- In Situ Mass Spectrometric and Kinetic Investigations of Soai's Asymmetric Autocatalysis
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Chemical reactions that lead to a spontaneous symmetry breaking or amplification of the enantiomeric excess are of fundamental interest in explaining the formation of a homochiral world. An outstanding example is Soai's asymmetric autocatalysis, in which small enantiomeric excesses of the added product alcohol are amplified in the reaction of diisopropylzinc and pyrimidine-5-carbaldehydes. The exact mechanism is still in dispute due to complex reaction equilibria and elusive intermediates. In situ high-resolution mass spectrometric measurements, detailed kinetic analyses and doping with in situ reacting reaction mixtures show the transient formation of hemiacetal complexes, which can establish an autocatalytic cycle. We propose a mechanism that explains the autocatalytic amplification involving these hemiacetal complexes. Comprehensive kinetic experiments and modelling of the hemiacetal formation and the Soai reaction allow the precise prediction of the reaction progress, the enantiomeric excess as well as the enantiomeric excess dependent time shift in the induction period. Experimental structural data give insights into the privileged properties of the pyrimidyl units and the formation of diastereomeric structures leading to an efficient amplification of even minimal enantiomeric excesses, respectively.
- Lamour, Saskia,Maier, Frank,Siegle, Alexander F.,Straub, Bernd F.,Trapp, Oliver,Zawatzky, Kerstin
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- Visible-Light-Promoted Nickel- and Organic-Dye-Cocatalyzed Formylation Reaction of Aryl Halides and Triflates and Vinyl Bromides with Diethoxyacetic Acid as a Formyl Equivalent
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A simple formylation reaction of aryl halides, aryl triflates, and vinyl bromides under synergistic nickel- and organic-dye-mediated photoredox catalysis is reported. Distinct from widely used palladium-catalyzed formylation processes, this reaction proceeds by a two-step mechanistic sequence involving initial in situ generation of the diethoxymethyl radical from diethoxyacetic acid by a 4CzIPN-mediated photoredox reaction. The formyl-radical equivalent then undergoes nickel-catalyzed substitution reactions with aryl halides and triflates and vinyl bromides to form the corresponding aldehyde products. Significantly, besides aryl bromides, less reactive aryl chlorides and triflates and vinyl halides serve as effective substrates for this process. Since the mild conditions involved in this reaction tolerate a plethora of functional groups, the process can be applied to the efficient preparation of diverse aromatic aldehydes.
- Huang, He,Li, Xiangmin,Yu, Chenguang,Zhang, Yueteng,Mariano, Patrick S.,Wang, Wei
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- One-pot synthesis of pyrimidine-5-carboxaldehyde and ethyl pyrimidine -5- carboxylate by utilizing pyrimidin-5-yl-lithium
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Pyrimidine-5-carboxaldehyde was prepared in a one-pot reaction from 5- bromo-pyrimidine via metal halogen exchange. Pyrimidin-5-yl-lithium reacted with formate ester and ethyl cyanoformate, forming respectively the aldehyde and carboxy ethyl ester.
- Rho,Abuh
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- Nonpeptide alphavbeta3 antagonists. Part 11: discovery and preclinical evaluation of potent alphavbeta3 antagonists for the prevention and treatment of osteoporosis.
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3-(S)-Pyrimidin-5-yl-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acid (5e) and 3-(S)-(methylpyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acid (5f) were identified as potent and selective antagonists of the alpha(v)beta(3) receptor. These compounds have excellent in vitro profiles (IC(50) = 0.07 and 0.08 nM, respectively), significant unbound fractions in human plasma (6 and 4%), and good pharmacokinetics in rat, dog, and rhesus monkey. On the basis of the efficacy shown in an in vivo model of bone turnover following once-daily oral administration, these two compounds were selected for clinical development for the treatment of osteoporosis.
- Coleman, Paul J,Brashear, Karen M,Askew, Ben C,Hutchinson, John H,McVean, Carol A,Duong,Feuston, Bradley P,Fernandez-Metzler, Carmen,Gentile, Michael A,Hartman, George D,Kimmel, Donald B,Leu, Chih-Tai,Lipfert, Lorraine,Merkle, Kara,Pennypacker, Brenda,Prueksaritanont, Thomayant,Rodan, Gideon A,Wesolowski, Gregg A,Rodan, Sevgi B,Duggan, Mark E
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- NOVEL THYROMIMETICS
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Compounds are provided having the structure of Formula (I): or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein A, X1, X2, Q, R1, R2 and n are as defined herein. Such compounds function as thyromimetics and have utility for treating diseases such as neurodegenerative disorders and fibrotic diseases. Pharmaceutical compositions containing such compounds are also provided, as are methods of their use and preparation.
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Page/Page column 126
(2020/09/19)
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- Continuous-flow Synthesis of Aryl Aldehydes by Pd-catalyzed Formylation of Aryl Bromides Using Carbon Monoxide and Hydrogen
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A continuous-flow protocol utilizing syngas (CO and H2) was developed for the palladium-catalyzed reductive carbonylation of (hetero)aryl bromides to their corresponding (hetero)aryl aldehydes. The optimization of temperature, pressure, catalyst and ligand loading, and residence time resulted in process-intensified flow conditions for the transformation. In addition, a key benefit of investigating the reaction in flow is the ability to precisely control the CO-to-H2 stoichiometric ratio, which was identified as having a critical influence on yield. The protocol proceeds with low catalyst and ligand loadings: palladium acetate (1 mol % or below) and cataCXium A (3 mol % or below). A variety of (hetero)aryl bromides at a 3 mmol scale were converted to their corresponding (hetero)aryl aldehydes at 12 bar pressure (CO/H2=1:3) and 120 °C reaction temperature within 45 min residence time to afford products mostly in good-to-excellent yields (17 examples). In particular, a successful scale-up was achieved over 415 min operation time for the reductive carbonylation of 2-bromo-6-methoxynaphthalene to synthesize 3.8 g of 6-methoxy-2-naphthaldehyde in 85 % isolated yield. Studies were conducted to understand catalyst decomposition within the reactor by using inductively coupled plasma–mass spectrometry (ICP–MS) analysis. The palladium could easily be recovered using an aqueous nitric acid wash post reaction. Mechanistic aspects and the scope of the transformation are discussed.
- Hone, Christopher A.,Lopatka, Pavol,Munday, Rachel,O'Kearney-McMullan, Anne,Kappe, C. Oliver
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p. 326 - 337
(2018/11/23)
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- A pharmaceutical intermediate pyrimidine -5 - formaldehyde preparation method (by machine translation)
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The present invention discloses a pharmaceutical intermediate pyrimidine - 5 - formaldehyde preparation method, which belongs to the technical field of drug synthesis. Technical proposal of the invention points are: to uracil as a starting material, in the presence of protective agent aluminum trichloride or the boric acid in high yield wells meyer - Harker reaction generating pyrimidine - 5 - formaldehyde. The invention has the mild reaction conditions and the advantage of high yield, is with the value of industrial production of synthetic method. (by machine translation)
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Paragraph 0008; 0009; 0010; 0011; 0012; 0013
(2018/07/30)
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- Inhibition of the Cysteine Protease Human Cathepsin L by Triazine Nitriles: Amide???Heteroarene π-Stacking Interactions and Chalcogen Bonding in the S3 Pocket
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We report an extensive “heteroarene scan” of triazine nitrile ligands of the cysteine protease human cathepsin L (hCatL) to investigate π-stacking on the peptide amide bond Gly67–Gly68 at the entrance of the S3 pocket. This heteroarene???peptide bond stacking was supported by a co-crystal structure of an imidazopyridine ligand with hCatL. Inhibitory constants (Ki) are strongly influenced by the diverse nature of the heterocycles and specific interactions with the local environment of the S3 pocket. Binding affinities vary by three orders of magnitude. All heteroaromatic ligands feature enhanced binding by comparison with hydrocarbon analogues. Predicted energetic contributions from the orientation of the local dipole moments of heteroarene and peptide bond could not be confirmed. Binding of benzothienyl (Ki=4 nm) and benzothiazolyl (Ki=17 nm) ligands was enhanced by intermolecular C?S???O=C interactions (chalcogen bonding) with the backbone C=O of Asn66 in the S3 pocket. The ligands were also tested for the related enzyme rhodesain.
- Giroud, Maude,Ivkovic, Jakov,Martignoni, Mara,Fleuti, Marianne,Trapp, Nils,Haap, Wolfgang,Kuglstatter, Andreas,Benz, J?rg,Kuhn, Bernd,Schirmeister, Tanja,Diederich, Fran?ois
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supporting information
p. 257 - 270
(2017/02/15)
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- Use of derivatives of indoles for the treatment of cancer
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The present invention relates to the use of derivatives of indoles having a general formula (I) as follow: for the manufacture of a pharmaceutical composition intended for the treatment of cancer.
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Page/Page column 42
(2016/01/09)
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- AMIDO-BENZYL SULFONE AND SULFOXIDE DERIVATIVES
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The present invention relates to certain amido-benzyl sulfoxide and sulfone compounds, pharmaceutical compositions comprising such compounds, and methods of treatment using such compounds.
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Page/Page column 144
(2013/09/12)
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- PYRIDINYL AND PYRIMIDINYL SULFOXIDE AND SULFONE DERIVATIVES
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Disclosed are certain pyridinyl and pyrimidinyl sulfoxide and sulfone compounds, pharmaceutical compositions comprising such compounds and methods of treatment using such compounds.
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Page/Page column 95; 96
(2013/09/12)
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- AMIDO-BENZYL SULFONE AND SULFONAMIDE DERIVATIVES
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Disclosed are certain amido-benzyl sulfone and sulfonamide compounds, pharmaceutical compositions comprising such compounds, land methods of treatment using such compounds.
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Page/Page column 69; 70
(2013/09/12)
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- AMIDO-BENZYL SULFOXIDE DERIVATIVES
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The present invention relates to certain amido-benzyl sulfoxide compounds, pharmaceutical compositions comprising such compounds, and methods of treatment of an NAMPT-mediated disease or condition in a subject, selected from solid or liquid tumor, rheumat
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Paragraph 0217
(2013/09/12)
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- ALKYL-AND DI-SUBSTITUTED AMIDO-BENZYL SULFONAMIDE DERIVATIVES
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The present invention relates to certain alkyl- and di-substituted amido-benzyl sulfonamide compounds, pharmaceutical compositions comprising such compounds, and to methods of treatment of NAMPT-mediated disorders, such as diabetes, rheumatoid arthritis,
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Paragraph 0225
(2013/09/12)
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- IMIDAZOTRIAZINONE COMPOUNDS
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The present invention provides imidazotriazinone compounds which are inhibitors of phosphodiesterase 9 and pharmaceutically acceptable salt thereof. The present invention further provides processes, pharmaceutical compositions, pharmaceutical preparations and pharmaceutical use of the compounds in the treatment of PDE9 associated diseases or disorders in mammals, including humans.
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Paragraph 0745; 0746
(2013/10/08)
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- Use of derivatives of indoles for the treatment of cancer
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The present invention relates to the use of derivatives of indoles having a general formula (I) as follow: for the manufacture of a pharmaceutical composition intended for the treatment of cancer.
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- NOVEL 2-OXO-1,2,3,4-TETRAHYDROPYRIMIDINES, BICYCLIC PYRIMIDINE DIONES AND IMIDAZOLIDINE-2,4-DIONES USEFUL AS INDUCIBLE NITRIC OXIDE SYNTHASE INHIBITORS
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The present invention relates to novel 2-oxo-l,2,3,4-tetrahydropyrimidines, bicyclic pyrimidine diones and imidizolidine-2,4-diones and methods useful as inhibitors of nitric oxide synthase.
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(2010/11/28)
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- 6-O-substituted erythromycin derivatives having improved gastrointestinal tolerance
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Compounds having formula (I) are useful for treating bacterial infections while avoiding the concomitant liability of gastrointestinal intolerance. Compositions containing the compounds and methods of treatment using the compounds are also disclosed.
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(2008/06/13)
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- Pyrimidine derivatives as ghrelin receptor modulators
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The present invention is related to compounds of formula (I), or a therapeutically suitable salt or prodrug thereof, the preparation of the compounds, compositions containing the compounds and the use of the compounds in the prevention or treatment of disorders regulated by ghrelin including anorexia, cancer cachexia, eating disorders, age-related decline in body composition, weight gain, obesity, and diabetes mellitus.
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Page/Page column 42
(2010/02/11)
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- Diaminopyrimidine derivatives as growth hormone secrectgogue receptor (GHS-R) antagonists
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The present invention is related to compounds of formula (I), or a therapeutically suitable salt or prodrug thereof, the preparation of the compounds, compositions containing the compounds and the use of the compounds in the prevention or treatment of disorders regulated by the action of ghrelin receptor, including Prader-Willi syndrome, eating disorder, weight gain, weight-loss maintainance following diet and exercise, obesity, and disorders associated with obesity such as noninsulin dependent diabetes mellitus.
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Page/Page column 41
(2010/02/13)
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- Pyridocarbazole derivatives having cGMP-PDE inhibitory activity
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PCT No. PCT/JP97/01829 Sec. 371 Date Jan. 29, 1998 Sec. 102(e) Date Jan. 29, 1998 PCT Filed May 29, 1997 PCT Pub. No. WO97/45427 PCT Pub. Date Dec. 4, 1997The invention relates to novel pyridocarbazole derivatives having highly selective action in inhibiting cyclic GMP-phosphodiesterase (hereinafter abbreviated as cGMP-PDE), processes for producing such derivatives, agents containing at least one of such derivatives as an active ingredient for preventing and/or treating pulmonary hypertension, ischemic heart diseases or diseases against which the cGMP-PDE inhibitory action is effective, and intermediates useful for the production of pyridocarbazole derivatives.
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