- Total synthesis of remdesivir
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Remdesivir, the first drug approved by the FDA to treat COVID-19, is in high demand for patients infected with the SARS-CoV-2 virus. Herein, we report a facile approach minimizing the protecting group manipulations to afford remdesivir in good overall yield.
- Kumar Palli, Kishore,Ghosh, Palash,Krishna Avula, Shiva,Sridhara Shanmukha Rao,Patil, Amol D.,Ghosh, Subhash,Sudhakar, Gangarajula,Raji Reddy, Chada,Mainkar, Prathama S.,Chandrasekhar, Srivari
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supporting information
(2021/12/20)
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- N-protected heterocyclic compound, preparation method thereof and method for preparing C-nucleoside derivative by using N-protected heterocyclic compound
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The invention provides an N-protected heterocyclic compound, a preparation method thereof and a method for preparing a C-nucleoside derivative by using the N-protected heterocyclic compound. Specifically, the invention provides a method for preparing the C-nucleoside derivative by using a heterocyclic compound protected by N-carbobenzoxy or N-tert-butyloxycarboryl. According to the method, halogenation is not needed, temporary amino protection is not needed, protons of the heterocyclic compound are removed by directly using an organic lithium or organic magnesium compound, and addition with ribose lactone is carried out. According to the method, the synthesis route of the C-nucleoside derivative is shortened, and the yield of the reaction of the heterocyclic compound and the ribose lactone is remarkably improved under the condition that no halogen atom is used as a substituent group.
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- Preparation method of ridecevir compound
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The invention belongs to the field of medicinal chemistry, and particularly relates to a novel synthesis and preparation method of a ridecevir compound. (2R, 3R, 4R, 5R)-2-(4-aminopyrrole[2, 1-f][1, 2, 4]triazin-7-yl)-3, 4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-nitrile is taken as an initial raw material, and is subjected to ketal protection, BC protection, resolution, phosphorylation reaction, substitution reaction and deprotection reaction to prepare ridecevir. The method has the advantages of mild and easily-controlled reaction conditions, simple operation, high product yield and high purity, and is suitable for industrial mass production.
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Paragraph 0060-0063
(2021/08/07)
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- Preparation method of remdesivir
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The invention relates to the technical field of medical intermediates, in particular to a preparation method of remdesivir. A synthesis route of the remdesivir includes the following steps: 1) reacting a compound I with a compound II in the presence of Lewis acid and alkali to obtain a compound III; and 2) reacting the compound III with a compound IV in the presence of a hydroxyl activator and alkali to obtain a compound V. The invention effectively solves problems that the synthesis route is tedious in step, purification is not easy, and the risk that genotoxic impurities exist in the prior art. Meanwhile, the whole route is mild in reaction condition, operation is convenient, and the yield and purity are high, and the preparation method is suitable for industrial large-scale production.
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- ISOMORPHS OF REMDESIVIR AND METHODS FOR SYNTHESIS OF SAME
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A new isoform of 2-ethylbutyl (2S)-2-[[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3/4-dihydroxyoxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate (Remdesivir) having increased water solubility is disclosed, along with methods
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- Method for preparing retegravir by using micro-channel reactor
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The invention discloses a method for synthesizing retegravir by using a micro-channel reactor, which realizes continuous flow synthesis of retegravir by using a scale effect of a micro-flow field technology and using a novel micro-channel reactor to repla
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- Practical Remdesivir Synthesis through One-Pot Organocatalyzed Asymmetric (S)-P-Phosphoramidation
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Remdesivir, an inhibitor of RNA-dependent RNA polymerase developed by Gilead Sciences, has been used for the treatment of COVID-19. The synthesis of remdesivir is, however, challenging, and the overall cost is relatively high. Particularly, the stereoselective assembly of the P-chirogenic center requires recrystallization of a 1:1 isomeric p-nitrophenylphosphoramidate mixture several times to obtain the desired diastereoisomer (39%) for further coupling with the d-ribose-derived 5-alcohol. To address this problem, a variety of chiral bicyclic imidazoles were synthesized as organocatalysts for stereoselective (S)-P-phosphoramidation employing a 1:1 diastereomeric mixture of phosphoramidoyl chloridates as the coupling reagent to avoid a waste of the other diastereomer. Through a systematic study of different catalysts at different temperatures and concentrations, a mixture of the (S)- and (R)-P-phosphoramidates was obtained in 97% yield with a 96.1/3.9 ratio when 20 mol % of the chiral imidazole-cinnamaldehyde-derived carbamate was utilized in the reaction at -20 °C. A 10-g scale one-pot synthesis via a combination of (S)-P-phosphoramidation and protecting group removal followed by one-step recrystallization gave remdesivir in 70% yield and 99.3/0.7 d.r. The organocatalyst was recovered in 83% yield for reuse, and similar results were obtained. This one-pot process offers an excellent opportunity for industrial production of remdesivir.
- Gannedi, Veeranjaneyulu,Villuri, Bharath Kumar,Reddy, Sivakumar N.,Ku, Chiao-Chu,Wong, Chi-Huey,Hung, Shang-Cheng
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p. 4977 - 4985
(2021/04/02)
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- Synthesis method of antiviral drug ridexivir and intermediate thereof
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The invention discloses a synthesis method of an antiviral drug retegravir, which comprises the following steps: carrying out addition reaction on a compound 1 and a compound 2 to obtain a compound 3,carrying out cyanation reaction under the action of Lewis acid to obtain a compound 4, carrying out copper-catalyzed ammonolysis reaction to obtain a compound 5, carrying out palladium-catalyzed hydrogenation debenzylation to obtain a compound 6, and finally, reacting with a compound 7 to obtain a retegravir product. According to the method, the compound 1 is directly used as a raw material, no extra active hydrogen exists, and the reaction yield is high,the method has the advantages of simple operation, no amino interference, high cyanation reaction yield, clean and efficient palladium-carbon alkylation debenzylation reaction, convenient palladium-carbon recovery, and less three wastes. In addition, the leaving group of the compound 7 is improved to improve the activity of the compound 7, and the unprotected docking reaction of 6 and 7 is optimized by adding a proper auxiliary agent, so that the selectivity and the reaction yield can be greatly improved. The route is simple to operate, high in total yield, high in product purity and suitable for large-scale production.
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Paragraph 0060-0063
(2021/02/06)
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- Preparation method of high-purity Remdesivir
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The invention belongs to the field of medicinal chemistry, and particularly relates to a preparation method of a compound Remdesivir as shown in a formula I defined in the description. The method is simple and convenient to operate, mild in reaction condi
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Paragraph 0041-0054
(2021/06/23)
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- Synthesis method of
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The method comprises the following steps: (2R, 3R, 4S, 5R) -2 - (4 - 2) [1 - f, 1, 2] triazine 4-yl) -7 -3-hydroxy 4 - (hydroxymethyl) tetrahydrofuran -5 -2 - carbonitrile. 2,2 - Dimethoxypropane and first acid catalyst were added first solvent, stirred,
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Paragraph 0022-0025
(2021/12/07)
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- Catalytic Asymmetric Synthesis of the anti-COVID-19 Drug Remdesivir
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The catalytic asymmetric synthesis of the anti-COVID-19 drug Remdesivir has been realized by the coupling of the P-racemic phosphoryl chloride with protected nucleoside GS441524. The chiral bicyclic imidazole catalyst used is crucial for the dynamic kinetic asymmetric transformation (DyKAT) to proceed smoothly with high reactivity and excellent stereoselectivity (96 % conv., 22:1 SP:RP). Mechanistic studies showed that this DyKAT is a first-order visual kinetic reaction dependent on the catalyst concentration. The unique chiral bicyclic imidazole skeleton and carbamate substituent of the catalyst are both required for the racemization process, involving the phosphoryl chloride, and subsequent stereodiscriminating step. A 10 gram scale reaction was also conducted with comparably excellent results, showing its potential for industrial application.
- Chen, Jianzhong,Huo, Xiaohong,Li, Panpan,Wang, Mo,Wu, Zhengxing,Yuan, Qianjia,Zhang, Lu,Zhang, Wanbin,Zhang, Zhenfeng,Zou, Yashi
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p. 20814 - 20819
(2020/10/15)
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- Synthesis method of retegravir
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The invention discloses a synthesis method of retegravir, which belongs to the field of pharmaceutical chemicals, and comprises the following steps: reacting a compound V with hydroxypyridines under the action of alkali to obtain a compound IV; reacting the compound IV with a compound III in the presence of alkali and Lewis acid to generate a compound II; and splitting the compound II to obtain acompound I. The method disclosed by the invention is mild in reaction condition, easy in process control, simple in operation, capable of effectively improving the yield of the target product and reducing the production cost, and suitable for industrial large-scale production.
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Paragraph 0020-0022
(2020/06/20)
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- Synthesis method of retegravir
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The invention relates to the technical field of medicine, in particular to a synthesis method of retegravir. The method specifically comprises the following steps: firstly, synthesizing (3aR, 4R, 6R,6aR)-4-(4-aminopyrrole[2, 1-f][1, 2, 4]triazine-7-yl)-6-
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Paragraph 0034-0035
(2020/06/17)
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- Synthesis method of remdesivir
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The invention relates to a synthesis method of remdesivir, which belongs to the field of pharmaceutical chemicals. The method comprises the following steps: reacting a compound V with N-hydroxysuccinimide under the action of an alkali to obtain a compound IV; splitting the compound IV to obtain a compound III; and reacting the compound III and the compound II in the presence of an alkali and a Lewis acid to generate a compound I. According to the method disclosed by the invention, the N-hydroxysuccinimide which is harmless in toxicology is used as a leaving group, the reaction process is safe,the purity of the obtained target product is relatively high, the market demand of the product can be met, and the production cost is reduced.
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Paragraph 0008; 0020-0028
(2020/08/09)
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- Preparation method of (by machine translation)
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To the method disclosed by the invention, compound, compound, and compound V react IV; through acid hydrolysis to obtain compound IV compound III; compound III is subjected to further resolution under the action of a base, and the method disclosed by the invention is suitable for industrialized large-scale production II by avoiding the use, of genotoxic nitro substituent to reduce the risk I. of genotoxic impurities. (by machine translation)
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- Preparation method of retegravir
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The invention discloses a preparation method of retegravir, which belongs to the field of pharmaceutical chemicals, and comprises the following steps: reacting a compound V with 4-trifluoromethoxyphenol under the action of alkali to obtain a compound IV; further performing chiral resolution on the compound IV to obtain a compound III; and carrying out an acid hydrolysis reaction on the compound III and the compound II under the action of organic base with large steric hindrance to obtain a compound I. According to the method disclosed by the invention, the use of genotoxic nitro substitutes isavoided, the risk of genotoxic impurities is reduced, and the method is suitable for industrial large-scale production.
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- CRYSTALLINE FORMS OF (S) 2 ETHYLBUTYL 2 (((S) (((2R,3S,4R,5R) 5 (4 AMINOPYRROLO[2,1-F] [1,2,4]TRIAZIN-7-YL)-5-CYANO-3,4-DIHYDROXYTETRAHYDROFURAN-2 YL)METHOXY)(PHENOXY) PHOSPHORYL)AMINO)PROPANOATE
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The present invention relates to novel salts and crystalline forms of (S)-2-ethylbutyl2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl) methoxy)(phenoxy)phosphoryl)amino)propanoate (Formula I)
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Paragraph 0270; 0271; 0272; 0273
(2018/12/03)
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- METHODS FOR TREATING FLAVIVIRIDAE VIRUS INFECTIONS
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Provided are methods for treating Flaviviridae virus infections by administering ribosides, riboside phosphates and prodrugs thereof, of Formula I:, wherein the 1' position of the nucleoside sugar is substituted. The compounds, compositions, and methods provided are particularly useful for the treatment of Zika virus infections.
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- METHODS FOR TREATING ARENAVIRIDAE AND CORONAVIRIDAE VIRUS INFECTIONS
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Provided are methods for treating Arenaviridae and Coronaviridae virus infections by administering nucleosides and prodrugs thereof, of Formula I: wherein the 1′ position of the nucleoside sugar is substituted. The compounds, compositions, and methods provided are particularly useful for the treatment of Lassa virus and Junin virus infections.
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- Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1-f][triazin-4-amino] Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses
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The recent Ebola virus (EBOV) outbreak in West Africa was the largest recorded in history with over 28,000 cases, resulting in >11,000 deaths including >500 healthcare workers. A focused screening and lead optimization effort identified 4b (GS-5734) with anti-EBOV EC50 = 86 nM in macrophages as the clinical candidate. Structure activity relationships established that the 1′-CN group and C-linked nucleobase were critical for optimal anti-EBOV potency and selectivity against host polymerases. A robust diastereoselective synthesis provided sufficient quantities of 4b to enable preclinical efficacy in a non-human-primate EBOV challenge model. Once-daily 10 mg/kg iv treatment on days 3-14 postinfection had a significant effect on viremia and mortality, resulting in 100% survival of infected treated animals [Nature 2016, 531, 381?385]. A phase 2 study (PREVAIL IV) is currently enrolling and will evaluate the effect of 4b on viral shedding from sanctuary sites in EBOV survivors.
- Siegel, Dustin,Hui, Hon C.,Doerffler, Edward,Clarke, Michael O.,Chun, Kwon,Zhang, Lijun,Neville, Sean,Carra, Ernest,Lew, Willard,Ross, Bruce,Wang, Queenie,Wolfe, Lydia,Jordan, Robert,Soloveva, Veronica,Knox, John,Perry, Jason,Perron, Michel,Stray, Kirsten M.,Barauskas, Ona,Feng, Joy Y.,Xu, Yili,Lee, Gary,Rheingold, Arnold L.,Ray, Adrian S.,Bannister, Roy,Strickley, Robert,Swaminathan, Swami,Lee, William A.,Bavari, Sina,Cihlar, Tomas,Lo, Michael K.,Warren, Travis K.,Mackman, Richard L.
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p. 1648 - 1661
(2017/03/17)
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- METHODS FOR TREATING FILOVIRIDAE VIRUS INFECTIONS
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Provided are compounds, methods, and pharmaceutical compositions for treating Filoviridae vims infections by administering ribosides, riboside phosphates and prodrugs thereof, of Formula (IV): The compounds, compositions, and methods provided are particularly useful for the treatment of Marburg virus, Ebola virus and Cueva virus infections.
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