscyamine, synthesizing several derivatives of tropic and 2-phenylpropionic acids, with the aim of obtaining drugs which are able to increase ACh release and consequently to show analgesic and nootropic activities. The results showed that several new compounds are indeed potent analgesics (with an analgesic efficacy comparable to that of morphine) and that the most potent one ((±)-19, PG9) also has remarkable cognition- enhancing properties. Our study confirmed that the mechanism of action involves ACh release even if it is still unclear whether only muscarinic autoreceptors or, also, heteroreceptors are involved.
- Gualtieri,Conti,Dei,Giovannoni,Nannucci,Romanelli,Scapecchi,Teodori,Fanfani,Ghelardini,Giotti,Bartolini
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p. 1704 - 1711
(2007/10/02)
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- PHASE-TRANSFER CATALYSIS IN COBALT CATALYZED CARBONYLATION OF SECONDARY BENZYL HALIDES
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Application of the phase-transfer technique to the cobalt carbonyl-catalyzed carbonylation of secondary benzyl halides gives either monocarbonyl and double carbonyl insertion or coupling of organic halides as the major reaction, depending on the experimental conditions.Alcohols or ethers mainly give salts of carboxylic acids.Use of higher pressures of CO association with a hydrocarbon organic phase, favours coupling rather than carbonylation.A possible reaction mechanism is discussed.
- Francalanci, F.,Foa, M.
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