- 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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Read Online
- The ester and amide derivatives of 4-(4-methyl piperazinomethyl) benzoic acid
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Synthesis of 4-(4-methyl piperazinomethyl) benzoic acid (1) from a commercially available and inexpensive starting material with enhanced yields. This acid (1) is then further used for the synthesis of the ester and amide.
- Sairam,Puranik, Ramachandra,Kelkar, Avijit S.,Sasikiran,Veerender,Parvathi
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Read Online
- Accessing Aliphatic Amines in C-C Cross-Couplings by Visible Light/Nickel Dual Catalysis
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A general aminoalkylation of aryl halides was developed, overcoming intolerance of free amines in nickel-mediated C-C coupling. This transformation features broad functional group tolerance and high efficiency. Taking advantage of the fast desilylation of α-silylamines upon single-electron transfer (SET) facilitated by carbonate, α-amino radicals are generated regioselectively, which then engage in nickel-mediated C-C coupling. The reaction displays high chemoselectivity for C-C over C-N bond formation. Highly functionalized pharmacophores and peptides are also amenable.
- Badir, Shorouk O.,Dong, Weizhe,Molander, Gary A.,Zhang, Xuange
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supporting information
p. 4250 - 4255
(2021/06/27)
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- Method of preparing 4-[(4-Methylpiperazin-1-yl)methyl]benzoic acid dihydrochloride by one-pot method
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The invention discloses a method of preparing 4-[(4-Methylpiperazin-1-yl)methyl]benzoic acid dihydrochloride by a one-pot method. The method comprises the following steps of: carrying out condensationreaction on N-methyl piperazine and p-cyanobenzyl chlor
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Paragraph 0024-0033
(2020/05/01)
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- Development of inhibitors against mycobacterium abscessus tRNA (m1G37) Methyltransferase (TrmD) Using Fragment-Based Approaches
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Mycobacterium abscessus (Mab) is a rapidly growing species of multidrug-resistant nontuberculous mycobacteria that has emerged as a growing threat to individuals with cystic fibrosis and other pre-existing chronic lung diseases. Mab pulmonary infections are difficult, or sometimes impossible, to treat and result in accelerated lung function decline and premature death. There is therefore an urgent need to develop novel antibiotics with improved efficacy. tRNA (m1G37) methyltransferase (TrmD) is a promising target for novel antibiotics. It is essential in Mab and other mycobacteria, improving reading frame maintenance on the ribosome to prevent frameshift errors. In this work, a fragment-based approach was employed with the merging of two fragments bound to the active site, followed by structure-guided elaboration to design potent nanomolar inhibitors against Mab TrmD. Several of these compounds exhibit promising activity against mycobacterial species, including Mycobacterium tuberculosis and Mycobacterium leprae in addition to Mab, supporting the use of TrmD as a target for the development of antimycobacterial compounds.
- Whitehouse, Andrew J.,Thomas, Sherine E.,Brown, Karen P.,Fanourakis, Alexander,Chan, Daniel S.-H.,Libardo, M. Daben J.,Mendes, Vitor,Boshoff, Helena I. M.,Floto, R. Andres,Abell, Chris,Blundell, Tom L.,Coyne, Anthony G.
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p. 7210 - 7232
(2019/08/20)
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- Synthesis of Imatinib by C-N Coupling Reaction of Primary Amide and Bromo-Substituted Pyrimidine Amine
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A new method for imatinib synthesis is described by using the C-N coupling reaction of 4-(4-methylpiperazine-1-methyl)benzamide with N-(5-bromo-2-tolyl)-4-(3-pyridyl)pyrimidin-2-amine to form imatinib. In this synthetic route, the high efficiency and high selectivity of nano-ZnO as a catalyst is key to the mild hydrolysis of 4-(4-methylpiperazine-1-methyl)benzonitrile into the corresponding amide. The total imatinib yield was 51.3%, and the purity was 99.9%. This simple and effective synthetic pathway avoids gene-impurity production (as classified by the FDA Center for Drug Evaluation and Research), and the synthesis is environmentally friendly with a short reaction time.
- Wang, Cuiling,Bai, Xiao,Wang, Rui,Zheng, Xudong,Ma, Xiumei,Chen, Huan,Ai, Yun,Bai, Yajun,Liu, Yifeng
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p. 1918 - 1925
(2019/09/07)
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- Cyano-pyrrolo-heteroaryl derivative, preparation method thereof and application of derivative to medicine
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The invention relates to a cyano-pyrrolo-heteroaryl derivative, a preparation method thereof and an application of the derivative to medicine, and particularly relates to a novel cyano-pyrrolo-heteroaryl derivative as shown in a general formula (I), a pre
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Paragraph 0254; 0255; 0256; 0257; 0258-0261
(2019/10/23)
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- Structural-based design, synthesis, and antitumor activity of novel alloxazine analogues with potential selective kinase inhibition
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Protein kinases are promising therapeutic targets for cancer therapy. Here, we applied multiple approaches to optimize the potency and selectivity of our reported alloxazine scaffold. Flexible moieties at position 2 of the hetero-tricyclic system were inc
- Malki, Waleed H.,Gouda, Ahmed M.,Ali, Hamdy E.A.,Al-Rousan, Rabaa,Samaha, Doaa,Abdalla, Ashraf N.,Bustamante, Juan,Abd Elmageed, Zakaria Y.,Ali, Hamed I.
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- Preparation of 4 - (4-methyl piperazin-l-methyl) benzamide method of
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The invention relates to a preparation method for a key intermediate 4-(4-methyl piperazine-1-methyl)-benzoyl amide of imatinib. The method is as follows: adopting a solid-phase organic synthesis method to synthesize 4-(4-methyl piperazine-1-methyl) cyano
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Paragraph 0022; 0023; 0024; 0029; 0030
(2016/10/17)
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- HETEROARYL COMPOUNDS AS BTK INHIBITORS AND USES THEREOF
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The present invention relates to imidazo pyridine compounds, and pharmaceutically acceptable compositions thereof, useful as BTK inhibitors.
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Paragraph 0449
(2016/05/02)
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- Transnitrilation from Dimethylmalononitrile to Aryl Grignard and Lithium Reagents: A Practical Method for Aryl Nitrile Synthesis
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An electrophilic cyanation of aryl Grignard or lithium reagents, generated in situ from the corresponding aryl bromides or iodides, by a transnitrilation with dimethylmalononitrile (DMMN) was developed. DMMN is a commercially available, bench-stable solid. The transnitrilation with DMMN avoids the use of toxic reagents and transition metals and occurs under mild reaction conditions, even for extremely sterically hindered substrates. The transnitrilation of aryllithium species generated by directed ortho-lithiation enabled a net C-H cyanation. The intermediacy of a Thorpe-type imine adduct in the reaction was supported by isolation of the corresponding ketone from the quenched reaction. Computational studies supported the energetic favorability of retro-Thorpe fragmentation of the imine adduct. (Chemical Equation Presented).
- Reeves, Jonathan T.,Malapit, Christian A.,Buono, Frederic G.,Sidhu, Kanwar P.,Marsini, Maurice A.,Sader, C. Avery,Fandrick, Keith R.,Busacca, Carl A.,Senanayake, Chris H.
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supporting information
p. 9481 - 9488
(2015/08/11)
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- Exploration of the nicotinamide-binding site of the tankyrases, identifying 3-arylisoquinolin-1-ones as potent and selective inhibitors in vitro
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Tankyrases-1 and -2 (TNKS-1 and TNKS-2) have three cellular roles which make them important targets in cancer. Using NAD+ as a substrate, they poly(ADP-ribosyl)ate TRF1 (regulating lengths of telomeres), NuMA (facilitating mitosis) and axin (in wnt/β-catenin signalling). Using molecular modelling and the structure of the weak inhibitor 5-aminoiso quinolin-1-one, 3-aryl-5-substituted-isoquinolin-1-ones were designed as inhibitors to explore the structure-activity relationships (SARs) for binding and to define the shape of a hydrophobic cavity in the active site. 5-Amino-3-arylisoquinolinones were synthesised by Suzuki-Miyaura coupling of arylboronic acids to 3-bromo-1-methoxy-5-nitro-isoquinoline, reduction and O-demethylation. 3-Aryl-5-methylisoquinolin-1-ones, 3-aryl-5-fluoroisoquinolin-1-ones and 3-aryl-5-methoxyisoquinolin-1-ones were accessed by deprotonation of 3-substituted-N,N,2-trimethylbenzamides and quench with an appropriate benzonitrile. SAR around the isoquinolinone core showed that aryl was required at the 3-position, optimally with a para-substituent. Small meta-substituents were tolerated but groups in the ortho-positions reduced or abolished activity. This was not due to lack of coplanarity of the rings, as shown by the potency of 4,5-dimethyl-3-phenylisoquinolin-1-one. Methyl and methoxy were optimal at the 5-position. SAR was rationalised by modelling and by crystal structures of examples with TNKS-2. The 3-aryl unit was located in a large hydrophobic cavity and the para-substituents projected into a tunnel leading to the exterior. Potency against TNKS-1 paralleled potency against TNKS-2. Most inhibitors were highly selective for TNKSs over PARP-1 and PARP-2. A range of highly potent and selective inhibitors is now available for cellular studies.
- Paine, Helen A.,Nathubhai, Amit,Woon, Esther C.Y.,Sunderland, Peter T.,Wood, Pauline J.,Mahon, Mary F.,Lloyd, Matthew D.,Thompson, Andrew S.,Haikarainen, Teemu,Narwal, Mohit,Lehti?, Lari,Threadgill, Michael D.
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supporting information
p. 5891 - 5908
(2015/11/11)
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- PROCESSES FOR THE PREPARATION OF IMATINIB BASE AND INTERMEDIATES THEREOF
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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 20
(2013/03/26)
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- A facile total synthesis for large-scale production of imatinib base
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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
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p. 1794 - 1804
(2013/01/15)
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- Aminomethylation via cyclopalladated-ferrocenylimine-complexes-catalyzed Suzuki-Miyaura coupling of aryl halides with potassium N, N - dialkylaminomethyltrifluoroborates
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Using cyclopalladated ferrocenylimine complexes (1-3 mol%) as catalysts, the Suzuki-Miyaura coupling of potassium N,N-dialkylaminomethyltrifluoroborates with aryl and heteroaryl halides were carried out in a 10:1 THF-H2O mixture at 80° in the presence of Cs2CO3 (3.0 equiv) as base, giving the desired cross-coupling products in 14-87% yields. A variety of potassium alkyltrifluoroborates were also examined. Georg Thieme Verlag Stuttgart New York.
- Zou, Dapeng,Cui, Hongmeng,Qin, Lijin,Li, Jingya,Wu, Yangjie,Wu, Yusheng
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scheme or table
p. 349 - 356
(2011/03/23)
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- Synthesis and biological evaluation of N-hydroxyphenylacrylamides and N-hydroxypyridin-2-ylacrylamides as novel histone deacetylase inhibitors
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The histone deacetylases (HDACs) are able to regulate gene expression, and histone deacetylase inhibitors (HDACi) emerged as a new class of agents in the treatment of cancer as well as other human disorders such as neurodegenerative diseases. In the prese
- Thaler, Florian,Colombo, Andrea,Mai, Antonello,Amici, Raffaella,Bigogno, Chiara,Boggio, Roberto,Cappa, Anna,Carrara, Simone,Cataudella, Tiziana,Fusar, Fulvia,Gianti, Eleonora,Di Ventimiglia, Samuele Joppolo,Moroni, Maurizio,Munari, Davide,Pain, Gilles,Regalia, Nickolas,Sartori, Luca,Vultaggio, Stefania,Dondio, Giulio,Gagliardi, Stefania,Minucci, Saverio,Mercurio, Ciro,Varasi, Mario
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supporting information; experimental part
p. 822 - 839
(2010/07/05)
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- A new class of histone deacetylase inhibitors
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This invention is related to new histone deacetylase inhibitors according to the general formula (I) wherein: Q is a bond, CH2, NR5 or oxygen, X is CH or nitrogen, Y is a bond, CH2, oxygen or NR6, Z is CH or nit
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Page/Page column 14
(2009/04/23)
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- A NEW CLASS OF HISTONE DEACETYLASE INHIBITORS
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New histone deacetylase inhibitors according to the general formula (I) wherein: Q is a bond, CH2, CH-NR3R4, NR5 or oxygen, X is CH or nitrogen, Y is a bond, CH2, oxygen or NR6, Z is CH or
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Page/Page column 39
(2008/06/13)
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- PYRAZOLOPYRIMIDINES AS KINASE INHIBITORS
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The present invention relates generally to inhibitors of the kinases and more particularly to novel pyrazolopyrimidine compounds.
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- Tricyclic benzazepine and benzothiazepine derivatives
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The tricyclic benzazepine and benzothiazepine derivatives represented by the formula (I) and pharmacologically acceptable salts thereof are disclosed. STR1 wherein Z represents CO, --CR6 R7 -- or --S(O)n, R represents hydrogen, alkyl, phenylalkyl, or a protective group of a triazole ring, R1 -R5 represent hydrogen, alkyl, alkenyl, alkoxy, amino, oxim or hydroxyl. These compounds have anti-allergic effect and are useful for the treatment and prophylaxis of allergic diseases.
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- Synthesis of 2,2,4-Trisubstituted-1,2-dihydroquinazolines
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Synthesis of 2,2,4-trisubstituted-1,2-dihydroquinazolines 6 from readily available 2-aminobenzonitrile (1) is described.The scope and limitations of the method are discussed.
- Strekowski, Lucjan,Cegla, Marek T.,Kong, Suk-Bin,Harden, Donald B.
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p. 923 - 928
(2007/10/02)
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- Process for the preparation of substituted isoxazolo[4,5-c]pyridin-4-(5H)-ones
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An improved process for the preparation of substituted isoxazolo[4,5-c]pyridin-4(5H)-ones which are either useful as intermediates in the preparation of compounds having pharmaceutical activity or as hypolipidemic agents which comprises cyclizing a corresponding 5-(2-amino-2-phenyl- or substituted phenyl-ethenyl)-3-substituted-N-alkyl isoxazole-4-carboxamide under acidic conditions.
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