- Efficient Syntheses of Diverse, Medicinally Relevant Targets Planned by Computer and Executed in the Laboratory
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The Chematica program was used to autonomously design synthetic pathways to eight structurally diverse targets, including seven commercially valuable bioactive substances and one natural product. All of these computer-planned routes were successfully executed in the laboratory and offer significant yield improvements and cost savings over previous approaches, provide alternatives to patented routes, or produce targets that were not synthesized previously. Although computers have demonstrated the ability to challenge humans in various games of strategy, their use in the automated planning of organic syntheses remains unprecedented. As a result of the impact that such a tool could have on the synthetic community, the past half century has seen numerous attempts to create in silico chemical intelligence. However, there has not been a successful demonstration of a synthetic route designed by machine and then executed in the laboratory. Here, we describe an experiment where the software program Chematica designed syntheses leading to eight commercially valuable and/or medicinally relevant targets; in each case tested, Chematica significantly improved on previous approaches or identified efficient routes to targets for which previous synthetic attempts had failed. These results indicate that now and in the future, chemists can finally benefit from having an “in silico colleague” that constantly learns, never forgets, and will never retire. Multistep synthetic routes to eight structurally diverse and medicinally relevant targets were planned autonomously by the Chematica computer program, which combines expert chemical knowledge with network-search and artificial-intelligence algorithms. All of the proposed syntheses were successfully executed in the laboratory and offer substantial yield improvements and cost savings over previous approaches or provide the first documented route to a given target. These results provide the long-awaited validation of a computer program in practically relevant synthetic design.
- Klucznik, Tomasz,Mikulak-Klucznik, Barbara,McCormack, Michael P.,Lima, Heather,Szymku?, Sara,Bhowmick, Manishabrata,Molga, Karol,Zhou, Yubai,Rickershauser, Lindsey,Gajewska, Ewa P.,Toutchkine, Alexei,Dittwald, Piotr,Startek, Micha? P.,Kirkovits, Gregory J.,Roszak, Rafa?,Adamski, Ariel,Sieredzińska, Bianka,Mrksich, Milan,Trice, Sarah L.J.,Grzybowski, Bartosz A.
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p. 522 - 532
(2018/03/21)
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- Convergent synthesis of dronedarone, an antiarrhythmic agent
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We have developed a convergent synthesis of dronedarone, an antiarrhythmic agent. The key steps of the process are the construction of a benzofuran skeleton by iodocyclization and the carbonylative Suzuki-Miyaura cross-coupling for biaryl ketone formation. This synthetic route required only eight steps from 2-amino-4-nitrophenol in 23% overall yield.
- Okitsu, Takashi,Ogasahara, Mizuki,Wada, Akimori
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p. 1149 - 1153
(2016/08/11)
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- METHOD FOR PREPARING 3-KETO-BENZOFURANE DERIVATIVES
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The invention relates to a method for preparing 3-keto-benzofurane derivatives of the general formula: Formula (I), where R is an alkyl or aryl group, R1 is hydrogen or an alkyl or aryl group, and R2 is a substituted alkyl or phenyl group. Said preparation method involves coupling a derivative of Formula III, where X is chlorine, bromine, or iodine or a sulfonate grouping: Formula (III) with a sulfonamide derivative of the formula R—SO2—NH2 in the presence of a basic agent and a catalytic system formed of a complex between a palladium compound and a ligand.
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Paragraph 0060
(2013/07/05)
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- PROCESS FOR PREPARING BENZOFURAN DERIVATIVES SUBSTITUTED AT POSITION 5
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The disclosure relates to a process for preparing benzofuran derivatives of general formula I: in which R, R1, and R2 are as defined in the disclosure; by coupling the hydroxylamine with a diketone of general formula III: in order to form an oxime that is then cyclized by heating in order to form the desired compound.
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Paragraph 0116
(2013/07/05)
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- Methanesulphonamido-benzofuran, preparation method and use thereof as synthesis intermediate
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The invention relates to 2-butyl-5-(methanesulfonamido)benzofuran, its preparation and its use. This compound is a synthesis intermediate, in particular for the preparation of dronedarone.
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Page/Page column 3
(2008/06/13)
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- 2-butyl-3-(4-[3(dibutylamino)propoxy]benzoyl)-5-nitro-benzofuran hydrochloride and preparation thereof
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The invention relates to 2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl-5-nitrobenzofuran hydrochloride, to its preparation and to its use as synthetic intermediate, in particular in preparing 2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-nitrobenzofuran, itself an intermediate for dronedarone.
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Page/Page column 3
(2008/06/13)
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- Phenol compound having antioxidative activity and the process for preparing the same
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Disclosed are a phenol compound represented by the formula (1): STR1 wherein R0 represents H, alkyl or alkyloxy; R1 represents alkyl; R2 represents alkyl or alkyloxy; OR3 represents OH; R4 represents H, lower alkyl or acyl, each of the above substituents may be substituted; W represents O, S or NR7 ; where R7 represents H, alkyl, aryl, OH or alkyloxy, a group of the formula (2): STR2 represents an amino which may be mono- or di-substituted or heterocyclic group containing N atom, or a pharmaceutically acceptable salt thereof, and a process for preparing the same.
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