- Industrial Cunninghamia lanceolata carbon supported FeO(OH) nanoparticles-catalyzed hydrogenation of nitroarenes
-
The development of green and efficient methods for hydrogenation of nitroarenes is still highly demanding in organic synthesis. Herein, we report an industrial Cunninghamia lanceolata carbon supported FeO(OH) nanoparticles process for the synthesis of aryl amines with good yields via hydrogenation of nitroarenes. Nine key anti-cancer drug intermediates were successfully achieved with protocol. And Osimertinib intermediate 4m can be smoothly synthesized at a 2.67 kg-scale with >99.5% HPLC purity. This protocol features cheap carbon source, highly catalytic activity, simple operation, kilogram-scalable and recyclable catalysts (eight times without observable losing activity).
- Fu, Lihua,Li, Dingzhong,Lu, Hao,Qiu, Renhua,Sun, Tulai,Xing, Chen,Yang, Tianbao
-
-
- Selective and Additive-Free Hydrogenation of Nitroarenes Mediated by a DMSO-Tagged Molecular Cobalt Corrole Catalyst
-
We report on the first cobalt corrole that effectively mediates the homogeneous hydrogenation of structurally diverse nitroarenes to afford the corresponding amines. The given catalyst is easily assembled prior to use from 4-tert-butylbenzaldehyde and pyrrole followed by metalation of the resulting corrole macrocycle with cobalt(II) acetate. The thus-prepared complex is self-contained in that the hydrogenation protocol is free from the requirement for adding any auxiliary reagent to elicit the catalytic activity of the applied metal complex. Moreover, a containment system is not required for the assembly of the hydrogenation reaction set-up as both the autoclave and the reaction vessels are readily charged under a regular laboratory atmosphere.
- Sch?fberger, Wolfgang,Timelthaler, Daniel,Topf, Christoph
-
supporting information
p. 2114 - 2120
(2021/07/22)
-
- SUBSTITUTED ARYLUREA COMPOUNDS FOR INDUCING APOPTOSIS AND COMPOSITION FOR ANTICANCER COMPRISING THE SAME
-
The present invention relates to a substituted arylurea compound inducing apoptosis and an anticancer composition comprising the same. The present invention relates to a novel compound capable of preventing, treating and alleviating cancer diseases such as prostate cancer, breast cancer, lung cancer, colorectal cancer, and skin cancer by inhibiting apoptosis of cancer cells and inhibiting proliferation of cancer cells.
- -
-
Paragraph 0097; 0103-0106
(2021/08/17)
-
- SYNTHESIS OF 6-METHYL-N1-(4-(PYRIDIN-3-YL)PYRIMIDIN-2-YL)BENZENE-1,3-DIAMINE
-
Processes and useful intermediates for the synthesis of the tyrosine kinase inhibitors Formula (II) nilotinib and Formula (IV) imatinib. Key intermediates, method for their synthesis and their use in a divergent synthesis, making use of a Curtius rearrangement, to nilotinib and imatinib are described.
- -
-
-
- Synthesis method of imatinib and imatinib mesylate
-
The invention relates to a synthesis method of imatinib and imatinib mesylate. The method comprises the following steps: condensing 3-acetylpyridine and N,N-dimethylformamide dimethyl acetal which aretaken as initial raw materials to obtain 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one, then reacting with 2-methyl-5-nitrophenylguanidine nitrate to form a pyrimidine ring, performing nitro reductionto obtain N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine, amidating the N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine and 4-(chloromethyl)benzoyl chloride, performing affinitysubstitution with 1-methylpiperazine to obtain imatinib, and salifying the imatinib and methanesulfonic acid. The products obtained by the method have the advantages of few impurities, simplicity in post-treatment, high total yield, greenness, environmental protection and safety, and is suitable for a production process for large-scale industrial production of imatinib mesylate.
- -
-
Paragraph 0085-0091
(2020/05/02)
-
- Synthetic method of N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-pyrimidinamine
-
The invention discloses a synthetic method of N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-pyrimidinamine. The synthetic method comprises the following steps: (1) synthesizing 2-(methylthio)-4-(3-pyridyl) pyrimidine; (2) synthesizing 2-(methylsulfonyl)-4-(3-pyridine) pyrimidine; (3) synthesizing N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidinamine and (4) synthesizing the N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-pyrimidinamine. Synthesis raw materials used in the method are low in price and easy to obtain, reaction conditions are mild, the product yield and purity are high, and the methodis suitable for industrial production. Therefore, the synthetic method disclosed by the invention has good advantages in the aspects of production cost control, environmental friendliness and productquality improvement.
- -
-
Paragraph 0033; 0043-0047; 0049; 0060-0061
(2020/08/02)
-
- Molecular requirements for the expression of antiplatelet effects by synthetic structural optimized analogues of the anticancer drugs imatinib and nilotinib
-
Background: Platelets play important roles in cancer progression and metastasis, as well as in cancer-associated thrombosis (CAT). Tyrosine kinases are implicated in several intracellular signaling pathways involved in tumor biology, thus tyrosine kinase inhibitors (TKIs) represent an important class of anticancer drugs, based on the concept of targeted therapy. Purpose: The objective of this study is the design and synthesis of analogues of the TKIs imatinib and nilotinib in order to develop tyrosine kinase inhibitors, by investigating their molecular requirements, which would express antiplatelet properties. Methods: Based on a recently described by us improved approach in the preparation of imatinib and/or nilotinib analogues, we designed and synthesized in five-step reaction sequences, 8 analogues of imatinib (I–IV), nilotinib (V, VI) and imatinib/nilotinib (VII, VIII). Their inhibitory effects on platelet aggregation and P-selectin membrane expression induced by arachidonic acid (AA), adenosine diphosphate (ADP) and thrombin receptor activating peptide-6 (TRAP-6), in vitro, were studied. Molecular docking studies and calculations were also performed. Results: The novel analogues V–VIII were well established with the aid of spectroscopic methods. Imatinib and nilotinib inhibited AA-induced platelet aggregation, exhibiting IC50 values of 13.30 μΜ and 3.91 μΜ, respectively. Analogues I and II exhibited an improved inhibitory activity compared with imatinib. Among the nilotinib analogues, V exhibited a 9-fold higher activity than nilotinib. All compounds were less efficient in inhibiting platelet aggregation towards ADP and TRAP-6. Similar results were obtained for the membrane expression of P-selectin. Molecular docking studies showed that the improved antiplatelet activity of nilotinib analogue V is primarily attributed to the number and the strength of hydrogen bonds. Conclusion: Our results show that there is considerable potential to develop synthetic analogues of imatinib and nilotinib, as TKIs with antiplatelet properties and therefore being suitable to target cancer progression and metastasis, as well as CAT by inhibiting platelet activation.
- Alivertis, Dimitrios,Brentas, Alexios,Ntemou, Nikoleta,Pantazi, Despoina,Skobridis, Konstantinos,Tselepis, Alexandros D.
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p. 4225 - 4238
(2019/12/25)
-
- Imatinib derivative as well as preparation method and application thereof
-
The invention discloses an imatinib derivative. The chemical name of the imatinib derivative is (E)-1-(3,5-dibromobenzyl)-4-(4-methyl-3-(4-(pyridine-3-yl)pyrimidine-2-amino)phenyl)semicarbazide, and the structural formula of the derivative is shown in the description, wherein R is 3,5-dibromobenzyl. The invention further discloses a preparation method of the imatinib derivative. The preparation ofthe imatinib derivative with a new structure is disclosed and the derivative has certain antitumor activity; the preparation method of the compound is also disclosed, the reaction cost is low, the yield is high, the reaction process is simple and easy to control, and the preparation method is suitable for industrial production.
- -
-
Paragraph 0043; 0044; 0049-0050
(2019/09/17)
-
- N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine derivative with medicine activity, and preparation method thereof
-
The invention discloses an N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine derivative with medicine activity, and a preparation method thereof, and belongs to the technical field of medicine synthesis. The structural formula of the N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine derivative with medicine activity is shown in the description. The invention also discloses a preparation method for the N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine derivative with anti-cancer activity. The N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine derivative prepared with the preparation method has good inhibition activity for lung carcinoma cells A549, and has a potential for becoming an anti-tumor medicine.
- -
-
Paragraph 0044; 0045; 0046
(2019/02/19)
-
- Synthesis and biological evaluation of phenyl-amino-pyrimidine and indole/oxindole conjugates as potential BCR-ABL inhibitors
-
Abstract: Indole/isatin conjugated phenyl-amino-pyrimidine derivatives have been synthesized, characterized and evaluated in vitro for their potential as BCR-ABL inhibitors. Among the series, all derivatives (7a–7o) were found to be more cytotoxic than standard Imatinib against K-562 cell line. Compound 7l was the most active in the series with almost two folds more potency than imitanib (IC50 0.65 μM). In vitro enzymatic studies with recombinant ABL kinase enzyme exhibited promising inhibition in the range of 30–71 μM for most of these novel conjugates. In addition, modelling and other computational studies have been carried out to draw insight into the BCR-ABL protein interactions with the target molecules and drug like properties of the conjugates, respectively. [Figure not available: see fulltext.].
- Rahim, Abdul,Syed, Riyaz,Poornachandra,Malik, M. Shaheer,Reddy, Ch. Venkata Ramana,Alvala, Mallika,Boppana, Kiran,Sridhar,Amanchy, Ramars,Kamal, Ahmed
-
p. 633 - 645
(2019/03/23)
-
- One-pot propagation of (Hetero)Arylamines: Modular synthesis of diverse Amino-di(hetero)arylamines
-
Formal propagation of (hetero)arylamine is achieved via a one-pot Buchwald–Hartwig C–N cross-coupling and nitro reduction sequence, enabling a rapid modular synthesis of diverse amino-di(hetero)arylamines from (hetero)arylamines and halogenated nitrobenzenes. Various functionalized aromatic amines with different electronic and steric environments can be efficiently prolongated to formally incorporate another arylamino fragments. This approach has been successfully applied in the synthesis of more than forty amino-di(hetero)arylamines. The applicability of this method has also been demonstrated in the synthesis of oligoanilines and the tyrosine-kinase inhibitor Imatinib.
- Liang, Xueting,Xu, Liang,Li, Cuihua,Jia, Xin,Wei, Yu
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p. 721 - 731
(2019/01/08)
-
- Preparative Procedure for the Reduction of Substituted Nitroarenes with Hydrazine Hydrate in the Presence of a Nickel–Cobalt Nanocatalyst
-
A preparative procedure has been proposed for the reduction of substituted nitroarenes with hydrazine hydrate in the presence of a nanocatalyst based on cobalt–nickel nanoparticles, which ensured selective formation of the corresponding anilines in 78–80% yield in 20–45 min.
- Ignatovich, Zh. V.,Ermolinskaya,Koroleva,Eremin
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p. 943 - 944
(2018/07/31)
-
- Catalytic Activity of Nickel Nanoparticles in the Reaction of Reduction of Nitroarenes
-
Techniques for the production of nickel and nickel-cobalt nanoparticles and of their composites with polyvinylpyrrolidone were developed. The catalytic activity of the resulting compounds towards reduction of substituted nitroarenes was examined.
- Ignatovich, Zh. V.,Ermolinskaya,Katok, Ya. M.,Koroleva,Eremin,Agabekov
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p. 410 - 417
(2018/04/23)
-
- Design, synthesis and anti-inflammatory activity of pyrimidine scaffold benzamide derivatives as epidermal growth factor receptor tyrosine kinase inhibitors
-
Novel serious of pyrimidine scaffold benzamide derivatives (9 a-k) were synthesized and characterized by IR, HRMS, and NMR. Docking study of compounds 9 g, 9 h exhibited H-bonding interacts with Met769 into ATP binding site of EGFR-TK which showed similar binding mode to Lapitinib (PDB code: 1M17). Results indicated the ability to potent and selective inhibitors of the Epidermal Growth Factor Receptor tyrosine kinase (EGFR-TK). The molecular electrostatic potential (MEP), frontier molecular orbitals (FMOs) and HOMO-LUMO energy gap of the title compounds were investigated by using the B3LYP/6-31G method. The synthesized compounds were screened for in vitro anti-inflammatory activity.
- Thirumurugan,Lakshmanan, Sivalingam,Govindaraj, Dharman,Daniel Prabu, D. Sam,Ramalakshmi,Arul Antony
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p. 541 - 550
(2018/06/20)
-
- An efficient method for reduction of nitroaromatic compounds to the corresponding aromatic amines with NH2NH2·H2O catalysed by H2O2-treated activated carbon
-
An efficient and green protocol for the reduction of nitroaromatic compounds to the corresponding amines has been developed. The reduction catalyst system includes NH2NH2·H2O and H2O2-treated activated carbon. Without adding additional metals, the H2O2-treated activated carbon could be reused for many cycles without decreasing catalytic efficiency. The aromatic amines could be obtained in good to excellent yields.
- Jiang, Yuqin,Suo, Huajun,Zhang, Dandan,Li, Xiyong,Sun, Yamin,Ren, Baoqi,Zhang, Weiwei,Xu, Guiqing
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p. 509 - 512
(2017/10/03)
-
- Method for synthesizing imatinib intermediate
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The invention provides a method for synthesizing an imatinib intermediate, and belongs to the field of organic synthesis. The method comprises the steps that firstly, an imatinib intermediate nitration substance is added into an organic solvent, an activated carbon catalyst loaded with 10%(w/w) Pd is added, and then the mixture serves as a material I and enters a preheating module of a micro-channel reactor or a micro-reactor; secondly, the pre-heated materials I and a material II, namely hydrogen, are pumped into reaction modules of the micro-channel reactor or the micro-reactor respectively for reaction, an effluent reaction solution is collected, post-treatment is conducted, and the imatinib intermediate amide, namely 2-[N-(2-methyl-5-aminophenyl)amino]-4-(3-pyridyl)pyrimidine, is obtained. The method is mild in reaction and high in environmental protection safety, the yield is high, the product purity is high, and the catalyst recycling efficiency is high.
- -
-
Paragraph 0050; 0051; 0052; 0053; 0054; 0055; 0056-0068
(2017/09/26)
-
- Design, Synthesis, and Evaluation of the Kinase Inhibition Potential of Pyridylpyrimidinylaminophenyl Derivatives
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In view of potent kinase inhibitors for the treatment of myriad human disorders, we synthesized some structurally variant amide/cyclic amide derivatives based on pyridylpyrimidinylaminophenyl amine, the key pharmacophore of the kinase inhibitor drug molecule, imatinib, and evaluated their kinase inhibition potency. Among the various synthesized amides, compound 20, a cyclic amide/pyridin-2(1H)-one derivative, exhibited an IC50 value comparable to that of the drug imatinib against c-Src kinase, and another compound (14) containing a 2-((4-methyl-2-oxo-2H-chromen-6-yl)oxy)acetamide demonstrated an IC50 value of 8.39 μM. Furthermore, the constitution of the cyclic amide derivative was confirmed by the single-crystal X-ray diffraction technique. These results may serve as a gateway for developing novel next-generation kinase inhibitors.
- Manchanda, Priyanka,Parshad, Badri,Kumar, Amit,Tiwari, Rakesh K.,Shirazi, Amir N.,Parang, Keykavous,Sharma, Sunil K.
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-
- Preparation method of non-acicular alpha crystal form imatinib mesylate
-
The invention discloses a preparation method of non-acicular alpha crystal form imatinib mesylate. The method comprises the following steps: (1) performing reduction reaction by taking N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-aminopyrimidine as a raw material, methanol as a solvent, KBH4 as a reducing agent and ZrCl4 as a catalyst to obtain N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine; (2) after activating 4-[(4-methylpiperazin-1-yl)methyl]benzoic acid dihydrochloride hemihydrates by using CBMIT, performing acylation reaction with equimolar N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine by taking DMF as a solvent to obtain imatinib alkali; and (3) suspending the imatinib alkali in isopropanol, adding an acetone solution of methylsulfonic acid, heating for reflux reaction, cooling for crystallization, filtering, and drying to obtain a non-acicular imatinib mesylate alpha crystal form. The preparation method disclosed by the invention has the advantages of being simple in operation, small in environmental harm, safe, reliable, relatively short in reaction time, good in product quality, high in yield and the like, and is suitable for industrial production.
- -
-
Paragraph 0042-0044
(2016/12/01)
-
- New method for preparing imatinib intermediate
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The invention discloses a new method for preparing an imatinib intermediate N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine. The method comprises the following steps: stirring, refluxing and reacting FeCl3.6H2O and sodium hydroxide in an aqueous solution with the pH value of 7.0-8.0 at 100DEG C for 12, carrying out pumping filtration, drying the obtained solid in an oven to obtain a required catalyst FeO(OH), and reducing a nitro group in N-(5-nitro-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine with FeO(OH) as a catalyst and hydrazine hydrate as a reducing agent to generate N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine. The method for preparing N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine has the advantages of easily available raw materials, simple operation, high total yield of the above reaction, and is a synthesis route suitable for industrially producing N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine.
- -
-
Paragraph 0010
(2016/11/21)
-
- An optimized approach in the synthesis of imatinib intermediates and analogues
-
We revisited the classical synthetic procedure for imatinib synthesis providing an improved and optimized approach in the preparation of a series of new imatinib analogues. The proposed methodology effectively overcomes certain problematic steps, saves time and labor, provides a very high yield and purity and has the potential to be used for the synthesis of many analogues. The formation of the desired guanidine salt 4, one of the key steps to the imatinib synthesis, was proceeded almost quantitatively by the reaction of the hydrochloride of the suitable aniline 3 with excess of molten cyanamide, without any solvent. Pure arylamine intermediates 6a-d were obtained quantitatively in a short reaction time after reduction of the nitro group of the intermediate pyrimidines 5a-d with hydrogen over the Adam's catalyst. In addition, the application of this optimized approach can be extended in the synthesis of nilotinib and its analogues intermediates.
- Kinigopoulou,Filippidou,Gogou,Giannousi,Fouka,Ntemou,Alivertis,Georgis,Brentas,Polychronidou,Voulgari,Theodorou,Skobridis
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p. 61458 - 61467
(2016/07/12)
-
- 2,3-dimethyl-6-urea -2H-indazoles and its preparation method and application
-
The invention discloses a 2, 3-dimethyl-6-urea-2H-indazole compound shown by the following general formula (I), medicinal salt or a solvent compound thereof, wherein Ar is substituted or unsubstituted phenyl or aromatic matrix. The invention also discloses a preparation method and application of the compound. The compound can regulate signal transduction of tyrosine kinase, inhibit bad cellular proliferation, and particularly has obvious curative effect for tumors.
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-
Paragraph 0181-0184
(2016/10/09)
-
- Aniline pyrimidine compound and its preparation and use
-
The invention belongs to the field of synthesis of medicaments, and relates to an aniline pyrimidine compound of a general formula (I), in particular to an N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino] phenyl]-benzamide of which the 4th site is substituted by a quaternary heterocyclic ring, a preparation method for the compound and application in medicine. In vitro anti-tumor activity test results show that the in vitro anti-tumor activity IC50 value of the compound on MKN-45 gastric cancer strains is nM level and the compound can obviously inhibit activity of tumor cells and can be used for preparing new anti-tumor medicaments.
- -
-
Paragraph 0029; 0034; 0041; 0042
(2019/06/09)
-
- Enantioselective synthesis of α-secondary and α-tertiary piperazin-2- Ones and piperazines by catalytic asymmetric allylic alkylation
-
The asymmetric palladium-catalyzed decarboxylative allylic alkylation of differentially N-protected piperazin-2- ones allows the synthesis of a variety of highly enantioenriched tertiary piperazine-2-ones. Deprotection and reduction affords the corresponding tertiary piperazines, which can be employed for the synthesis of medicinally important analogues. The introduction of these chiral tertiary piperazines resulted in imatinib analogues which exhibited comparable antiproliferative activity to that of their corresponding imatinib counterparts.
- Korch, Katerina M.,Eidamshaus, Christian,Behenna, Douglas C.,Stoltz, Brian M.,Nam, Sangkil,Horne, David
-
supporting information
p. 179 - 183
(2015/02/05)
-
- Oligomer-protein tyrosine kinase inhibitor conjugates
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The invention relates to (among other things) oligomer-PTK inhibitor conjugates and related compounds. A compound of the invention, when administered by any of a number of administration routes, exhibits advantages over PTK inhibitor compounds lacking a water-soluble, non-peptidic oligomer.
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Page/Page column 32; 33
(2015/09/22)
-
- Design, Synthesis, and Characterization of a Photoactivatable Caged Prodrug of Imatinib
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Imatinib is the first protein kinase inhibitor approved for clinical use and is a seminal drug for the concept of targeted therapy. Herein we report on the design, synthesis, photokinetic properties, and in vitro enzymatic evaluation of a photoactivatable caged prodrug of imatinib. This approach allows spatial and temporal control over the activation of imatinib triggered by ultraviolet light. The successful application of the photoactivation concept to this significant kinase inhibitor provides further evidence for the caging technique as a feasible approach in the kinase field. The presented photoactivatable imatinib prodrug will be highly useful as a pharmacological tool to study the impact of imatinib toward biological systems in greater detail. Don′t fence me in! A caged prodrug of imatinib, the first approved kinase inhibitor, was designed, synthesized, and characterized for photokinetic properties. By using a PDGF-Rβ assay, we demonstrated that upon UV irradiation at λ=365nm the biological activity of imatinib is restored.
- Zindler, Melanie,Pinchuk, Boris,Renn, Christian,Horbert, Rebecca,D?bber, Alexander,Peifer, Christian
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p. 1335 - 1338
(2015/08/03)
-
- Imatinib analogs as potential agents for PET imaging of Bcr-Abl and c-KIT expression at a kinase level
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We synthesized two series of imatinib mesylate (STI-571) analogs to develop a Bcr-Abl and c-KIT receptor-specific labeling agent for positron emission tomography (PET) imaging to measure Bcr-Abl and c-KIT expression levels in a mouse model. The methods of molecular modeling, synthesis of STI-571 and its analogs, in vitro kinase assays, and radiolabeling are described. Molecular modeling revealed that these analogs bind the same Bcr-Abl and c-KIT binding sites as those bound by STI-571. The analogs potently inhibit the tyrosine kinase activity of Bcr-Abl and c-KIT, similarly to STI-571. [ 18F]-labeled STI-571 was prepared with high specific activity (75 GBq/μmol) by nucleophilic displacement and an average radiochemical yield of 12%. [131I]-labeled STI-571 was prepared with high purity (>95%) and an average radiochemical yield of 23%. The uptake rates of [ 18F]-STI-571 in K562 cells expressing Abl and in U87WT cells overexpressing c-KIT were significantly higher than those in the U87 cell and could be inhibited by STI-71 (confirming the specificity of uptake). PET scans of K562 and U87WT tumor-bearing mice with [18F]-STI-571 as a contrast agent showed visible tumor uptake and tumor-to-non-target contrast.
- Peng, Zhenghong,Maxwell, David S.,Sun, Duoli,Bhanu Prasad, Basvoju A.,Pal, Ashutosh,Wang, Shimei,Balatoni, Julius,Ghosh, Pradip,Lim, Seok T.,Volgin, Andrei,Shavrin, Aleksander,Alauddin, Mian M.,Gelovani, Juri G.,Bornmann, William G.
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p. 623 - 632
(2014/01/17)
-
- Imatinib intermediate as a two in one dual channel sensor for the recognition of Cu2+ and I- ions in aqueous media and its practical applications
-
An imatinib intermediate, 6-methyl-N-[4-(pyridin-3-yl)pyrimidin-2-yl] benzene-1,3-diaminepyridopyrimidotoluidine (PPT-1), was developed for the colorimetric sensing of Cu2+ ions in aqueous solution. With Cu 2+, the receptor PPT-1 showed a highly selective naked-eye detectable color change from colorless to red over the seventy other tested cations. The colorimetric sensing ability of PPT-1 was successfully utilized in the preparation of test strips and supported silica for the real samples analysis to detect Cu2+ ions from 100% aqueous environment. Moreover, the iodide-sensing ability of receptor PPT-1 was explored among the ten examined anions.
- Patil, Samadhan R.,Nandre, Jitendra P.,Jadhav, Devising,Bothra, Shilpa,Sahoo,Devi, Manisha,Pradeep, Chullikkattil P.,Mahulikar, Pramod P.,Patil, Umesh D.
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p. 13299 - 13306
(2014/10/16)
-
- Design and synthesis of minimalist terminal alkyne-containing diazirine photo-crosslinkers and their incorporation into kinase inhibitors for cell- and tissue-based proteome profiling
-
Less is more: A minimalist "clickable" photo-crosslinker (see scheme) was incorporated with numerous small-molecule kinase inhibitors. The resulting probes were used for both in vitro (cell lysates) and in situ (live cells) proteome profiling, for large-scale identification of their potential cellular kinase targets and shows improved outcomes over previous probes. Copyright
- Li, Zhengqiu,Hao, Piliang,Li, Lin,Tan, Chelsea Y. J.,Cheng, Xiamin,Chen, Grace Y. J.,Sze, Siu Kwan,Shen, Han-Ming,Yao, Shao Q.
-
supporting information
p. 8551 - 8556
(2013/09/12)
-
- PROCESSES FOR THE PREPARATION OF IMATINIB BASE AND INTERMEDIATES THEREOF
-
The invention relates to an improved process for the preparation of highly pure imatinib base (99.99% HPLC purity) of formula (I) and the pharmaceutically acceptable acid addition salts thereof. This invention also relates to processes for the preparation of the intermediates in the synthesis of imatinib base.
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-
Page/Page column 22
(2013/03/26)
-
- A "catch-react-release" method for the flow synthesis of 2-aminopyrimidines and preparation of the imatinib base
-
The development of a monolith-supported synthetic procedure is reported, taking advantage of flow processing and the superior flow characteristics of monolithic reagents over gel-phase beads, to allow facile access to an important family of 2-aminopyrimidine derivatives. The process has been successfully applied to a key precursor on route to Imatinib (Ar = 3-pyridyl, R1 = 2-methyl-5-nitrobenzyl, R2 = H).
- Ingham, Richard J.,Riva, Elena,Nikbin, Nikzad,Baxendale, Ian R.,Ley, Steven V.
-
scheme or table
p. 3920 - 3923
(2012/09/22)
-
- A facile total synthesis for large-scale production of imatinib base
-
An efficient, economic process has been developed for the production of imatinib with 99.99% purity and 50% overall yield from four steps. Formation and control of all possible impurities is described. The synthesis comprises the condensation of N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine with 4-(4-methylpiperazinomethyl)benzoyl chloride in isopropyl alcohol solvent in the presence of potassium carbonate to yield imatinib base.
- Kompella, Amala,Adibhatla, Bhujanga Rao Kalisatya,Muddasani, Pulla Reddy,Rachakonda, Sreenivas,Gampa, Venugopala Krishna,Dubey, Pramod Kumar
-
p. 1794 - 1804
(2013/01/15)
-
- Preparation of copper(II) oxide bound on polystyrene beads and its application in the aryl aminations: Synthesis of Imatinib
-
CuO nanoflakes bound on polystyrene beads (PS-CuO) were prepared through the oxidation of copper(I) bromide in a suspension of polystyrene. The use of PS-CuO as a catalyst in the presence of KOtBu in the coupling reactions of aryl bromides and amines afforded the coupled products with a yield range of 15-89%. This catalytic system also afforded the key fragment in good yield for the synthesis of Imatinib (Gleevec).
- Heo, Yumi,Hyun, Dajung,Kumar, Manian Rajesh,Jung, Hyun Min,Lee, Sunwoo
-
supporting information
p. 6657 - 6661
(2013/01/15)
-
- N-[2-methyl-5-(triazol-1-yl)phenyl]pyrimidin-2-amine as a Scaffold for the synthesis of inhibitors of Bcr-Abl
-
N-[2-Methyl-5-(triazol-1-yl)phenyl]pyrimidin-2-amine derivatives were synthesized and evaluated invitro for their potential use as inhibitors of Bcr-Abl. The design is based on the bioisosterism between the 1,2,3-triazole ring and the amide group. The synthesis involves a copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) as the key step, with the exclusive production of anti-(1,4)-triazole derivatives. One of the compounds obtained shows general activity similar to that of imatinib; in particular, it was observed to be more effective in decreasing the fundamental function of cdc25A phosphatases in the K-562 cell line. Willing and Abl inhibitors! N-[2-Methyl-5-(triazol-1-yl)phenyl]pyrimidin-2-amine derivatives were synthesized by a copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) as a key step, with anti-(1,4)-triazole derivatives as the exclusive products. One of these compounds shows general activity similar to that of imatinib, and in particular, it is more effective in decreasing the fundamental function of cdc25A phosphatases in the K-562 cell line.
- Arioli, Federica,Borrelli, Stella,Colombo, Francesco,Falchi, Federico,Filippi, Irene,Crespan, Emmanuele,Naldini, Antonella,Scalia, Giusy,Silvani, Alessandra,Maga, Giovanni,Carraro, Fabio,Botta, Maurizio,Passarella, Daniele
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experimental part
p. 2009 - 2018
(2012/06/30)
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- PROCESSES FOR PREPARING IMATINIB AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
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The processes for preparing imatinib and its pharmaceutically acceptable salts, specifically imatinib mesylate, are disclosed.
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Page/Page column 15
(2011/04/25)
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- Synthesis and apoptosis inducing ability of new anilino substituted pyrimidine sulfonamides as potential anticancer agents
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A series of anilino substituted pyrimidine sulfonamides were prepared and evaluated for their anticancer activity. These sulfonamides showed promising activity with IC50 values ranging from 5.6 to 12.3 μM. The detailed biological aspects of some of the promising compounds (3d, 3e and 3g) on the K562 cell line were studied. Interestingly, compounds induced G1 cell cycle arrest and down regulation of G1 phase cell cycle regulatory proteins such as cyclin D1, CDK4. These compounds also exhibited inhibition of NF-κB as well as its downstream target gene Akt1 and the phosphorylated form of AKt ser 474 proteins. One of the representative compound 3e could be considered as the potential lead for its development as a new anticancer agent.
- Kamal, Ahmed,Dastagiri,Janaki Ramaiah,Surendranadha Reddy,Vijaya Bharathi,Kashi Reddy,Victor Prem Sagar,Lakshminarayan Reddy,Pushpavalli,Pal-Bhadra, Manika
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experimental part
p. 5817 - 5824
(2011/12/22)
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- PROCESS FOR THE PREPARATION OF IMATINIB AND INTERMEDIATES THEREOF
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It is the object of the present invention a process for the preparation of 4-methyl-N3-[4-(3-pyridinyl)-2-pyrimidinyl]-1,3-benzenediamine and analogues thereof, intermediates useful for the synthesis of Imatinib, or 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide.
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Page/Page column 9
(2010/04/23)
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- A novel synthesis of imatinib and its intermediates
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A convenient method has been developed for the synthesis of imatinib and two of its intermediates. N-(2-Methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidin amine, obtained from 2-(methylsulfonyl)-4-(3-pyridyl)pyrimidine via nucleophilic substitution, was reduced by N2H4H2O/FeCl 3·6H2O/C in 92% yield. The resulting amine was condensed with 4-[(4-methylpiperazin-1-yl)methyl]benzoic acid dihydrochloride, which was prepared from 4-(chloromethyl)benzonitrile via substitution and hydrolysis reactions, to provide the final product imatinib in good yield and high purity. Springer-Verlag 2010.
- Liu, Haiyan,Xia, Wenpin,Luo, Yu,Lu, Wei
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experimental part
p. 907 - 911
(2011/06/28)
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- Novel imatinib derivatives with altered specificity between Bcr-Abl and FMS, KIT, and PDGF receptors
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Imatinib is a clinically important ATP analogue inhibitor that targets the tyrosine kinase domain of the intracellular Abl kinase and the PDGF receptor family. Imatinib has revolutionised the treatment of chronic myeloid leukaemia, which is caused by the oncogene Bcr-Abl and certain solid tumours that harbor oncogenic mutations of the PDGF receptor family. As a leading kinase inhibitor, imatinib also provides an excellent model system to investigate how changes in drug design impact biological activity, which is an important consideration for rational drug design. Herein we report a new series of imatinib derivatives that in general have greater activity against the family of PDGF receptors and poorer activity against Abl, as a result of modifications of the phenyl and N-methylpiperazine rings. These new compounds provide a platform for further drug development against the therapeutically important PDGF receptor family and they also provide insight into the engineering of drugs with altered biological activity.
- Skobridis, Konstantinos,Kinigopoulou, Maria,Theodorou, Vassiliki,Giannousi, Emilia,Russell, Alison,Chauhan, Rakhee,Sala, Roberta,Brownlow, Nicola,Kiriakidis, Serafim,Domin, Jan,Tzakos, Andreas G.,Dibb, Nick J.
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scheme or table
p. 130 - 139
(2010/11/02)
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- Small molecule probes that target Abl kinase
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Two different strategies, namely a dialdehyde-based cross-linking and photo-affinity labeling, have been developed to generate small molecule activity-based probes (ABPs) for the Abelson (Abl) tyrosine kinase, of which probe 13, derived from the photo-affinity approach, showed specific labeling of Abl kinase present in a crude mammalian proteome.
- Kalesh, Karunakaran A.,Sim, Derek S. B.,Wang, Jigang,Liu, Kai,Lin, Qingsong,Yao, Shao Q.
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supporting information; experimental part
p. 1118 - 1120
(2010/06/18)
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- Synthesis and biological evaluation of anilino substituted pyrimidine linked pyrrolobenzodiazepines as potential anticancer agents
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A series of new anilino substituted pyrimidine linked pyrrolo[2,1-c][1,4] benzodiazepine (PBD) conjugates were prepared and evaluated for their anticancer activity. The effects of four promising PBD conjugates on cell cycle of cancerous cell line A375 were investigated. These compounds showed the characteristic features of apoptosis like enhancement in the levels of p53, release of cytochrome c, and cleavage of PARP.
- Kamal, Ahmed,Reddy, J. Surendranadha,Ramaiah, M. Janaki,Bharathi, E. Vijaya,Dastagiri,Reddy, M. Kashi,Pushpavalli,Pal-Bhadra, Manika
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scheme or table
p. 5232 - 5236
(2010/10/18)
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- ALGORITHM FOR DESIGNING IRREVERSIBLE INHIBITORS
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The invention is an algorithm and method for designing an inhibitor that covalently binds a target polypeptide. The algorithm and method can be used to rapidly and efficiently convert reversible inhibitors into irreversible inhibitors.
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- Rapid synthesis of Abelson tyrosine kinase inhibitors using click chemistry
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Protein kinases catalyze the phosphorylation of serine, threonine, tyrosine and histidine residues in proteins. Aberrant regulation of kinase activity has been implicated in many diseases including cancer. Thus development of new strategies for kinase inhibitor design remains an active area of research with direct relevance to drug development. Abelson (Abl) tyrosine kinase is one of the Src-family of tyrosine kinases and is directly implicated in Chronic Myelogenous Leukemia (CML). In this article, we have, for the first time, developed an efficient method for the construction of small molecule-based bisubstrate inhibitors of Abl kinase using click chemistry. Subsequent biochemical screenings revealed a set of moderately potent inhibitors, a few of which have comparable potency to Imatinib (an FDA-approved drug for treatment of chronic myeloid leukemia) against Abl.
- Kalesh, Karunakaran A.,Liu, Kai,Yao, Shao Q.
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experimental part
p. 5129 - 5136
(2010/04/04)
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- Synthesis of imatinib: A convergent approach revisited
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A classical convergent approach for the synthesis of the anticancer drug imatinib has been substantially improved. Imatinib was assembled by coupling the amine and carboxylic acid precursors by using N,N′-carbonyldiimidazole (CDI) as a condensing agent. Both intermediates have been synthesized by novel efficient methods.
- Ivanov, Andrey S.,Shishkov, Sergey V.
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experimental part
p. 619 - 623
(2010/05/02)
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- Design and synthesis of novel 2-phenylaminopyrimidine (PAP) derivatives and their antiproliferative effects in human chronic myeloid leukemia cells
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A series of novel 2-phenylaminopyrimidine (PAP) derivatives structurally related to STI-571 were designed and synthesized. The abilities of these compounds to inhibit proliferation were tested in human chronic myeloid leukemia K562 cells. (E)-3-(2-bromophenyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2- ylamino)phenyl]acrylamide( 12d) was the most effective cell growth inhibitor and was 3-fold more potent than STI-571.
- Chang, Sheng,Yin, Shi-Liang,Wang, Jian,Jing, Yong-Kui,Dong, Jin-Hua
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experimental part
p. 4166 - 4179
(2009/12/28)
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- Polymorphic forms of imatinib mesylate and processes for preparation of novel crystalline forms as well as amorphous and form alpha
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Solvates and crystalline forms of imatinib mesylate are described. Further, methods for preparing such solvates and crystalline forms of imatinib mesylate are described.
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Page/Page column 21
(2009/10/30)
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- Design of chimeric histone deacetylase- and tyrosine kinase-inhibitors: A series of Imatinib hybrides as potent Inhibitors of wild-type and mutant BCR-ABL, PDGF-Rβ, and histone deacetylases
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Inhibitors of histone deacetylases are a new class of cancer therapeutics with possibly broad applicability. Combinations of HDAC inhibitors with the kinase inhibitor 1 (Imatinib) in recent studies showed additive and synergistic effects. Here we present a new concept by combining inhibition of protein kinases and HDACs, two independent pharmacological activities, in one synthetic small molecule. In general, the HDAC inhibition profile, the potencies, and the probable binding modes to HDAC1 and HDAC6 were similar as for 6 (SAHA). Inhibition of Abl kinase in biochemical assays was maintained for most compounds, but in general the kinase selectivity profile differed from that of 1 with nearly equipotent inhibition of the wildtype and the Imatinib resistant Abl T315I mutant. A potent cellular inhibition of PDGFR and cytotoxicity toward EOL-1 cells, a model for idiopathic hypereosinophilic syndrome (HES), are restored or enhanced for selected analogues (12b, 14b, and 18b). Cytotoxicity was evaluated by using a broad panel of tumor cell lines, with selected analogues displaying mean IC50 values between 3.6 and 7.1 μM.
- Mahboobi, Siavosh,Dove, Stefan,Sellmer, Andreas,Winkler, Matthias,Eichhorn, Emerich,Pongratz, Herwig,Ciossek, Thomas,Baer, Thomas,Maier, Thomas,Beckers, Thomas
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scheme or table
p. 2265 - 2279
(2009/12/31)
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- NOVEL BIFUNCTIONAL COMPOUNDS WHICH INHIBIT PROTEIN KINASES AND HISTONE DEACETYLASES
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The present invention relates to a bifunctional compound of formula I or its pharmaceutically acceptable salts or solvates A-L-B (I) wherein A is a histone deacetylase (HDAC) inhibitory moiety, L is a single bond or a linker group and B is a protein kinase inhibitory moiety. The bifunctional compound according to formula (I) is useful for the treatment of malignant and non-malignant neoplasia and diseases related to abnormal cell growth
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Page/Page column 97
(2009/06/27)
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- A facile total synthesis of imatinib base and its analogues
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Imatinib and its analogues were successfully synthesized by an improved method in 19.5-46.2% total yield of six main steps. Pyrimidinyl amine was prepared by the reaction of enaminone and guanidine nitrate without the use of a toxic cyanamide. N-(2-Methyl-5-nitrophenyl)-4-(pyridin-3-yl) pyrimidin-2-amine as a key intermediate for the synthesis of imatinib was prepared by coppercatalyzed iV-arylation of heteroarylamme in 82% yield. The copper salts were used instead of the expensive palladium compounds in this C-N bond-forming reaction. The intermediate nitro compound was reduced by a N2H 4.H2O/FeCl3/C system using water as a solvent in good yield.
- Liu, Yi-Feng,Wang, Cui-Ling,Bai, Ya-Jun,Han, Ning,Jiao, Jun-Ping,Qi, Xiao-Li
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p. 490 - 495
(2013/01/03)
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- HETEROCYCLIC COMPOUNDS AND USES THEREOF
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The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same.
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Page/Page column 50-51
(2009/01/20)
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- A NOVEL METHOD OF PREPARATION OF IMATINIB
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Imatinib base (I) is prepared by a novel method by reduction of N-(2-Methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine amine (IV) employing sodium disulphide and condensing the resulting amine N-(5-Amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine (II) with the acid chloride 4-[(4-Methylpiperazin-1-yl) methyl]benzoylchloride dihydrochloride (III), in presence of potassium carbonate.
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Page/Page column title page; 3
(2008/12/04)
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