- Terminal-Selective C(sp3)-H Arylation: NiH-Catalyzed Remote Hydroarylation of Unactivated Internal Olefins
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A terminal-selective migratory hydroarylation of unactivated olefins has been developed though a NiH-catalyzed alkene isomerization-hydroarylation relay process. This sp3C-H arylation was achieved with a simple pyrox ligand under mild conditions. The practicality and synthetic flexibility of the method is highlighted by the successful regioconvergent conversion of isomeric mixtures of alkenes to value-added linear arylation products on a gram scale.
- He, Yuli,Han, Bo,Zhu, Shaolin
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supporting information
p. 2253 - 2264
(2021/05/05)
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- Synthesis of Fingolimod Employing Regioselective Aziridine Ring-Opening Reaction as a Key Step
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An efficient and scalable synthesis of the immunomodulating drug fingolimod hydrochloride has been developed with the aziridine regioselective ring-opening reaction as a key step. This manuscript describes design, detailed synthetic route scouting, and optimization study of the aziridine ring-opening reaction. As a starting material for the polar part of the fingolimod molecule, cheap, common, and widely commercially available tris(hydroxymethyl)aminomethane was used. n-Octyl group was introduced into the molecule either via Kumada or Negishi cross-couplings, or alternatively by Sonogashira cross-coupling followed by hydrogenation. The final step consists of a one-pot acidic deprotection both of the acetonide and Boc group, providing thus highly pure fingolimod hydrochloride from the crude reaction mixture directly. The described process is highly effective, is industrially applicable, and has been successfully applied to 500 g scales of the target product.
- Cinibulk, Josef,Doubsky, Jan,Klvaňa, Robert,Rádl, Stanislav
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- SELECTIVE INHIBITORS AND ALLOSTERIC ACTIVATORS OF SPHINGOSINE KINASE
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Sphingosine 1-phosphate (S1P) is involved in hyper-proliferative diseases, such as cancer and vascular remodeling in pulmonary arterial hypertension. Inhibitors of sphingosine kinase 1 and 2 (SK1 and SK2), which catalyze the synthesis of S1P, may be useful anti- proliferative agents. We have synthesized a series of sphingosine-based inhibitors of SK and SK2. Also provided in this invention are compounds that activate SK1 which can be used in diseases such as fibrosis, where intracellular S1P is anti-fibrotic.
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- A METHOD FOR THE PREPARATION OF FINGOLIMOD
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The invention relates to a method of preparation of 2-amino-2-[2-(4-octylphenyl)- ethyl]propane-1,3-diol (I), comprising opening of the aziridine ring of the intermediates (LVI) by the treatment with organometallic compounds, preferably the Grignard reage
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- Structure-Activity relationships and molecular modeling of sphingosine kinase inhibitors
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The design, synthesis, and evaluation of the potency of new isoform-selective inhibitors of sphingosine kinases 1 and 2 (SK1 and SK2), the enzyme that catalyzes the phosphorylation of d-erythro-sphingosine to produce the key signaling lipid, sphingosine 1-phosphate, are described. Recently, we reported that 1-(4-octylphenethyl)piperidin-4-ol (RB-005) is a selective inhibitor of SK1. Here we report the synthesis of 43 new analogues of RB-005, in which the lipophilic tail, polar headgroup, and linker region were modified to extend the structure-activity relationship profile for this lead compound, which we explain using modeling studies with the recently published crystal structure of SK1. We provide a basis for the key residues targeted by our profiled series and provide further evidence for the ability to discriminate between the two isoforms using pharmacological intervention.
- Baek, Dong Jae,MacRitchie, Neil,Anthony, Nahoum G.,MacKay, Simon P.,Pyne, Susan,Pyne, Nigel J.,Bittman, Robert
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p. 9310 - 9327
(2014/01/06)
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- A convenient synthesis of the immunosuppressive agent FTY720
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This paper describes a practical synthetic approach to preparation of an immunosuppressant, FTY720. The key steps involve an iron-catalyzed cross-coupling reaction and a Wittig reaction. The advantages of this synthesis include readily available starting
- Feng, Xiangjun,Mei, Yuhua,Luo, Yu,Lu, Wei
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p. 161 - 164
(2012/07/03)
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- S1P RECEPTORS MODULATORS AND THEIR USE THEREOF
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The invention relates to novel compounds that have S1P receptor modulating activity. Further, the invention relates to a pharmaceutical comprising at least one compound of the invention for the treatment of diseases and/or conditions caused by or associated with inappropriate S1P receptor modulating activity or expression, for example, autoimmune response. A further aspect of the invention relates to the use of a pharmaceutical comprising at least one compound of the invention for the manufacture of a medicament for the treatment of diseases and/or conditions caused by or associated with inappropriate S1P receptor modulating activity or expression such as autoimmune response.
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Page/Page column 51
(2010/04/30)
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- S1P RECEPTORS MODULATORS
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The invention relates to novel compounds that have S1P receptor modulating activity and, preferably, apoptotic activity and/or anti proliferative activity against cancer cells and other cell types. Further, the invention relates to a pharmaceutical comprising at least one compound of the invention for the treatment of diseases and/or conditions caused by or associated with inappropriate S1P receptor modulating activity or expression, for example, cancer. A further aspect of the invention relates to the use of a pharmaceutical comprising at least one compound of the invention for the manufacture of a medicament for the treatment of diseases and/or conditions caused by or associated with inappropriate S1P receptor modulating activity or expression such as cancer.
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Page/Page column 87; 88
(2010/04/30)
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- Nickel-catalyzed reductive cross-coupling of aryl halides with alkyl halides
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(Chemical Equation Presented) The direct reductive cross-coupling of alkyl halides with aryl halides is described. The transformation is efficient (equimolar amounts of the starting materials are used), generally high-yielding (all but one between 55 and 88% yield), highly functional-group-tolerant [OH, NHBoc, NHCbz, Bpin, C(O)Me, CO2Et, and CN are all tolerated], and easy to perform (uses only benchtop-stable reagents, tolerates small amounts of water and oxygen, changes color when complete, and uses filtration workup). The reaction appears to avoid the formation of intermediate organomanganese species, and a synergistic effect was found when a mixture of two ligands was employed.
- Everson, Daniel A.,Shrestha, Ruja,Weix, Daniel J.
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supporting information; experimental part
p. 920 - 921
(2010/03/31)
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- Synthesis and characterization of stilbene derivatives for possible incorporation as smart additives in polymers used as packaging films
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Several series of stilbene derivatives for possible use as smart additives in polymers used as packaging films have been prepared and characterized. Differential scanning calorimetry was performed on some of the stilbenes in order to determine any liquid crystal properties. Those compounds which had multiple phase transitions were also shown to have two liquid crystalline phases according to optical microscopy.
- Day, Gary M.,Howell, Owen T.,Metzler, Michael R.,Woodgate, Paul D.
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p. 425 - 434
(2007/10/03)
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- Influence of substrate structure on the catalytic efficiency of hydroxysteroid sulfotransferase STa in the sulfation of alcohols
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Sulfotransferase a (STa) is an isoform of hydroxysteroid (alcohol) sulfotransferase that catalyzes the formation of sulfuric acid esters from both endogenous and xenobiotic alcohols. Among its various functions in toxicology, STa is the major form of hepatic sulfotransferase in the rat that catalyzes the formation of genotoxic and carcinogenic sulfuric acid esters from hydroxymethyl polycyclic aromatic hydrocarbons. The goal of the present study was to elucidate fundamental quantitative relationships between substrate structure and catalytic activity of STa that would be applicable to these and other xenobiotics. We have modified previous procedures for purification of STa in order to obtain sufficient amounts of homogeneous enzyme for determination of k(cat)/K(m) values, a quantitative measure of catalytic efficiency. We determined the catalytic efficiency of STa with benzyl alcohol and eight benzylic alcohols that were substituted with n- alkyl groups (C(n)H(2n+1), where n = 1-8) in the para position, and the optimum value for k(cat)/K(m) in these reactions was obtained with n- pentylbenzyl alcohol. Correlations between logarithms of k(cat)/K(m) values and logarithms of partition coefficients revealed that hydrophobicity of the substrate was a major factor contributing to the catalytic efficiency of STa. Primary n-alkanols (C(n)H(2n+1)OH, where n = 3-16) exhibited an optimum k(cat)/K(m) for C9-C11 and a linear decrease in v(max) of the reaction for C3-C14; 15- and 16-carbon n-alkanols were not substrates for STa. These results indicated limits to the length of the extended carbon chain in substrates. Such limits may also apply to hydroxysteroids, since cholesterol was inactive as either substrate or inhibitor of STa. Furthermore, the importance of steric effects on the catalytic efficiency of STa was also evident with a series of linear, branched, and cyclic seven-carbon aliphatic alcohols. In conclusion, our results provide fundamental quantitative relationships between substrate structure and catalytic efficiency that yield insight into the specificity of STa for both endogenous and xenobiotic alcohols.
- Chen, Guangping,Banoglu, Erden,Duffel, Michael W.
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- Enantioselective Extraction of Di-O-benzoyltartrate Anion by Ion-Pair Extractant Having Binaphthyl-Unit
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A lipophilic diphosphonium salt 1 having binaphthyl-type axial chirality was developed as a novel ion-pair extractant.By use of (R)-1, (-)-di-O-benzoyltartrate ((-)-DBT) was extracted more effectively than (+)-DBT.The enantioselectivity (α=D(-)
- Ohki, Akira,Miyashita, Ryo,Naka, Kensuke,Maeda, Shigeru
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p. 2714 - 2719
(2007/10/02)
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- Synthesis of 4-Alkyl-2-iodosobenzoic Acids: Potent Catalysts for the Hydrolysis of Phosphorous Esters
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The syntheses of five new 4-alkyl-2-iodosobenzoic acids (3) are described.The iodine atom was introduced by ortho-directed lithiation of 4-alkylbenzyl alcohols followed by treatment with I2.The catalytic effectiveness of each of the products in the hydrolysis of 4-nitrophenyl diphenyl phosphate in microemulsions was studied.The 4-methyl- and 4-ethyl-substituted products were each found to be significantly better catalysts than the standard nonalkylated 2-iodosobenzoic acid (3, R=H).These results would indicate that microemulsions of these materials may find use in detoxification procedures.
- Panetta, Charles A.,Garlick, Stephanie M.,Durst, H. Dupont,Longo, Frederick R.,Ward, J. Richard
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p. 5202 - 5205
(2007/10/02)
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- α-Hydroxy thioethers
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Novel asymmetric thioethers of the formula STR1 in which the general symbols have the following meanings: a is an integer of from 1 to 7, Ro represents hydrogen or C1-7 -alkanoyl, R1 represents C1-3 -alkyl which may be substituted at the terminal carbon atom by a free or acylated hydroxy group, by a halogen atom having an atomic number of at most 17, or by methoxy, or represents C1-3 -perfluoroalkyl, R2 represents an optionally unsaturated aliphatic radical having from 5 to 15 carbon atoms, A represents ethylene or alternatively, if R1 represents a halogenated radical and/or B represents phenylene or ethylene, a single bond or vinylene, B represents a single bond, ethynylene or phenylene, R3 represents hydroxy, C1-7 -alkoxy or an optionally substituted amino group, and --X-- represents a single bond, a methylene group of an optionally N-acylated primary aminomethylene group, and their salts are active as leucotriene antagonists since they eliminate the contractions of smooth muscles brought about by leucotrienes, and are therefore suitable for the treatment of allergic, especially asthmatic, conditions.
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- Sebosuppressive preparations containing benzyl alcohol derivatives
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Sebosuppressive cosmetic preparations containing benzyl alcohol derivatives which are substituted on the benzene ring by alkyl, aryl, alkyloxymethyl radicals or by a fused aromatic ring, and methods for their use.
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