- Expanding Access to Remdesivir via an Improved Pyrrolotriazine Synthesis: Supply Centered Synthesis
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Pyrrolotriazine 1 is an important precursor to remdesivir. Initial results toward an efficient synthesis are disclosed consisting of sequential cyanation, amination, and triazine formation beginning from pyrrole. This route makes use of highly abundant, commoditized raw material inputs. The yield of triazine was doubled from 31% to 59%, and the synthetic step count was reduced from 4 to 2. These efforts help to secure the remdesivir supply chain.
- Agrawal, Toolika,Burns, Justina M.,Cardoso, Flavio S. P.,Cook, Daniel W.,Gupton, B. Frank,Paymode, Dinesh J.,Sieber, Joshua D.,Snead, David R.,Stringham, Rodger W.,Tomlin, John W.
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Read Online
- Facile and Scalable Methodology for the Pyrrolo[2,1-f][1,2,4]triazine of Remdesivir
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Pyrrolo[2,1-f][1,2,4]triazine (1) is an important regulatory starting material in the production of the antiviral drug remdesivir. Compound 1 was produced through a newly developed synthetic methodology utilizing simple building blocks such as pyrrole, chloramine, and formamidine acetate by examining the mechanistic pathway for the process optimization exercise. Triazine 1 was obtained in 55% overall yield in a two-vessel-operated process. This work describes the safety of the process, impurity profiles and control, and efforts toward the scale-up of triazine for the preparation of kilogram quantity.
- Roy, Sarabindu,Yadaw, Ajay,Roy, Subho,Sirasani, Gopal,Gangu, Aravind,Brown, Jack D.,Armstrong, Joseph D.,Stringham, Rodger W.,Gupton, B. Frank,Senanayake, Chris H.,Snead, David R.
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supporting information
p. 82 - 90
(2022/01/28)
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- Klein's Remdesivir-nucleobase synthesis revisited: Chemoselective cyanation of pyrrol-2-carboxaldehyde
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4-Aminopyrrolo[2,1-f][1,2,4]triazine is a fundamental raw material in the synthesis of remdesivir, which demand has increased due to the tests and potential repositioning of this drug against Coronavirus disease 2019 (COVID-19). Here, three chemical steps route for the preparation of remdesivir's nucleobase is described. Particularly, a highly chemoselective cyanation of Klein's route and successful application of monochloramine prepared from commercial bleach as an N-amination reagent are presented.
- Amarante, Giovanni W.,Pereira, Vinicius R. D.,da Silva, Adilson D.,dos Santos, Juliana A.
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p. 1391 - 1395
(2021/06/14)
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- Synthesis method of remdesivir intermediate triazinamine derivative
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The invention discloses a synthesis method of a remdesivir intermediate triazinamine derivative. The remdesivir intermediate triazinamine derivative is prepared by adopting a unique synthesis method. The invention solves the problems of expensive raw materials, large amount of wastewater in the production process and the like in existing reaction of a remdesivir intermediate triazinamine derivative, and provides the novel synthesis method of the remdesivir intermediate triazinamine derivative, wherein the synthesis method has the advantages of simple preparation method, cheap and easily available raw materials, greatly reduced production cost, less wastewater and the like; the synthesis method is never reported in the prior art, is a brand-new preparation method of the remdesivir intermediate triazinamine derivative, and provides a new synthesis idea for similar compounds of remdesivir.
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Paragraph 0020; 0028; 0033; 0036; 0041
(2021/04/10)
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- Synthesis method of key intermediate 7-halogenated pyrrolo[1,2-F][1,2,4]triazin-4-amine of remdesivir
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The invention discloses a synthesis method of a key intermediate 7-halogenated pyrrolo[1,2-F][1,2,4]triazin-4-amine of remdesivir as shown in a formula (h). Phthalimide is used as a raw material, and the key intermediate 7-halogenated pyrrolo[1,2-F][1,2,4]triazin-4-amine of remdesivir is synthesized through a series of reactions such as substitution, cyclization, bromination, cyano substitution, hydrazinolysis, heterocyclic ring synthesis and iodination . The post-treatment operation is optimized, and the method has the advantages of being short in reaction time, high in yield, suitable for industrial production and the like.
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Paragraph 0076-0079
(2021/08/14)
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- Synthesis process of retegravir intermediate
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The invention relates to a synthesis process of a retegravir intermediate 7-iodine-4-amido pyrrolo [2,1-F] [1, 2, 4] triazine. The method comprises the following steps: by using pyrrole as an initialraw material, carrying out aldehyde groupintroduction through phosphorus oxychloride-DMF to obtain 2-aldehyde group pyrrole; preparing a 2-cyano key intermediate through ammonium sulfate, wherein thesteps is the key step of the process; cyclizing the cyano intermediate and formamidine acetate to prepare a 4-amino intermediate; reacting with NIS and adding iodine to prepare the target compound 7-iodine-4-amido pyrrolo [2,1-F] [1, 2, 4] triazine. The whole process has the advantages of simple and easily available raw materials, simple and easy operation, and very high economic value and socialbenefit.
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Paragraph 0005; 0022; 0023
(2021/03/11)
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- Method for rapidly preparing remdesivir intermediate
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The present invention relates to a method for rapidly preparing a remdesivir intermediate represented by a following formula (I) without complex purification and separation, wherein X represents a halogen element. The method is simple, high in yield and single in product, and can be obtained through simple filtration and separation; complicated separation operation such as column chromatography isnot needed; the remdesivir intermediate represented by the formula (I) can be rapidly, efficiently, and massively prepared; and sufficient intermediates are provided for large-scale preparation of remdesivir drugs that may be used to treat new corona viruses.
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Paragraph 0059
(2020/06/24)
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- Substituted heteroaryl compounds and compositions and uses thereof
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The invention provides a substituted heteroaryl compound and a composition thereof, and applications of the compound and the composition. The compound is a compound as shown in a formula I, or stereoisomer, tautomer, oxynitride, solvate, metabolite, pharmaceutically-acceptable salt or prodrug of the compound as shown in the formula I. The invention also provides a pharmaceutical composition containing the above-mentioned compound; and the above-mentioned compound and the pharmaceutical composition are capable of adjusting the activity of JAK kinases and are applied in prevention, treatment, therapy and alleviation of JAK kinase mediated diseases or disorders.
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Paragraph 0510; 0511; 0512; 0513
(2017/12/27)
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- Heterocyclic amines Hedgehog signal pathway inhibitor
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The invention relates to the field of biological medicine, in particular to a heterocyclic amine compound and an application thereof, namely a general formula (I) compound and acceptable salt in the pharmaceutical field. The compound can be used in the Hedgehog signal transduction inhibitor application and various medical applications (please see the formula in the specification). The invention further relates to a preparation method with the general formula (I).
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Paragraph 0131; 0132; 0134
(2017/10/06)
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- 2 - amino-pyrrolo [1, 2 - f] [1, 2, 4] triazine compounds, synthetic method and application
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The invention discloses 2-aminopyrrolo[1,2-f][1,2,4]triazine compounds, and a synthesis method and application thereof, particularly 2-aminopyrrolo[1,2-f][1,2,4]triazine compounds, or pharmaceutically acceptable salts, hydrate, solvate or prodrug thereof.
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Paragraph 0066-0068
(2017/07/01)
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- SUBSTITUTED HETEROARYL COMPOUNDS AND METHODS OF USE
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The present invention provides novel heteroaryl compounds, pharmaceutical acceptable salts and formulations thereof useful in preventing, treating or lessening the severity of a JAK-mediated disease. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of JAK-mediated disease.
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Paragraph 0340
(2016/12/22)
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- Design, synthesis, and evaluation of pyrrolo[2,1-f][1,2,4]triazine derivatives as novel hedgehog signaling pathway inhibitors
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A novel series of Hh signaling pathway inhibitors were designed by replacing the pyrimidine skeleton of our earlier reported lead compound 1 with pyrrolo[2,1-f][1,2,4]triazine scaffold. Starting from this new scaffold, SAR exploration was investigated based on structural modification on A-ring, C-ring and D-ring. And several much potent compounds were studies in vivo to profile their pharmacokinetic properties. Finally, optimization leads to the identification of compound 19a, a potent Hh signaling pathway inhibitor with superior potency in vitro and satisfactory pharmacokinetic properties in vivo.
- Xin, Minhang,Zhang, Liandi,Tang, Feng,Tu, Chongxing,Wen, Jun,Zhao, Xinge,Liu, Zhaoyu,Cheng, Lingfei,Shen, Han
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p. 1429 - 1440
(2014/03/21)
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- JAK KINASE MODULATING COMPOUNDS AND METHODS OF USE THEREOF
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Provided herein are pyrrolotriazine compounds for treatment of JAK kinase, including JAK2 kinase mediated diseases. Also provided are pharmaceutical compositions comprising the compounds and methods of using the compounds and compositions.
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Page/Page column 88-89
(2010/04/03)
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- AURORA KINASE MODULATORS AND METHOD OF USE
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The present invention relates to chemical compounds having a general formula (I) wherein A1-5 and 7-8, D', L1, L2, R1, R3, R6-8, n and o are defined herein, and synthetic intermediates, which are capable of modulating the activity of Aurora kinase proteins and, thereby, influencing various disease states and conditions related to the activities of Aurora kinases. For example, the compounds are capable of influencing the process of cell cycle and cell proliferation to treat cancer and cancer-related diseases. The invention also includes pharmaceutical compositions, including the compounds, and methods of treating disease states related to the activity of Aurora kinase.
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Page/Page column 47
(2009/10/22)
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- HCV INHIBITING BI-CYCLIC PYRIMIDINES
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The present invention relates to the use of bi-cyclic pyrimidines as inhibitors of HCV replication as well as their use in pharmaceutical compositions aimed to treat or combat HCV infections. In addition, the present invention relates to processes for pre
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Page/Page column 50; 51
(2010/10/20)
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- N-Amination of Pyrrole and Indole Heterocycles with Monochloramine (N H2Cl)
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A survey of several electrophilic ammonia reagents for the N-amination of indole- and pyrrole-containing heterocycles revealed that monochloramine (NH2Cl) is an excellent reagent for this transformation. Pyrroles and indoles containing a variety of substitution were aminated on nitrogen with isolated yields ranging from 45% to 97%.
- Hynes Jr., John,Doubleday, Wendel W.,Dyckman, Alaric J.,Godfrey Jr., Jollie D.,Grosso, John A.,Kiau, Susanne,Leftheris, Katerina
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p. 1368 - 1371
(2007/10/03)
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- Discovery of the pyrrolo[2,1-f][1,2,4]triazine nucleus as a new kinase inhibitor template
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The pyrrolo[2,1-f][1,2,4]triazine nucleus was identified as a novel kinase inhibitor template which effectively mimics the well-known quinazoline kinase inhibitor scaffold. Attachment of a 4-((3-chloro-4-fluorophenyl)amino) substituent to the template provided potent biochemical inhibitors of the tyrosine kinase activity of EGFR, as well as inhibition of cellular proliferation of the human colon tumor cell line DiFi. Attachment of a 4-((3-hydroxy-4-methylphenyl)amino) substituent provided potent inhibitors of VEGFR-2 which also showed effects on the VEGF-dependent proliferation of human umbilical vein endothelial cells. Biological activity was maintained with substitution at positions 5 or 6, but not 7, suggesting that the former positions are promising sites for introducing side chains which modulate physicochemical. properties. Preliminary inhibition studies with varying ATP concentrations suggest that, like the quinazoline-based kinase inhibitors, the pyrrolotriazine-based inhibitors bind in the ATP pocket.
- Hunt, John T.,Mitt, Toomas,Borzilleri, Robert,Gullo-Brown, Johnni,Fargnoli, Joseph,Fink, Brian,Han, Wen-Ching,Mortillo, Steven,Vite, Gregory,Wautlet, Barri,Wong, Tai,Yu, Chiang,Zheng, Xiaoping,Bhide, Rajeev
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p. 4054 - 4059
(2007/10/03)
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- Synthesis of pyrrolo[2,1-f][1,2,4]triazine congeners of nucleic acid purines via the N-amination of 2-substituted pyrroles
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The synthesis of several new 4-mono- and 2,4-disubstituted pyrrolo[2,1-f][1,2,4]triazines is described. Key 1-aminopyrrole-2-carbonitrile intermediates 3 and 15 were obtained by N-amination of the corresponding pyrrole-2-carboxaldehyde followed by CHO → CN conversion with either hydroxylamine-O-sulfonic acid for 3 or O-mesitylenesulfonylhydroxylamine for 15. Cyclization of 3 or 15 with a variety of amidine reagents or, after conversion of 3 to its corresponding amide, base-catalyzed annulation completed the synthesis of the title products.
- Patil,Otter,Klein
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p. 781 - 786
(2007/10/02)
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