- Cyanoamidine Cyclization Approach to Remdesivir's Nucleobase
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We report an alternative approach to the unnatural nucleobase fragment seen in remdesivir (Veklury). Remdesivir displays broad-spectrum antiviral activity and is currently being evaluated in Phase III clinical trials to treat patients with COVID-19. Our route relies on the formation of a cyanoamidine intermediate, which undergoes Lewis acid-mediated cyclization to yield the desired nucleobase. The approach is strategically distinct from prior routes and could further enable the synthesis of remdesivir and other small-molecule therapeutics.
- Knapp, Rachel R.,Tona, Veronica,Okada, Taku,Sarpong, Richmond,Garg, Neil K.
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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; 0034; 0036; 0042
(2021/04/10)
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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; 0024; 0025
(2021/03/11)
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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 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 0080-0082
(2021/08/14)
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- Process for synthesizing 7 -iodopyrrolo [2,F] [1,m-triazine -4 - amine
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The invention belongs to the technical field of chemical synthesis of medicines, and relates to a synthesis process of 7-iodo pyrrolo [2, 1-F] [1, 2, 4] triazine-4-amine. According to the invention, 2, 5-dimethoxy tetrahydrofuran and acethydrazide are used as initial raw materials, and are subjected to substitution, cyanation, deacetylation, cyclization and iodination reactions to obtain 7-iodopyrrolo [2, 1-F] [1, 2, 4] triazine-4-amine. The preparation method is simple, the initial raw materials are 2, 5-dimethoxytetrahydrofuran and acethydrazide which are cheap and easy to obtain. Meanwhile,the yields of the first four steps all reach 85% or above, the productivity is also greatly improved, the total yield of the product is 50% or above, and the purity can reach 99% or above. And meanwhile, the intermediate product is good in quality, so that the dosage of formamidine acetate is reduced when the intermediate IV is prepared. Through experimental comparison, the route has obvious advantages compared with the traditional process route.
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Paragraph 0036-0039
(2021/11/21)
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- Preparation method of 4-aminopyrrolo[2,1-f][1,2,4]triazine
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The invention discloses a preparation method of 4-aminopyrrolo[2,1-f][1,2,4]triazine, and belongs to the technical field of medicine synthesis. The method comprises the following steps: reacting 2,5-dimethoxytetrahydrofuran serving as a raw material with formylhydrazine to obtain formylamino pyrrole, then reacting formylamino pyrrole with cyanamide and a nucleophilic reagent in a polar solvent, and carrying out simple post-treatment and cyclization under the action of a catalyst to obtain 4-aminopyrrolo[2,1-f][1,2,4]triazine. The raw materials easy to obtain in the market are adopted, the whole process is easy and convenient to operate, the two-step yield is improved by improving an existing literature method, and development of a synthesis route conforming to industrialization is facilitated.
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Paragraph 0038-0044
(2021/10/11)
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- Novel synthesis method of compound 7-iodopyrrolo[2, 1-f][1, 2, 4]triazin-4-amine
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The invention provides a method for preparing a triazine compound as shown in a formula (I). According to the invention, pyruvic acid and formamidine are taken as starting materials to synthesize an intermediate, and the intermediate is subjected to two-step reaction to obtain the compound shown in the formula (I). The method provided by the invention is mild in condition, simple and convenient to operate, capable of greatly reducing the cost and suitable for industrial mass production.
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Paragraph 0049-0051
(2021/09/04)
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- Weinreb Amide Approach to the Practical Synthesis of a Key Remdesivir Intermediate
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Currently, remdesivir is the first and only FDA-approved antiviral drug for COVID-19 treatment. Adequate supplies of remdesivir are highly warranted to cope with this global public health crisis. Herein, we report a Weinreb amide approach for preparing the key intermediate of remdesivir in the glycosylation step where overaddition side reactions are eliminated. Starting from 2,3,5-tri-O-benzyl-d-ribonolactone, the preferred route consisting of three sequential steps (Weinreb amidation, O-TMS protection, and Grignard addition) enables a high-yield (65%) synthesis of this intermediate at a kilogram scale. In particular, the undesirable PhMgCl used in previous methods was successfully replaced by MeMgBr. This approach proved to be suitable for the scalable production of the key remdesivir intermediate.
- Xie, Yuanchao,Hu, Tianwen,Zhang, Yan,Wei, Daibao,Zheng, Wei,Zhu, Fuqiang,Tian, Guanghui,Aisa, Haji A.,Shen, Jingshan
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p. 5065 - 5072
(2021/04/12)
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- Preparation method of 4-aminopyrrolo [2, 1-f] [1, 2, 4] triazine
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The invention relates to a preparation method of 4-amino pyrrolo [2, 1-f] [1, 2, 4] triazine, in particular to a method for efficiently synthesizing 4-amino pyrrolo [2, 1-f] [1, 2, 4] triazine by taking 1-amino-1H-pyrrole-2-carbonitrile hydrochloride and thiourea as raw materials through two steps of cyclization reaction and desulfurization reaction. The preparation method of the 4-aminopyrrolo [2, 1-f] [1, 2, 4] triazine is high in yield, low in cost, less in three wastes, good in product purity and suitable for industrialization.
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Paragraph 0014-0018
(2021/04/03)
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- 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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supporting information
p. 7656 - 7661
(2020/10/09)
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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 0060-0061
(2020/06/24)
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- Continuous Flow C-Glycosylation via Metal-Halogen Exchange: Process Understanding and Improvements toward Efficient Manufacturing of Remdesivir
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As remdesivir is the first approved treatment for COVID-19 (SARS-CoV-2), its production is likely to be of vital importance in the near future. Continuous flow processing has been demonstrated as a key technology in the manufacturing of high-volume active pharmaceutical ingredients and is considered for use in this synthetic sequence. In particular, the challenging C-glycosylation of a pyrrolotriazinamine via metal-halogen exchange was identified as a transformation with significant potential benefit, as exemplified by calorimetric analysis of each reaction step. Multiple simplifications of this process were attempted in batch but in general were found to be unfruitful. The five-feed process was then transferred to a flow setup, where specific conditions were found to circumvent solid formation and permit stable processing. Detailed optimization of stoichiometries provided an improvement upon batch conditions with a total residence time of 1 min.
- Kappe, C. Oliver,Von Keutz, Timo,Williams, Jason D.
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supporting information
p. 2362 - 2368
(2020/11/02)
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- One-pot method for preparing pyrrolo[2,1-F][1,2,4]triazin-4-amine
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The invention discloses a one-pot method for preparing pyrrolo[2,1-F][1,2,4]triazin-4-amine, and belongs to the field of organic chemical synthesis. According to the method, a one-pot method is adopted, pyrrole is used as a raw material, chlorosulfonyl isocyanate is used as a cyanation reagent, O-[4-nitro-2-(trifluoromethyl)phenyl] hydroxylamine is used as an amination reagent, formamidine acetateis used as a cyclization reagent, and the pyrrolo[2,1-F][1,2,4]triazin-4-amine with a high yield and high purity is prepared. The method disclosed by the invention is simple to operate, high in product yield, high in purity, mild in reaction condition, less in energy consumption, less in pollution and very suitable for industrial production.
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Paragraph 0030-0031; 0038-0039; 0043-0044; 0048-0049; 0053
(2020/08/25)
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- Preparation method 7-bromopyrrolo [2,1-f][1, 2, 4]-thiazine -4- amine (by machine translation)
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[, ] The preparation method 7 - of [2,1 - f][1, 2, 4]-(, amino - ((((((((aopipelineao :1) aminopyrrolo 2,5 - thiopyrrole I,) obtained by reacting the intermediate 1 - Boc - 1 - with the formamidine in the following step ;2) can obtain the intermediate I (II, amino-(EC 1 - Boc - 1 -) to obtain the intermediate ;3), namely, II amino-(III, aminopyrrolopyrrole - 2 2-methanonitrile hydrochloride 1 -) to form the intermediate ;4) through the reaction of the intermediates III and the bromination reagent to obtain a final product IV, of the present invention. in an acidic condition and reacting the intermediate body with the bromination reagent. to obtain a final product (4 -aminopyrrolopyridine - 4 4) intermediate, [2,1 - f][1, 2, 4] [2,1 - f][1, 2, 4] obtained by the reaction of the intermediate body with the. bromination reagent and ;5) amino- pyrrolidine. IV-amine,aminopyrroyl hydrochloride 7 . (by machine translation)
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Paragraph 0048-0053
(2020/03/12)
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- SUBSTITUTED 4-AMINO-PYRROLOTRIAZINE DERIVATIVES USEFUL FOR TREATING HYPER-PROLIFERATIVE DISORDERS AND DISEASES ASSOCIATED WITH ANGIOGENESIS
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This invention relates to novel pyrrozolotriazine compounds, pharmaceutical compositions containing such compounds and and the use of those compounds or compositions for treating hyper-proliferative and/or angiogenesis disorders, as a sole agent or in combination with other active ingredients.
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Page/Page column 168
(2010/11/27)
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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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