- Preparation method of methanol solution of rupatadine fumarate intermediate methyl 5-methyl nicotinate
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The invention relates to a preparation method of a methanol solution of rupatadine fumarate intermediate methyl 5-methyl nicotinate, which comprises the following steps of: 1, adding 5-methyl nicotinic acid into methanol, stirring for dissolving, adding thionyl chloride, and heating for reflux reaction; and 2, carrying out vacuum concentration to remove part of the solvent, adding a sodium methoxide methanol solution at room temperature, adjusting the pH value, and filtering to obtain a methanol solution of 5-methyl nicotinate.
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Paragraph 0034-0037
(2021/08/06)
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- Design and Synthesis of 56 Shape-Diverse 3D Fragments
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Fragment-based drug discovery is now widely adopted for lead generation in the pharmaceutical industry. However, fragment screening collections are often predominantly populated with flat, 2D molecules. Herein, we describe a workflow for the design and synthesis of 56 3D disubstituted pyrrolidine and piperidine fragments that occupy under-represented areas of fragment space (as demonstrated by a principal moments of inertia (PMI) analysis). A key, and unique, underpinning design feature of this fragment collection is that assessment of fragment shape and conformational diversity (by considering conformations up to 1.5 kcal mol?1 above the energy of the global minimum energy conformer) is carried out prior to synthesis and is also used to select targets for synthesis. The 3D fragments were designed to contain suitable synthetic handles for future fragment elaboration. Finally, by comparing our 3D fragments with six commercial libraries, it is clear that our collection has high three-dimensionality and shape diversity.
- Atobe, Masakazu,Blakemore, David C.,Bond, Paul S.,Chan, Ngai S.,De Fusco, Claudia,Downes, Thomas D.,Firth, James D.,Hubbard, Roderick E.,Jones, S. Paul,Klein, Hanna F.,O'Brien, Peter,Roughley, Stephen D.,Vidler, Lewis R.,Waddelove, Laura,Whatton, Maria Ann,Wheldon, Mary C.,Woolford, Alison J.-A.,Wrigley, Gail L.
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supporting information
(2020/07/13)
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- Preparation process of Rupatadine
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The invention discloses a rupatadine preparation process, which comprises: S1, preparing methyl 5-methylnicotinate; S2, preparing 5-methyl-3-pyridinemethanol; S3, preparing 3-methyl-5-chloromethylpyridine hydrochloride; and S4, preparing rupatadine. According to the present invention, the preparation process has advantages of low cost, mild reaction condition, simple operation, low requirement onequipment, good product purity and high yield, and is suitable for large-scale industrial production.
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Paragraph 0054; 0060; 0066; 0072; 0078; 0084; 0090; 0096
(2017/08/28)
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- Preparation of 5-methyl-3-polybromide methylpyridinio hydrobromide method
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The invention relates to a method for preparing 5-methyl-3-bromomethylpyridine hydrobromide. The method comprises a step of preparing methyl 5-methyl nicotinate; a step of preparing 5-methyl-3-pyridinemethanol; a step of preparing 5-methyl-3-pyridinemethanol hydrobromide; and a step of preparing 5-methyl-3-bromomethylpyridine hydrobromide. In the step of preparing methyl 5-methyl nicotinate, esterification of 5-methyl nicotinic acid and thionyl chloride is carried out under heating reflux to obtain methyl 5-methyl nicotinate; in the step of preparing 5-methyl-3-pyridinemethanol, a reduction reaction of methyl 5-methyl nicotinate and sodium borohydride is carried out in an organic solvent to obtain 5-methyl-3-pyridinemethanol; in the step of preparing 5-methyl-3-pyridinemethanol hydrobromide, 5-methyl-3-pyridinemethanol reacts with hydrobromic acid to obtain 5-methyl-3-pyridinemethanol hydrobromide; and in the step of preparing 5-methyl-3-bromomethylpyridine hydrobromide, 5-methyl-3-pyridinemethanol hydrobromide reacts with hydrobromic acid in an organic solvent and water is removed from the reaction system to obtain 5-methyl-3-bromomethylpyridine hydrobromide. According to the method, 5-methyl-3-bromomethylpyridine hydrobromide is obtained by four steps; the process is simple; and yield is high.
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Paragraph 0035; 0036; 0037; 0038; 0054
(2019/02/02)
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- An improved process for the preparation of Rupatadine Fumarate
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The present invention provides an improved process for the preparation of Rupatadine Fumarate of Formula-1 resulting product which is substantially free from di-alcohols, dimer and quaternary impurities.
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Paragraph 0039
(2015/02/02)
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- Efficient synthesis of 3-(bromomethyl)-5-methylpyridine hydrobromide
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5-Methyl-3-(bromomethyl)pyridine is the key intermediate in the synthesis of rupatadine. In this article, a new preparation of 5-methyl-3-(bromomethyl)pyridine hydrobromide is reported, which used 5-methylnicotinic acid as the starting material, with a 65.9% overall yield. This method has the merits of being simple, efficient and environmentally friendly.
- Guo, Jianyu,Lu, Yan,Wang, Jin
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p. 203 - 205
(2015/08/24)
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- 1,5-Substituted nipecotic amides: Selective PDE8 inhibitors displaying diastereomer-dependent microsomal stability
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The first highly potent and selective PDE8 inhibitors are disclosed. The initial tetrahydroisoquinoline hit was transformed into a nipecotic amide series in order to address a reactive metabolite issue. Reduction of lipophilicity to address metabolic liab
- DeNinno, Michael P.,Wright, Stephen W.,Visser, Michael S.,Etienne, John B.,Moore, Dianna E.,Olson, Thanh V.,Rocke, Benjamin N.,Andrews, Melissa P.,Zarbo, Cynthia,Millham, Michele L.,Boscoe, Brian P.,Boyer, David D.,Doran, Shawn D.,Houseknecht, Karen L.
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scheme or table
p. 3095 - 3098
(2011/06/24)
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- Characterization of nicotinamidases: Steady state kinetic parameters, classwide inhibition by nicotinaldehydes, and catalytic mechanism
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Nicotinamidases are metabolic enzymes that hydrolyze nicotinamide to nicotinic acid. These enzymes are widely distributed across biology, with examples found encoded in the genomes of Mycobacteria, Archaea, Eubacteria, Protozoa, yeast, and invertebrates, but there are none found in mammals. Although recent structural work has improved our understanding of these enzymes, their catalytic mechanism is still not well understood. Recent data show that nicotinamidases are required for the growth and virulence of several pathogenic microbes. The enzymes of Saccharomyces cerevisiae, Drosophila melanogaster, and Caenorhabditis elegans regulate life span in their respective organisms, consistent with proposed roles in the regulation of NAD+ metabolism and organismal aging. In this work, the steady state kinetic parameters of nicotinamidase enzymes from C. elegans, Sa. cerevisiae, Streptococcus pneumoniae (a pathogen responsible for human pneumonia), Borrelia burgdorferi (the pathogen that causes Lyme disease), and Plasmodium falciparum (responsible for most human malaria) are reported. Nicotinamidases are generally efficient catalysts with steady state kcat values typically exceeding 1 s -1. The Km values for nicotinamide are low and in the range of 2 -110 μM. Nicotinaldehyde was determined to be a potent competitive inhibitor of these enzymes, binding in the low micromolar to low nanomolar range for all nicotinamidases tested. A variety of nicotinaldehyde derivatives were synthesized and evaluated as inhibitors in kinetic assays. Inhibitions are consistent with reaction of the universally conserved catalytic Cys on each enzyme with the aldehyde carbonyl carbon to form a thiohemiacetal complex that is stabilized by a conserved oxyanion hole. The S. pneumoniae nicotinamidase can catalyze exchange of 18O into the carboxy oxygens of nicotinic acid with H218O. The collected data, along with kinetic analysis of several mutants, allowed us to propose a catalytic mechanism that explains nicotinamidase and nicotinic acid 18O exchange chemistry for the S. pneumoniae enzyme involving key catalytic residues, a catalytic transition metal ion, and the intermediacy of a thioester intermediate.
- French, Jarrod B.,Cen, Yana,Vrablik, Tracy L.,Xu, Ping,Allen, Eleanor,Hanna-Rose, Wendy,Sauve, Anthony A.
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experimental part
p. 10421 - 10439
(2011/10/07)
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- Expedient synthesis of rupatadine
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Rupatadine, a new potent, orally active dual antagonist of histamine and platelet-activating factor (PAF), has been synthesized in 91% overall yield. Copyright Taylor & Francis Group, LLC.
- Agarwal, Rajendra,Bhirud, Shekhar Bhaskar,Bijukumar, Gopinathenpillai,Khude, Gopal Dnyandev
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p. 122 - 127
(2008/03/14)
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- PHARMACEUTICAL COMPOSITIONS FOR THE PREVENTION AND TREATMENT OF COMPLEX DISEASES AND THEIR DELIVERY BY INSERTABLE MEDICAL DEVICES
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The present invention relates to polyphenol-like compounds that are useful for inhibiting VCAM-1 expression, MCP-1 expression and/or SMC proliferation in a mammal. The disclosed compounds are useful for regulating markers of inflammatory conditions, including vascular inflammation, and for treatment and prevention of inflammatory and cardiovascular diseases and related disease states.
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Page/Page column 84-88
(2008/06/13)
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- A General Synthesis of Substituted Fluorenones and Azafluorenones
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Twenty-one variously substituted fluorenones and azafluorenones have been synthesized via photochemical Pschorr cyclizations of 2-diazoniodiaryl ketones as the key ring-forming step.Direct, (bipy)3RuII-, or (bipy)3RuII/CuII-photosensitized conditions were used, depending on the system to be cyclized.Where selectivities were possible in the ring closure, the isomer ratios obtained were in accord with an aryl radical as the reactive intermediate.The precursor aminodiaryl ketones were obtained from the sequence ortho lithiation of an arylpivalamide, reaction withan aryl aldehyde to give a 2-pivalamidodiarylcarbinol, oxidation to give a 2-pivalamidodiaryl ketone, and hydrolysis to give the 2-aminodiaryl ketone.
- Kyba, Evan P.,Liu, Shiuh-Tzung,Chockalingam, Kannappan,Reddy, B. Raghava
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p. 3513 - 3521
(2007/10/02)
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- Steric and Conformational Effects in Nicotine Chemistry
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The stereoselectivity of iodomethylation of nicotine and seven nicotine analogues having pyridine alkyl groups was determined by using 13C NMR.Alkylation at the pyridine (N) and at the pyrrolidine (N') nitrogens was observed.Two modes of N'-iodomethylation occur, cis and trans to the pyridine ring.N'-Iodomethylation occurs regioselectively cis to the pyridine ring for all compounds examined.The N/N' and N'cis/N'trans ratios for the nicotinoids were evaluated with regard to (1) the orientation of the N'-methyl group in the free base, (2) conformational properties of the pyridine ring with respect to the pyrrolidine ring, and (3) steric hindrance and buttressing effects on the pyridine nitrogen.The Curtin-Hammett principle and the Winstein-Holness equation are used to analyse reactions.
- Seeman, Jeffrey I.,Secor, Henry V.,Chavdarian, Charles G.,Sanders, Edward B.,Bassfield, Ronald L.,Whidby, Jerry F.
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p. 3040 - 3048
(2007/10/02)
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- STEREOSPECIFIC SYNTHESIS OF A NOVEL SERIES OF PYRIDINE NUCLEOSIDES
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Condensation of 3,5-di-O-benzoyl-β-D-ribofuranosyl chloride severally with 3-acetyl-5-alkylpyridines, 5-alkyl-3-methoxycarbonylpyridines (alkyl= Me, Et, Pr, and iPr), 5-isopropylnicotinamide, and 3,5-diacetylpyridine bis(ethylene acetal) in acetonitrile at -5 deg C gave the corresponding 1-(3,5-di-O-benzoyl-β-D-ribofuranosyl)-3,5-disubstituted pyridinium chlorides in excellent yield (90percent).From the reaction of a series of 2,3-O-isopropylidene-β-D-ribofuranosyl halides with 3-acetyl-5-methyl-pyridine at room temperature, the α-nucleosides were obtained.
- Freyne, Eddy J.,Esmans, Eddy L.,Lepoivre, Josef A.,Alderweireldt, Frank C.
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p. 235 - 242
(2007/10/02)
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