- Organic synthesis in a modular robotic system driven by a chemical programming language
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The synthesis of complex organic compounds is largely a manual process that is often incompletely documented. To address these shortcomings, we developed an abstraction that maps commonly reported methodological instructions into discrete steps amenable to automation. These unit operations were implemented in a modular robotic platform by using a chemical programming language that formalizes and controls the assembly of the molecules. We validated the concept by directing the automated system to synthesize three pharmaceutical compounds, diphenhydramine hydrochloride, rufinamide, and sildenafil, without any human intervention. Yields and purities of products and intermediates were comparable to or better than those achieved manually. The syntheses are captured as digital code that can be published, versioned, and transferred flexibly between platforms with no modification, thereby greatly enhancing reproducibility and reliable access to complex molecules.
- Steiner, Sebastian,Wolf, Jakob,Glatzel, Stefan,Andreou, Anna,Granda, Jaros?aw M.,Keenan, Graham,Hinkley, Trevor,Aragon-Camarasa, Gerardo,Kitson, Philip J.,Angelone, Davide,Cronin, Leroy
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- Highly regioselective and sustainable solar click reaction: A new post-synthetic modified triazole organic polymer as a recyclable photocatalyst for regioselective azide-alkyne cycloaddition reaction
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The synthesis of pharmaceutically active 1,2,3-triazoles has been continuously scrutinized in the search for unique and effective catalysts to make the process efficient, green, and sustainable. Here, we are presenting a new visible light active Ni(ii) cyclam-integrated triazole-linked organic polymer (Ni-TLOP) photocatalyst for the synthesis of 1,2,3-triazole compounds with excellent efficiency and regioselectivity. The reaction was studied for a series of substrates and the absolute regioselectivity of a representative triazole product has also been confirmed by X-ray crystallography. The proficiency and chemical orthogonality of the Ni-TLOP are remarkable and it shows enhanced efficiency and regioselectivity. The use of a recyclable photocatalyst and non-hazardous reagents makes the catalytic system sustainable and environmentally friendly. This photocatalyzed click reaction technique has been successfully applied to the expedient synthesis of one of the most sold anti-epileptic drugs rufinamide.
- Yadav, Dolly,Singh, Nem,Kim, Tae Wu,Kim, Jae Young,Park, No-Joong,Baeg, Jin-Ook
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p. 2677 - 2685
(2019/06/13)
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- From alcohol to 1,2,3-triazole: Via a multi-step continuous-flow synthesis of a rufinamide precursor
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Rufinamide is an antiepileptic drug used to treat the Lennox-Gastaut syndrome. It comprises a relatively simple molecular structure. Rufinamide can be synthesized from an organohalide in three steps. Recently we have shown that microreactor flow networks have better sustainability profiles in terms of life-cycle assessment than the respective consecutive processing in a batch. The analysis was based on the results of a single step conversion from batch to continuous mode. An uninterrupted continuous process towards rufinamide was developed, starting from an alcohol precursor, which is converted to the corresponding chloride with hydrogen chloride gas. The chloride is then converted to the corresponding organoazide that yields the rufinamide precursor via cycloaddition to the greenest and cheapest dipolarophile available on the market. The current process demonstrates chemical and process-design intensification aspects encompassed by novel process windows. Single reaction steps are chemically intensified via a wide range of conditions available in a microreactor environment. Meanwhile, the connection of reaction steps and separations results in process-design intensification. With two in-line separations the process consists of five stages resulting in a total yield of 82% and productivity of 9 g h-1 (11.5 mol h-1 L-1). The process minimizes the isolation and handling of strong alkylating or energetic intermediates, while minimizing water and organic solvent consumption.
- Borukhova, Svetlana,No?l, Timothy,Metten, Bert,De Vos, Eric,Hessel, Volker
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p. 4947 - 4953
(2016/10/06)
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- Direct access to 1,4-disubstituted 1,2,3-triazoles through organocatalytic 1,3-dipolar cycloaddition reaction of α,β-unsaturated esters with azides
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DBU-catalyzed organocatalytic 1,3-dipolar cycloaddition reactions of α,β-unsaturated esters with azides have been developed. This strategy generates 1,4-disubstituted 1,2,3-triazoles in high yields with high regioselectivities. It is demonstrated that some of these products can be transformed into important pharmaceutical agents.
- Li, Wenjun,Zhou, Xiao,Luan, Yepeng,Wang, Jian
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p. 88816 - 88820
(2015/11/09)
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- Pressure-accelerated azide-alkyne cycloaddition: Micro capillary versus autoclave reactor performance
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Pressure effects on regioselectivity and yield of cycloaddition reactions have been shown to exist. Nevertheless, high pressure synthetic applications with subsequent benefits in the production of natural products are limited by the general availability o
- Borukhova, Svetlana,Seeger, Andreas D.,Nol, Timothy,Wang, Qi,Busch, Markus,Hessel, Volker
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p. 504 - 512
(2015/03/04)
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- A PROCESS FOR PREPARING TRIAZOLE COMPOUNDS
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The present invention relates to process for preparing triazole compounds used in the treatment of epilepsy. The process comprises of reacting compound of 2, 6 difluoroazide (II) with 2, 3 dihalo compound (III) to form compound of formula I, which on further treatment with an aminating agent gives Rufinamide (IV). 2, 6 difluoroazide (II) is reacted with 2, 3 dihalo compound (III) in the presence of a solvent. The reaction can be carried out in a single pot without isolation of intermediates.
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Page/Page column 17
(2014/05/24)
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- PROCESS FOR PREPARATION OF RUFINAMIDE
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The present invention relates to a novel process for preparation of rufinamide (I) comprising: reacting 2,6-difluorobenzyl azide (II) and propiolic acid (III) in a mixture of alcohol and water to produce 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid (IV), esterifying the acid (IV) to ester (V) and treating ester (V) with ammonia. The invention further relates to process for purification of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid (IV), by crystallization from a mixture of alcohol and water. The present invention also provides process for purification of rufinamide (I) by crystallization from mixture of polar aprotic solvent with water or alcohol.
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Paragraph 0038; 0039
(2014/12/09)
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- PROCESS FOR PREPARATION OF RUFINAMIDE
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The present invention relates to a novel process for preparation of rufinamide (I) comprising: reacting 2,6-difluorobenzyl azide (II) and propiolic acid (III) in a mixture of alcohol and water to produce 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxyl
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Page/Page column 7
(2013/07/25)
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- Safe and highly efficient syntheses of triazole drugs using Cu2O nanoparticle in aqueous solutions
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Triazole moiety is frequently employed in drug discovery and optimization. However, most syntheses of triazole drugs involve isolation of highly explosive azides. Herein we report safe and high efficient syntheses of triazole drugs in aqueous/organic solvent systems with Cu2O nanoparticle (Cu 2O-NP) as the catalyst of azide-alkyne cycloaddition (CuAAC). Since Cu2O-NP can be efficiently dispensed in aqueous and some organic solvents, the azide solutions from the previous preparation could be used directly in the next CuAAC stage without isolation. Therefore, this synthetic strategy is safe, convenient, and high yielding for the syntheses of triazole drugs.
- Wang, Jing-Han,Pan, Cheng-Wen,Li, Yong-Tao,Meng, Fan-Fei,Zhou, Hong-Gang,Yang, Cheng,Zhang, Quan,Bai, Cui-Gai,Chen, Yue
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p. 3406 - 3409
(2013/07/19)
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- PROCESS FOR PREPARATION OF RUFINAMIDE
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The invention relates to a novel, industrially viable, cost effective process for the preparation of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide commonly known as Rufinamide and intermediates thereof.
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Paragraph 0029
(2013/07/25)
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- IMPROVED PROCESS FOR THE PREPARATION OF RUFINAMIDE
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The invention relates to a novel, industrially viable, cost effective process for the preparation of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide commonly known as Rufinamide and intermediates thereof.
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Page/Page column 9
(2012/03/26)
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- An efficient synthesis of rufinamide, an antiepileptic drug
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A two-step, one-pot synthesis of rufinamide, an antiepileptic drug, has been developed. 2,6-Difluorobenzyl azide reacts with methyl 3-methoxyacrylate followed by methanolic ammonia to afford rufinamide in 89% yield. The new method generates less waste and uses reagents that are both less expensive and less toxic than other reported syntheses.
- Mudd, Whitney H.,Stevens, Erland P.
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experimental part
p. 3229 - 3231
(2010/08/19)
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- METHOD FOR THE PREPARATION OF RUFINAMIDE
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The invention provides a novel process for the regioselective preparation of a compound of formula (I)
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Page/Page column 3
(2010/09/18)
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- Process for the preparation of rufinamide
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The invention provides a novel process for the regioselective preparation of a compound of formula (I)
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Page/Page column 7
(2010/10/03)
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- PROCESS FOR THE PREPARATION OF RUFINAMIDE
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The present invention relates to a process for the preparation of rufinamide of formula (I), which process comprises: (i) reacting a 2,6-difluorobenzylhaIide of formula (II), wherein X is chloride, bromide or iodide, with an azide to obtain 2-(azidomethyl)-1,3- difluorobenzene of formula (III); (ii) reacting 2-(azidomethyl)-1,3-difluorobenzene of formula (III) with methyl propiolate to obtain methyl 1-(2,6-difluorobenzyl)-1 H-1,2,3- triazole-4-carboxylic acid of formula (IV); and (iii) reacting methyl 1-(2,6-difluorobenzyl)- 1 H-1,2,3-triazole-4-carboxylic acid of formula (IV) with ammonia to obtain rufinamide of formula (I).
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Page/Page column 13
(2010/04/30)
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