- Dimethyl Fumarate: Heterogeneous Catalysis for the Development of an Innovative Flow Synthesis
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The present work describes the development of an improved synthesis of the active pharmaceutical ingredient (API) dimethyl fumarate. The use of continuous flow technology and the newly developed methylation conditions solve some of the issues of previous commercial production strategies, e.g., reaching complete conversion and avoiding the formation of toxic impurities. The optimization was carried out using the design of experiment approach and afforded a very efficient, sustainable process, suitable for the industrial application.
- Dedè, Fabiana,Piccolo, Oreste,Vigo, Daniele
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- Isolation and structure elucidation of the new fungal metabolite (-)-xylariamide A
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Chemical investigations of the terrestrial microfungus Xylaria sp. have afforded the new natural product (-)-xylariamide A (1). The gross structure of 1 was determined by interpretation of 1D and 2D NMM, UV, IR, and MS data. Confirmation of the structure and the absolute stereochemistry of 1 were determined by the total synthesis of (4-)-xylariamide A (2). Synthetic 2 was produced by N,O-bis(trimethylsilyl)-acetamide-induced coupling of 3-chloro-L-tyrosine (3) with (E)-but-2-enedioic acid 2,5-dioxo-pyrrolidin-1-yl ester methyl ester (4). Optical rotation comparison of 1 with 2 indicated that the natural product (1) contained 3-chloro-D-tyrosine. Both enantiomers of xylariamide A were tested in a brine shrimp lethality assay, and only the natural product (1) showed toxicity.
- Davis, Rohan A.
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- PROCESS FOR PREPARATION OF DIROXIMEL FUMARATE
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The present invention relates to a process for the preparation of diroximel fumarate, a compound of formula I. The present invention relates to amorphous solid dispersion comprising diroximel fumarate, a compound of formula I or salt thereof together with at least one pharmaceutically acceptable carrier and process for its preparation.
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Paragraph 0143
(2021/04/01)
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- Continuous-flow synthesis of dimethyl fumarate: A powerful small molecule for the treatment of psoriasis and multiple sclerosis
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Dimethyl fumarate (DMF) is a methyl ester of fumaric acid and has recently gained attention due to its use as a pro-drug in different pharmaceutical preparations, besides the low price of the final molecule and no active patents being available for the synthesis of DMF, the prices of multiple sclerosis treatment are still high. In our continuous effort for the development of process intensification strategies towards the synthesis of active pharmaceutical ingredients, here we present our work on a cascade methodology for dimethyl fumarate synthesis in short reaction times and quantitative yields.
- Lima, Marcelo T.,Finelli, Fernanda G.,De Oliveira, Alline V. B.,Kartnaller, Vinicius,Cajaiba, Joa? F.,Lea?, Raquel A. C.,De Souza, Rodrigo O. M. A.
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p. 2490 - 2494
(2020/02/03)
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- Hexahydro - 1H - pyrrolo [3, 4 - d] pyrimidine compound and its preparation method
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The invention discloses a hexahydro-1H-pyrrolo[3,4-d]pyrimidine compound and a preparation method thereof. The invention relates to the technical field of organic synthesis. The key point of the technical scheme of the invention is that the hexahydro-1H-pyrrolo[3,4-d]pyrimidine compound has a following structure shown in the specification, wherein R1 is H, methyl, ethyl, isopropyl, cyclopropylmethyl, methyletherethyl, isobutyl or benzyl; R2 is H or cyclopropylmethyl. The invention also discloses the preparation method of the hexahydro-1H-pyrrolo[3,4-d]pyrimidine compound. The preparation method provided by the invention is simple and feasible. The raw materials are cheap and easily available. The method also has the advantages of high reaction efficiency and good repeatability.
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Paragraph 0012; 0013; 0014; 0015
(2017/06/28)
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- AN IMPROVED PROCESS FOR THE SYNTHESIS OF DIMETHYL FUMARATE
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The present invention describes an improved process for the industrial scale production of dimethyl fumarate. The process involves a one-pot ring opening reaction of maleic anhydride to monomethyl maleate and isomerization into the corresponding monomethyl fumarate in presence of a Lewis acid. Finally the mono methyl fumarate was converted into the dimethyl fumarate by an acid catalyzed esterification reaction.
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Paragraph 0027
(2017/05/10)
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- METHOD FOR PRODUCING MONOMETHYL FUMARATE COMPOUNDS
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The present invention relates to a novel method for preparing monomethyl fumarate, which can preferably be used in the treatment and/or prevention of systemic diseases, autoimmune diseases, inflammatory diseases such as multiple sclerosis and psoriasis. Further, the present invention relates to the use of specific compounds as intermediates in the process for preparing a monomethyl fumarate prodrug.
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Page/Page column 60
(2017/07/14)
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- Synthesis, DFT and antimicrobial activity assays in vitro for novel cis/trans-but-2-enedioic acid esters
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Six novel cis/trans-but-2-enedioic acid esters had been synthesized to discover the new bioactive molecules that could kill food-related bacteria and fungi. Their structures were analyzed by melting point, LC-MS, 1H NMR and 13C NMR. 4-(Methoxycarbonyl) phenyl ethyl fumarate (6b) was also characterized by single-crystal X-ray diffraction. Their antimicrobial activities were evaluated in vitro by measuring the minimal inhibitory concentration (MIC). Compared with the single monomethyl fumarate and methyl 4-hydroxybenzoate, these compounds had stronger antimicrobial activity against all the eight microorganisms. Among the antibacterial and antifungal compounds, 4-(methoxycarbonyl) phenyl methyl fumarate (6a) showed the best antimicrobial activity. The electronic properties of these compounds were calculated by the density functional theory (DFT) method with 6-31G (d, p) basis set. DFT studies indicated that molecular electrostatic potential (MEP) map, ELUMO, energy gap, electronegativity and electrophilicity index could be helpful to understand the various antimicrobial activities among these compounds. The antimicrobial activity of compound 6a was evaluated in vitro against Salmonella choleraesuis subsp. choleraesuis, Lactococcus lactis subsp. lactis and Saccharomyces cerevisiae by time-kill, and it was found that compound 6a exhibited significant microbiocidal activity against the three microorganisms.
- Ma, Yan-Long,Zhou, Ru-Jin,Zeng, Xing-Ye,An, Ya-Xiong,Qiu, Song-Shan,Nie, Li-Jun
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p. 226 - 234
(2014/03/21)
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- METHOD OF MAKING MONOMETHYL FUMARATE
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Methods of making monomethyl fumarate, which can then also be used in methods of making prodrugs of monomethyl fumarate, are disclosed. Monomethyl fumarate and prodrugs of monomethyl fumarate are useful for treating neurodegenerative, inflammatory, and autoimmune diseases including multiple sclerosis, psoriasis, irritable bowel disorder, ulcerative colitis, arthritis, chronic obstructive pulmonary disease, asthma, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis.
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Paragraph 0205
(2015/01/06)
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- PROCESS FOR PREPARING HIGH PURITY AND CRYSTALLINE DIMETHYL FUMARATE
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The present invention describes a process for the preparation of dimethyl fumarate. The process involves the esterification of fumaric acid and methanol in the presence of sulfuric acid as an acid catalyst. The high purity dimethyl fumarate contains no more than trace amounts of dimethyl sulfate. The present invention also provides a process for the preparation of highly pure dimethyl fumarate with a particle size from 20 to 250 μπι.
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Page/Page column 20-21
(2013/02/27)
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- Allylic oxidations catalyzed by dirhodium caprolactamate via aqueous tert-butyl hydroperoxide: The role of the tert-butylperoxy radical
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Dirhodium(II) caprolactamate exhibits optimal efficiency for the production of the tert-butylperoxy radical, which is a selective reagent for hydrogen atom abstraction. These oxidation reactions occur with aqueous tert-butyl hydroperoxide (TBHP) without rapid hydrolysis of the caprolactamate ligands on dirhodium. Allylic oxidations of enones yield the corresponding enedione in moderate to high yields, and applications include allylic oxidations of steroidal enones. Although methylene oxidation to a ketone is more effective, methyl oxidation to a carboxylic acid can also be achieved. The superior efficiency of dirhodium(II) caprolactamate as a catalyst for allylic oxidations by TBHP (mol % of catalyst, % conversion) is described in comparative studies with other metal catalysts that are also reported to be effective for allylic oxidations. That different catalysts produce essentially the same mixture of products with the same relative yields suggests that the catalyst is not involved in product-forming steps. Mechanistic implications arising from studies of allylic oxidation with enones provide new insights into factors that control product formation. A previously undisclosed disproportionation pathway, catalyzed by the tert-butoxy radical, of mixed peroxides for the formation of ketone products via allylic oxidation has been uncovered.
- McLaughlin, Emily C.,Choi, Hojae,Wang, Kan,Chiou, Grace,Doyle, Michael P.
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supporting information; experimental part
p. 730 - 738
(2009/07/04)
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- Microwave-assisted solvent-free intramolecular 1,3-dipolar cycloaddition reactions leading to hexahydrochromeno[4,3-b]pyrroles: scope and limitations
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We report the microwave-assisted solvent-free synthesis of hexahydrochromeno[4,3-b]pyrroles. Intramolecular 1,3-dipolar cycloadditions proceed under these conditions within 15-40 min in 16-84% yields. An influence of the microwave irradiation upon various [3+2] cycloaddition reaction intermediates was studied. Additionally, a scope and limitations of these reactions including an influence of the dipolarophile geometry upon the cycloaddition selectivity and steric demands of the dipole upon its reactivity were also disclosed. These observations led us to postulate a preferable transition state of the reaction. Finally, an influence of the microwave irradiation to the isomerization of activated olefins was also described.
- Pospí?il, Ji?í,Potá?ek, Milan
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p. 337 - 346
(2007/10/03)
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- Synthesis of the fungal natural product (-)-xylariamide A
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The first synthesis of the fungal natural product (-)-xylariamide A 1 is reported. N,O-Bis(trimethylsilyl)acetamide induced coupling of d-tyrosine with (E)-but-2-enedioic acid 2,5-dioxo-pyrrolidin-1-yl ester methyl ester 5 produced the dechloro natural product 6, which was subsequently monochlorinated using oxone and KCl to yield synthetic 1. (-)-Xylariamide A 1, (+)-xylariamide A 2 and (-)-dechloroxylariamide A 6 displayed no cytotoxic or antimicrobial activity.
- Davis, Rohan A.,Kotiw, Michael
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p. 5199 - 5201
(2007/10/03)
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- Functionalised silane-based compounds, methods for producing them and their use in the area of rubber materials
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The invention relates first to compounds consisting essentially of a functionalised organosilane of formula (R1O)a(R2)3-aSiZ, wherein R1 and R2 are monovalent hydrocarbonated groups, a is a number chosen from 1, 2 and 3 and Z is a function containing an activated ethylenic double bond, chosen from the following:an ester-maleamic function and/or an ester-fumaramic function. The invention also relates to methods for producing said compounds, and to their use as white filler-elastomer coupling agents in rubber compositions containing a white filler, especially a siliceous white filler, as a reinforcing filler.
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- Ionization Shifts in 1H-NMR Spectra of α,β-Unsaturated Carboxylic Acids
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Changes in chemical shifts of olefinic protons in a number of α,β- and α,β,γ,δ-unsaturated carboxylic acids caused by ionization of the COOH group were investigated.The ionization shifts of α-H-atoms are -0.09 to 0.07 ppm, those of β-H-atoms are 0.32-0.47 ppm.The ionization shifts of δ-H-atoms are substantially larger than those of γ-H-atoms.The ionization shifts can be used for immediate determination of the esterification site in monoesters of (2E,4Z)-2,4-hexadienedioic (muconic) acid, which are of interest in connection with synthetic studies on verrucarins.Thus, isomerization by heating in aqueous solution of monoesters of (2Z,4Z)-2,4-hexadienedioic acid yields 1-monoesters rather than 6-monoesters of (2E,4Z)-2,4-hexadienedioic acid, in accordance with the isomerization mechanism involving anchimeric assistance of the free COOH group.Solutions of the ABXY spectra of olefinic protons of monomethyl (2E,4E)- and (2Z,4Z)-2,4-hexadienedioate are reported.
- Jaroszewski, Jerzy W.,Grossen, Peter,Mohr, Peter,Tamm, Christoph
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p. 718 - 725
(2007/10/02)
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- Process for the preparation of fumaric acid monoesters
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Fumaric acid monoesters can be prepared by introducing a hydroxyl compound at a rate corresponding to the progress of the reaction into a solution or a melt of maleic anhydride, which may optionally be substituted, if appropriate in the presence of a cis-trans catalyst. New fumaric acid monoesters can be formed by the process.
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- REARRANGEMENT DURING BROMINATION OF SUCCINATE HALF ESTER
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Bromination of succinate half ester, under conditions used for α-bromination of dicarboxylic acid half esters, is not regioselective, due to a rearrangement involving a symmetrical cyclic cation.
- Gutman, Arie L.
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p. 459 - 462
(2007/10/02)
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- Synthetic cephalotaxine esters having antileukemic activity
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Six acyl esters of cephalotaxine have been synthesized by ordinary and standard procedures, and all have demonstrated chemotherapeutic activity against leukemia in animals.
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