- 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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- Preparation method of rupatadine fumarate intermediate 5-methyl-3-hydroxymethylpyridine
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The present invention relates to a preparation method of rupatadine fumarate intermediate 5-methyl-3-hydroxymethylpyridine , which comprises: 1, sequentially adding tert-butanol and sodium borohydride into a reaction bottle, uniformly stirring and mixing, adding a methanol solution of 5-methyl nicotinate, and carrying out a heating reaction until the raw material disappears; and 2, adding water and an acid solution, fully stirring, concentrating under reduced pressure, adding an alkali solution and an organic solvent, fully stirring and extracting, separating out an organic phase, and concentrating under reduced pressure to obtain the 5-methyl-3-hydroxymethylpyridine.
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Paragraph 0011; 0035-0038
(2021/08/19)
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- New impurity of rupatine fumarate and preparation method and detection method thereof
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The invention provides a novel impurity (a compound shown in formula I) of lupatifen fumarate and a preparation method of the novel impurity. The novel impurity can be used for controlling the quality of the lupatifen fumarate and a preparation of the lupatifen fumarate, so that a foundation is set for effectively controlling the quality of lupatifen fumarate bulk drugs and a preparation of the lupatifen fumarate bulk drugs. (the formula structure is shown in the description), wherein an anion X are selected from F, Cl, Br and I; and preferably, the anion X is Br.
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Paragraph 0115
(2020/03/31)
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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 0055; 0061; 0067; 0073; 0079; 0085; 0091; 0096
(2017/08/28)
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- HETEROCYCLIC AMIDES AS KINASE INHIBITORS
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Disclosed are compounds having the formula: (I) wherein R1, R2, and R3 are as defined herein, and methods of making and using the same.
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Page/Page column 74
(2016/12/07)
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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; 0040; 0041; 0042; 0057
(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 0040
(2015/02/02)
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- Simultaneous dehalogenation and hydrogenation reduction of halogen-heteroaromatic aldehydes
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Treatment of halogen-heteroaromatic aldehydes with catalytic amount of PdCl2 under atmosphere pressure of hydrogen in base medium (sodium acetate) leads to the corresponding dehalogenated primary alcohols. The reaction system was especially effective for the heteroaromatic compounds bearing aldehyde groups and halides (bromo- or chloro-functions).
- Chen, Xi-Bo,Hu, Qiu-Peng,Yuan, Qian-Jia,Ding, Wei,Ren, Jiangmeng,Zeng, Bu-Bing
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experimental part
p. 3798 - 3801
(2012/09/21)
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- PYRAZOLOPYRIMIDINE DERIVATIVES AND USES AS ANTICANCER AGENTS
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Novel compounds having a fused pyrazolopyrimidine derivatives and related fused ring systems are disclosed. The compounds inhibit growth of a variety of types of cancer cells, and are thus useful for treating cancer. Pharmaceutical compositions, and methods of using these compounds and compositions to treat cancer and other diseases related to the dysregulation of kinase (such as Aurora A, Aurora B, Aurora C, cMet, JAK2, ROS1, but not limited to) pathways are disclosed. Efficacy of these compounds is demonstrated with a system for monitoring cell growth/migration, which shows they are potent inhibitors of growth and/or migration of cancer cells. Compositions comprising these compounds, and methods to use these compounds and compositions for treatment of cancers, are disclosed.
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Page/Page column 34
(2012/07/28)
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- (3-HYDROXY-4-AMINO-BUTAN-2-YL) -3- (2-THIAZOL-2-YL-PYRROLIDINE-1-CARBONYL) BENZAMIDE DERIVATIVES AND RELATED COMPOUNDS AS BETA-SECRETASE INHIBITORS FOR TREATING
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The present invention provides novel beta-secretase inhibitors and methods for their use, including methods of treating of Alzheimer's disease. (Formula)
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Page/Page column 89
(2009/05/29)
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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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- Synthesis, in vitro and in vivo activity of thiamine antagonist transketolase inhibitors
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Tumor cells extensively utilize the pentose phosphate pathway for the synthesis of ribose. Transketolase is a key enzyme in this pathway and has been suggested as a target for inhibition in the treatment of cancer. In a pharmacodynamic study, nude mice with xenografted HCT-116 tumors were dosed with 1 ('N3′-pyridyl thiamine'; 3-(6-methyl-2-amino-pyridin-3-ylmethyl)-5-(2-hydroxy-ethyl)-4-methyl-thiazol-3-ium chloride hydrochloride), an analog of thiamine, the co-factor of transketolase. Transketolase activity was almost completely suppressed in blood, spleen, and tumor cells, but there was little effect on the activity of the other thiamine-utilizing enzymes α-ketoglutarate dehydrogenase or glucose-6-phosphate dehydrogenase. Synthesis and SAR of transketolase inhibitors is described.
- Thomas, Allen A.,Le Huerou,De Meese,Gunawardana, Indrani,Kaplan, Tomas,Romoff, Todd T.,Gonzales, Stephen S.,Condroski, Kevin,Boyd, Steven A.,Ballard, Josh,Bernat, Bryan,DeWolf, Walter,Han, May,Lee, Patrice,Lemieux, Christine,Pedersen, Robin,Pheneger, Jed,Poch, Greg,Smith, Darin,Sullivan, Francis,Weiler, Solly,Wright, S. Kirk,Lin, Jie,Brandhuber, Barb,Vigers, Guy
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p. 2206 - 2210
(2008/12/20)
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- COMPOUNDS WHICH INHIBIT BETA-SECRETASE ACTIVITY AND METHODS OF USE THEREOF
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The present invention provides novel beta-secretase inhibitors of the general formula (I), where the variables A1, A2, L1, L2, L3, R1, R2, R3, R4, R5, R6 and R7 are as defined in the claims, a method for their use in treating Alzheimer's disease, and methods for their use in reducing memapsin 2 catalytic activity.
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Page/Page column 56
(2008/06/13)
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- Discovery of 4-aryl-4H-chromenes as a new series of apoptosis inducers using a cell- and caspase-based high-throughput screening assay. 1. Structure-activity relationships of the 4-aryl group
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By applying a novel cell- and caspase-based HTS assay, 2-amino-3-cyano-7- (dimethylamino)-4-(3-methoxy-4,5-methylenedioxyphenyl)-4H-chromene (1a) has been identified as a potent apoptosis inducer. Compound 1a was found to induce nuclear fragmentation and PARP cleavage, as well as to arrest cells at the G2/M stage and to induce apoptosis as determined by the flow cytometry analysis assay in multiple human cell lines (e.g. Jurkat, T47D). Through structure-activity relationship (SAR) studies of the 4-aryl group, a 4- and 7-fold increase in potency was obtained from the screening hit 1a to the lead compounds 2-amino-4-(3-bromo-4,5-dimethoxyphenyl)-3-cyano-7-(dimethylamino) -4H-chromene (1c) and 2-amino-3-cyano-7-(dimethylamino)-4-(5-methyl-3-pyridyl)- 4H-chromene (4e), with an EC50 of 19 and 11 nM in the caspase activation assay in T47D breast cancer cells, respectively. The 2-amino-4-aryl-3-cyano-7-(dimethylamino)-4H-chromenes also were found to be highly active in the growth inhibition MTT assay, with GI50 values in the low nanomolar range for compound 1c. Significantly, compound 1c was found to have a GI50 value of 2 nM in the paclitaxel resistant, p-glycoprotein overexpressed, MESSA/DX5 tumor cells. Functionally, compound 1c was found to be a potent inhibitor of tubulin polymerization and to effectively inhibit the binding of colchicine to tubulin. These results confirm that the cell-based caspase activation assay is a powerful tool for the discovery of potent apoptosis inducers and suggest that the 4-aryl-4H-chromenes have the potential to be developed into future anticancer agents.
- Kemnitzer, William,Drewe, John,Jiang, Songchun,Zhang, Hong,Wang, Yan,Zhao, Jianghong,Jia, Shaojuan,Herich, John,Labreque, Denis,Storer, Richard,Meerovitch, Karen,Bouffard, David,Rej, Rabindra,Denis, Real,Blais, Charles,Lamothe, Serge,Attardo, Giorgio,Gourdeau, Henriette,Tseng, Ben,Kasibhatla, Shailaja,Cai, Sui Xiong
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p. 6299 - 6310
(2007/10/03)
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- SUBSTITUTED 4H-CHROMENE AND ANALOGS AS ACTIVATORS OF CASPASES AND INDUCERS OF APOPTOSIS AND THE USE THEREOF
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The present invention is directed to substituted 4H-chromene and analogs thereof, represented by the general Formula I: wherein A, B, X, Y, Z and R5 are defined herein. The present invention also relates to the discovery that compounds having Formula I are activators of caspases and inducers of apoptosis. Therefore, the activators of caspases and inducers of apoptosis of this invention can be used to induce cell death in a variety of clinical conditions in which uncontrolled growth and spread of abnormal cells occurs.
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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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