- The synthesis and analysis of [phenyl-14C(U)]BMS-770767 and [13C6]BMS-770767 for use in discovery biotransformation, human ADME and bioanalytical studies
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Type 2 diabetes is a significant worldwide health problem. To support the development of BMS-770767 as an inhibitor of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) for type 2 diabetes was required the synthesis of carbon-14-labelled material for use in metabolic profiling and for the human adsorption, distribution, metabolism and excretion (ADME) study. Initially, [phenyl-14C(U)]BMS-770767 was synthesized in two steps from a late-stage intermediate and [14C(U)]2-chlorophenol to give the desired final product in 18% yield. Later, the synthesis was completed for the human ADME clinical study using a combination of the discovery and process chemistry routes under cGMP to prepare [phenyl-14C(U)]BMS-770767. The radiochemical purity of the synthesized [phenyl-14C(U)]BMS-770767 after dilution with unlabelled clinical grade BMS-770767 was 99.1% having a specific activity of 1.61 μCi/mg. In addition, to support the quantification of BMS-770767 in LC/MS analyses, [13C6]BMT-770767 was prepared in two steps from a late-stage intermediate and [13C6]2-chlorophenol.
- Maxwell, Brad D.,Bonacorsi, Samuel J.
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- ROR [gamma]t inhibitor, preparation method and application thereof
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The invention relates to the technical field of medicines, in particular to an ROR [gamma]t inhibitor, a preparation method and application thereof. The invention also relates to a pharmaceutical composition containing the compound, a method for preparing the pharmaceutical composition, and application of the compound or the pharmaceutical composition in treatment or prevention of ROR [gamma]t-mediated cancers, inflammations or autoimmune diseases of mammals, especially human beings.
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Paragraph 1565; 1567-1569
(2021/07/08)
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- Deuterium Exchange between Arenes and Deuterated Solvents in the Absence of a Transition Metal: Synthesis of D-Labeled Fluoroarenes
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Fluoroarenes can be selectively deuterated by H/D exchange with common deuterated solvents in the presence of a catalytic amount of an alkali metal carbonate or, for the less acidic arenes, stoichiometric quantities of potassium phosphate. This is a susta
- Salamanca, Vanesa,Albéniz, Ana C.
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supporting information
p. 3206 - 3212
(2020/04/15)
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- Nickel-catalyzed carboxylation of aryl and heteroaryl fluorosulfates using carbon dioxide
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The development of efficient and practical methods to construct carboxylic acids using CO2 as a C1 synthon is of great importance. Nickel-catalyzed carboxylation of aryl fluorosulfates and heteroaryl fluorosulfates with CO2 is described, affording arene carboxylic acids with good to excellent yields under mild conditions. In addition, a one-pot phenol fluorosulfation/carboxylation is developed.
- Ma, Cong,Zhao, Chuan-Qi,Xu, Xue-Tao,Li, Zhao-Ming,Wang, Xiang-Yang,Zhang, Kun,Mei, Tian-Sheng
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p. 2464 - 2467
(2019/04/10)
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- Sodium Methyl Carbonate as an Effective C1 Synthon. Synthesis of Carboxylic Acids, Benzophenones, and Unsymmetrical Ketones
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Reported is the synthesis of carboxylic acids, symmetrical ketones, and unsymmetrical ketones with selectivity achieved by exploiting the differential reactivity of sodium methyl carbonate with Grignard and organolithium reagents.
- Hurst, Timothy E.,Deichert, Julie A.,Kapeniak, Lucas,Lee, Roland,Harris, Jesse,Jessop, Philip G.,Snieckus, Victor
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supporting information
p. 3882 - 3885
(2019/06/07)
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- Continuous Platform to Generate Nitroalkanes On-Demand (in Situ) Using Peracetic Acid-Mediated Oxidation in a PFA Pipes-in-Series Reactor
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The synthetic utility of the aza-Henry reaction can be diminished on scale by potential hazards associated with the use of peracid to prepare nitroalkane substrates and the nitroalkanes themselves. In response, a continuous and scalable chemistry platform to prepare aliphatic nitroalkanes on-demand using the oxidation of oximes with peracetic acid and direct reaction of the nitroalkane intermediate in an aza-Henry reaction is reported. A uniquely designed pipes-in-series plug-flow tube reactor addresses a range of process challenges, including stability and safe handling of peroxides and nitroalkanes. The subsequent continuous extraction generates a solution of purified nitroalkane, which can be directly used in the following enantioselective aza-Henry chemistry to furnish valuable chiral diamine precursors with high selectivity, thus completely avoiding isolation of the potentially unsafe low-molecular-weight nitroalkane intermediate. A continuous campaign (16 h) established that these conditions were effective in processing 100 g of the oxime and furnishing 1.4 L of nitroalkane solution.
- Tsukanov, Sergey V.,Johnson, Martin D.,May, Scott A.,Kolis, Stanley P.,Yates, Matthew H.,Johnston, Jeffrey N.
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supporting information
p. 971 - 977
(2018/08/28)
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- LIQUID CRYSTAL COMPOUND, LIQUID CRYSTAL COMPOSITION, AND LIQUID CRYSTAL DISPLAY DEVICE
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PROBLEM TO BE SOLVED: To provide a liquid crystal compound, a liquid crystal composition, and a liquid crystal device using the compound or the composition. SOLUTION: The liquid crystal compound is represented by formula (I). In formula (I), R1 represents H, an alkyl having 1 to 10 carbon atoms, or the like; R2 represents an alkenyl having 2 to 10 carbon atoms or a fluoroalkenyl having 2 to 10 carbon atoms and one or two non-adjacent -CH2- in R2 is replaced by -O- or an ether having 2 to 10 carbon atoms; A1 to A4 each independently represent a formula below, where R3 independently represents H or a halogen; Z1 to Z3 each independently represents a sing bond, -CH2-, -CH2O-, -OCH2-, -CF=CF-, -COO-, -OCO-, -CF2O-, -OCF2-, -C≡C-, -CH=CH-, or the like; and n and m each independently represent 0 or 1. SELECTED DRAWING: None COPYRIGHT: (C)2016,JPOandINPIT
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Paragraph 0044; 0045; 0046
(2016/10/07)
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- Selenium catalyzed oxidation of aldehydes: Green synthesis of carboxylic acids and esters
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The stoichiometric use of hydrogen peroxide in the presence of a selenium-containing catalyst in water is here reported as a new ecofriendly protocol for the synthesis of variously functionalized carboxylic acids and esters. The method affords the desired products in good to excellent yields under very mild conditions starting directly from commercially available aldehydes. Using benzaldehyde as a prototype the gram scale synthesis of benzoic acid is described, in which the aqueous medium and the catalyst could be recycled at last five times while achieving an 87% overall yield.
- Sancineto, Luca,Tidei, Caterina,Bagnoli, Luana,Marini, Francesca,Lenardo, Eder J.,Santi, Claudio
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p. 10496 - 10510
(2015/08/06)
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- ORTHO ESTER DERIVATIVE, LIQUID CRYSTAL COMPOSITION, AND LIQUID CRYSTAL DISPLAY ELEMENT
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The invention is to provide a liquid crystal compound having a large dielectric anisotropy, a high voltage holding ratio and stability to heat, light and so forth, maintaining a nematic phase in a wide temperature range, having a suitable optical anisotropy and an excellent compatibility with other liquid crystal compounds, particularly, to provide a liquid crystal compound having a large dielectric anisotropy. The invention provides compound (1): In the formula, for example, R1 is alkyl and having 1 to 20 carbons; ring A1, ring A2, ring A3, ring A4, ring A5 and ring A6 are independently 1,4-cyclohexylene or 1,4-phenylene; Z1, Z2, Z3, Z4, Z5, Z6 and Z7 are independently a single bond, - (CH2) 2-, -COO-, -OCO-, CF2O-, -OCF2- or -CH=CH-; X1 is fluorine, -CF3 or -OCF3; and Y1 and Y2 are independently hydrogen or fluorine.
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Paragraph 0227
(2014/02/15)
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- Method for estimating SN1 rate constants: Solvolytic reactivity of benzoates
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Nucleofugalities of pentafluorobenzoate (PFB) and 2,4,6-trifluorobenzoate (TFB) leaving groups have been derived from the solvolysis rate constants of X,Y-substituted benzhydryl PFBs and TFBs measured in a series of aqueous solvents, by applying the LFER equation: log k = sf(Ef + Nf). The heterolysis rate constants of dianisylmethyl PFB and TFB, and those determined for 10 more dianisylmethyl benzoates in aqueous ethanol, constitute a set of reference benzoates whose experimental ΔG ? have been correlated with the ΔH? (calculated by PCM quantum-chemical method) of the model epoxy ring formation. Because of the excellent correlation (r = 0.997), the method for calculating the nucleofugalities of substituted benzoate LGs have been established, ultimately providing a method for determination of the SN1 reactivity for any benzoate in a given solvent. Using the ΔG? vs ΔH? correlation, and taking sf based on similarity, the nucleofugality parameters for about 70 benzoates have been determined in 90%, 80%, and 70% aqueous ethanol. The calculated intrinsic barriers for substituted benzoate leaving groups show that substrates producing more stabilized LGs proceed over lower intrinsic barriers. Substituents on the phenyl ring affect the solvolysis rate of benzhydryl benzoates by both field and inductive effects.
- Matic, Mirela,Denegri, Bernard,Kronja, Olga
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supporting information
p. 8986 - 8998,13
(2012/12/12)
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- INHIBITORS OF STEAROYL-COA DESATURASE
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Provided herein are compounds of the formula (I): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of diseases such as, for example, obesity.
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- Proton transfer equilibria between disubstituted benzoic acids and carbinol base of crystal violet in apolar aprotic solvents. Chemometric analysis of disubstituent effects on the strength of benzoic acid in chlorobenzene
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Proton transfer equilibria in chlorobenzene between a set of di-substituted (2,3-,2,5-,2,6-, 3,5-dichloro and difluoro) benzoic acids including the corresponding mono-substituted acids and the carbinol base of crystal violet have been studied spectrophotometrically. To investigate the effect of disubstitution at ortho- and/or meta- positions on the strength of benzoic acid, the results have been analysed chemometrically on the basis of Fujita Nishioka's multiparameter approach and the assumption of additivity for substituent effects. The model employed explains 94% of the variance for the disubstituent effects on log K. It is observed that the substituent effect is contributed by ordinary electronic and proximity electronic effects in an almost equal ratio (52:48).
- Sen Gupta, Susanta K.,Shrivastava, Ruchi
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p. 369 - 373
(2008/09/19)
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- Exploring Structural Opportunities: The Regioflexible Substitution of 1,3-Difluorobenzene
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To demonstrate the superiority of modern organometallic methods, the inexpensive starting material 1,3-difluorobenzene has been selectively converted into the three benzoic acids and all seven bromobenzoic acids containing the two fluorine atoms in homovicinal positions. The 2,6-difluorobenzoic acid (1) was prepared in a one-pot reaction consisting of direct metallation and carboxylation. The key step on the route to the bromobenzoic acid 4 was a deprotonation-triggered bromine migration from the 2- to the 4-position. All other products were attained through (2,6-difluorophenyl)triethylsilane (11). Consecutive deprotonation of the sites adjacent to the fluorine atoms, followed by appropriate electrophilic substitution, provided not only the acid 7 but also the dibromo and iodobromo derivatives 13 and 23. These in turn gave the isomers 14 and 24 upon base-mediated migration of the heaviest halogen, which made the acids 8 and 10 directly accessible. The regiocontrolled monodebromination of intermediate 14 afforded (4-bromo-2,6-difluoro)triethylsilane (15), which opened the route to the acids 3 and 5 (by carboxylation and protodesilylation) and to acid 9 (by carboxylation and bromodesilylation). Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.
- Schlosser, Manfred,Heiss, Christophe
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p. 4618 - 4624
(2007/10/03)
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- Fragmentation of radical anions of polyfluorinated benzoates
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A comprehensive study of the symmetry forbidden fragmentation of short-lived radical anions (RAs) has been undertaken for the complete set of polyfluorinated benzoates (C6FnH5-nCO22, n = 1-5). The decay rate constants (kc) of RAs have been determined in aqueous alkaline solution (pH 13.4) by electron photoinjection (EPI) from mercury electrodes and were found to increase dramatically from ≤3 × 103 s-1 (3-F - C6H4CO2-) to (1.2 ± 0.8) × 109 s-1 (C6F5CO2-). The regioselectivity of C-F bond cleavage in the RA fragmentation has been revealed by structure assignment of reduction products of the polyfluorinated benzoic acids by Na, K, and Zn in liquid NH3, as well as by Zn in aqueous NH3 and aqueous alkaline solutions. The kc values depend on the position of the cleaved fluorine to the CO2- group generally in the order para > ortho > meta, and to sharply increase if adjacent fluorine atoms are present. The observed trends reveal that the kinetics of the RA fragmentation reaction is not controlled by the reaction thermodynamics. Semiempirical UHF/INDO calculations, the validity of which has been confirmed by ab initio ROHF/6-31+G calculations, were done to rationalize the observed trends. The reaction transition state (TS) was considered to arise from the RA's and 2*states crossing avoided due to out-of-plane deviation of the cleaving C-F bond. The satisfactory linear correlation (R = 0.96) between the model reaction energy barrier Ea and log kc has been achieved with modeling the local solvation of the CO2- group by its protonation.
- Konovalov, Valery V.,Laev, Sergey S.,Beregovaya, Irina V.,Shchegoleva, Lyudmila N.,Shteingarts, Vitalij D.,Tsvetkov, Yuri D.,Bilkis, Itzhak
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p. 352 - 361
(2007/10/03)
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- Synthesis and mesomorphic properties of some fluoro-substituted benzoates
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Several series of fluoro-substituted benzoate liquid crystals have been synthesized. The results showed that the SmA phase is enhanced with the increasing of the degree of fluoro-substitution on the para- and meta-position of the terminal phenyl groups. And the molecules which have same molecular structural formula show nearly the same melting points. It is also discussed about the effect of the ester bond's direction on the mesomorphic properties.
- Yang,Tang,Gong,Wen
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p. 153 - 165
(2007/10/03)
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- On the difference in the results of reductive defluorination of pentafluorobenzoic acid by sodium and zinc in liquid ammonia medium
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Under the reduction of pentafluorobenzoic acid in liquid ammonia by sodium the deep defluorination with removal of three or more fluorine atoms has been observed, whereas with zinc only the product of para-defluorination has been obtained.
- Laev,Laev, Sergey S.,Shteingarts,Shteingarts, Vitalij D.,Bilkis,Bilkis, Isaak I.
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p. 4655 - 4658
(2007/10/02)
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