- Large-scale asymmetric synthesis of a cathepsin S inhibitor
-
(Chemical Equation Presented) A potent reversible inhibitor of the cysteine protease cathepsin-S was prepared on large scale using a convergent synthetic route, free of chromatography and cryogenics. Late-stage peptide coupling of a chiral urea acid fragment with a functionalized aminonitrile was employed to prepare the target, using 2-hydroxypyridine as a robust, nonexplosive replacement for HOBT. The two key intermediates were prepared using a modified Strecker reaction for the aminonitrile and a phosphonation-olefinationrhodium- catalyzed asymmetric hydrogenation sequence for the urea. A palladium-catalyzed vinyl transfer coupled with a Claisen reaction was used to produce the aldehyde required for the side chain.Key scale up issues, safety calorimetry, and optimization of all steps for multikilogram production are discussed.
- Lorenz, Jon C.,Busacca, Carl A.,Feng, XuWu,Grinberg, Nelu,Haddad, Nizar,Johnson, Joe,Kapadia, Suresh,Lee, Heewon,Saha, Anjan,Sarvestani, Max,Spinelli, Earl M.,Varsolona, Rich,Wei, Xudong,Zeng, Xingzhong,Senanayake, Chris H.
-
-
Read Online
- Efficient Synthesis of Benzothiazinone Analogues with Activity against Intracellular Mycobacterium tuberculosis
-
8-Nitrobenzothiazinones (BTZs) are a promising class of antimycobacterial agents currently under investigation in clinical trials. Starting from thiourea derivatives, a new synthetic pathway to BTZs was established. It allows the formation of the thiazinone ring system in one synthetic step and is applicable for preparation of a wide variety of BTZ analogues. The synthetic procedure furthermore facilitates the replacement of the sulphur atom in the thiazinone ring system by oxygen or nitrogen to afford the analogous benzoxazinone and quinazolinone systems. 36 BTZ analogues were prepared and tested in luminescence-based assays for in vitro activity against Mycobacterium tuberculosis (Mtb) using the microdilution broth method and a high-throughput macrophage infection assay.
- Av-Gay, Yossef,Imming, Peter,Narula, Gagandeep,Richter, Adrian,Rudolph, Ines,Wagner, Christoph,Seidel, Rüdiger W.
-
supporting information
(2021/12/27)
-
- An efficient one-pot synthesis of industrially valuable primary organic carbamates and: N -substituted ureas by a reusable Merrifield anchored iron(ii)-anthra catalyst [FeII(Anthra-Merf)] using urea as a sustainable carbonylation source
-
An efficient synthesis of primary carbamates and N-substituted ureas is explored with a newly developed heterogeneous polymer supported iron catalyst in the presence of a sustainable carbonylation source. The Merrifield anchored iron(ii)-anthra catalyst [FeII(Anthra-Merf)] was synthesized by functionalization of Merrifield polymer followed by grafting of iron metal. The catalyst [FeII(Anthra-Merf)] was characterized by several techniques, like SEM, EDAX, TGA, PXRD, XPS, FTIR, CHN, AAS and UV-Vis analysis. The designed polymer embedded [FeII(Anthra-Merf)] complex is a remarkably successful catalyst for the synthesis of primary organic carbamates and N-substituted ureas by using safe carbonylation agent urea with different derivatives of alcohols and amines, respectively. The reported catalyst is a potential candidate towards contributing a satisfactory yield of isolated products under suitable reaction conditions. The catalyst is recyclable and almost non-leaching in nature after six runs with an insignificant drop in catalytic activity. Thus we found an economical and viable catalyst [FeII(Anthra-Merf)] for primary carbamates and N-substituted urea synthesis under moderate reaction conditions.
- Basu, Priyanka,Dey, Tusar Kanto,Ghosh, Aniruddha,Biswas, Surajit,Khan, Aslam,Islam, Sk. Manirul
-
p. 2630 - 2643
(2020/02/20)
-
- Catalytic hydration of cyanamides with phosphinous acid-based ruthenium(ii) and osmium(ii) complexes: scope and mechanistic insights
-
The synthesis of a large variety of ureas R1R2NC(O)NH2 (R1 and R2 = alkyl, aryl or H; 26 examples) was successfully accomplished by hydration of the corresponding cyanamides R1R2NCN using the phosphinous acid-based complexes [MCl2(η6-p-cymene)(PMe2OH)] (M = Ru (1), Os (2)) as catalysts. The reactions proceeded cleanly under mild conditions (40-70 °C), in the absence of any additive, employing low metal loadings (1 molpercent) and water as the sole solvent. In almost all the cases, the osmium complex 2 featured a superior reactivity in comparison to that of its ruthenium counterpart 1. In addition, for both catalysts, the reaction rates observed for the hydration of the cyanamide substrates were remarkably faster than those involving classical aliphatic and aromatic nitriles. Computational studies allowed us to rationalize all these trends. Thus, the calculations indicated that the presence of a nitrogen atom directly linked to the CN bond depopulates electronically the nitrile carbon by inductive effect when coordinated to the metal center, thus favouring the intramolecular nucleophilic attack of the OH group of the phosphinous acid ligand to this carbon. On the other hand, the higher reactivity of Os vs. Ru seems to be related with the lower ring strain on the incipient metallacycle that starts to form in the transition state associated with this key step in the catalytic cycle. Indirect experimental evidence of the generation of the metallacyclic intermediates was obtained by studying the reactivity of [RuCl2(η6-p-cymene)(PMe2OH)] (1) towards dimethylcyanamide in methanol and ethanol. The reactions afforded compounds [RuCl(η6-p-cymene)(PMe2OR)(NCNMe2)][SbF6] (R = Me (5a), Et (5b)), resulting from the alcoholysis of the metallacycle, which could be characterized by single-crystal X-ray diffraction. This journal is
- álvarez, Daniel,Cadierno, Victorio,Crochet, Pascale,González-Fernández, Rebeca,López, Ramón,Menéndez, M. Isabel
-
p. 4084 - 4098
(2020/07/09)
-
- Regioselective Formal [3+2] Cycloadditions of Urea Substrates with Activated and Unactivated Olefins for Intermolecular Olefin Aminooxygenation
-
A new class of intermolecular olefin aminooxygenation reaction is described. This reaction utilizes the classic halonium intermediate as a regio- and stereochemical template to accomplish the selective oxyamination of both activated and unactivated alkenes. Notably, urea chemical feedstock can be directly introduced as the N and O source and a simple iodide salt can be utilized as the catalyst. This formal [3+2] cycloaddition process provides a highly modular entry to a range of useful heterocyclic products with excellent selectivity and functional-group tolerance.
- Wu, Fan,Alom, Nur-E,Ariyarathna, Jeewani P.,Na?, Johannes,Li, Wei
-
supporting information
p. 11676 - 11680
(2019/07/31)
-
- Solid dispersions containing an apoptosis-inducing agent
-
A pro-apoptotic solid dispersion comprises, in essentially non-crystalline form, a Bcl-2 family protein inhibitory compound of Formula I as defined herein, dispersed in a solid matrix that comprises (a) a pharmaceutically acceptable water-soluble polymeric carrier and (b) a pharmaceutically acceptable surfactant. A process for preparing such a solid dispersion comprises dissolving the compound, the polymeric carrier and the surfactant in a suitable solvent, and removing the solvent to provide a solid matrix comprising the polymeric carrier and the surfactant and having the compound dispersed in essentially non-crystalline form therein. The solid dispersion is suitable for oral administration to a subject in need thereof for treatment of a disease characterized by overexpression of one or more anti-apoptotic Bcl-2 family proteins, for example cancer.
- -
-
Page/Page column 286
(2019/03/15)
-
- Superparamagnetic Fe3O4 Nanoparticles in a Deep Eutectic Solvent: An Efficient and Recyclable Catalytic System for the Synthesis of Primary Carbamates and Monosubstituted Ureas
-
Superparamagnetic Fe3O4 nanoparticles were used to synthesize various primary carbamates as well as monosubstituted and N,N-disubstituted ureas. This efficient phosgene-free process used urea as an eco-friendly carbonyl source in the presence of a biocompatible deep eutectic solvent (DES) to provide an inexpensive and attractive route that afforded the products in moderate to excellent yields. The employed DES serves both a catalytic role and as the green reaction medium. The magnetic nanocatalyst and DES can been reused several times without a significant loss of activity.
- Inaloo, Iman Dindarloo,Majnooni, Sahar,Esmaeilpour, Mohsen
-
p. 3481 - 3488
(2018/07/29)
-
- A practically simple, catalyst free and scalable synthesis of: N -substituted ureas in water
-
A practically simple, mild and efficient method is developed for the synthesis of N-substituted ureas by nucleophilic addition of amines to potassium isocyanate in water without organic co-solvent. Using this methodology, a variety of N-substituted ureas (mono-, di- and cyclic-) were synthesized in good to excellent yields with high chemical purity by applying simple filtration or routine extraction procedures avoiding silica gel purification. The developed methodology was also found to be suitable for gram scale synthesis of molecules having commercial application in large volumes. The identified reaction conditions were found to promote a unique substrate selectivity from a mixture of two amines.
- Tiwari, Lata,Kumar, Varun,Kumar, Bhuvesh,Mahajan, Dinesh
-
p. 21585 - 21595
(2018/06/26)
-
- Iron-catalyzed reaction of urea with alcohols and amines: A safe alternative for the synthesis of primary carbamates
-
A general study of the iron-catalyzed reaction of urea with nucleophiles is here presented. The carbamoylation of alcohols allows for the synthesis of N-unsubstituted (primary) carbamates, including present drugs (Felbamate and Meprobamat, without the necessity to apply phosgene and related derivatives. Using amines as nucleophiles gave rise to the respective mono-and disubstituted ureas via selective transamidation reaction. These atom-economical transformations provide a direct and selective access to valuable compounds from cheap and readily available urea using a simple Lewis-acidic iron(Icatalyst.
- Pe?a-López, Miguel,Neumann, Helfried,Beller, Matthias
-
p. 2233 - 2238
(2017/07/25)
-
- Transamidation of primary amides with amines catalyzed by zirconocene dichloride
-
Zirconocene dichloride (Cp2ZrCl2) has been shown to be an effective catalyst for the transamidation of primary amides with amines in cyclohexane at 80°C in 5-24 hours. For favourable substrates, the reaction can be performed at temperatures as low as 30°C.
- Atkinson, Benjamin N.,Chhatwal, A. Rosie,Lomax, Helen V.,Walton, James W.,Williams, Jonathan M. J.
-
supporting information
p. 11626 - 11628,3
(2012/12/12)
-
- Transamidation of primary amides with amines catalyzed by zirconocene dichloride
-
Zirconocene dichloride (Cp2ZrCl2) has been shown to be an effective catalyst for the transamidation of primary amides with amines in cyclohexane at 80°C in 5-24 hours. For favourable substrates, the reaction can be performed at temperatures as low as 30°C.
- Atkinson, Benjamin N.,Chhatwal, A. Rosie,Lomax, Helen V.,Walton, James W.,Williams, Jonathan M. J.
-
supporting information
p. 11626 - 11628
(2013/01/15)
-
- COMPOSITIONS COMPRISING AND METHODS OF USING INHIBITORS OF SODIUM-GLUCOSE COTRANSPORTERS 1 AND 2
-
Pharmaceutical dosage forms useful for improving the cardiovascular and/or metabolic health of patients, particularly those suffering from type 2 diabetes, are disclosed, as well as methods of their manufacture.
- -
-
-
- Pyrrolo[3,2,1-ij]quinoline-4-one derivatives for treating tuberculosis
-
Tricyclic nitrogen-containing compounds of Formula (I) and pharmaceutically acceptable derivatives thereof: compositions containing them, their use in the treatment of tuberculosis, and methods for the preparation of such compounds.
- -
-
-
- Novel anthranilamide pyridinureas as VEGF receptor kinase inhibitors
-
The invention relates to novel anthranilamide pyridinureas as VEGF receptor kinase inhibitors, their production and use as pharmaceutical agents for treating diseases that are triggered by persistent angiogenesis.
- -
-
Page/Page column 25
(2008/06/13)
-
- PROCESS FOR PREPARING SYNTHETIC MATRIX METALLOPROTEASE INHIBITORS
-
Synthetic mammalian matrix metalloprotease inhibitors are disclosed that are useful for treating or preventing diseases wherein said diseases are caused by unwanted mammalian matrix metalloprotease activity and include skin disorders, keratoconus, restenosis, rheumatoid arthritis, wounds, cancer, angiogenesis and shock.
- -
-
-
- Inhibitors of β-amyloid protein production
-
This invention relates to compounds and pharmaceutical compositions, and methods for inhibiting or preventing the amyloid protein deposits in the brain which are associated with Alzheimer's disease and aged Down's syndrome patients. More particularly, it relates to the treatment of Alzheimer's disease.
- -
-
-
- Process for the preparation of asymmetrically substituted ureas
-
Process for the preparation of asymmetrically substituted ureas by reaction of a gaseous mixture of isocyanic acid and ammonia having a temperature of 260° to 600° C. with a primary or secondary amine.
- -
-
-
- The Vilsmeier-Haack Reaction of Isoxazolin-5-ones. Synthesis and Reactivity of 2-(Dialkylamino)-1,3-oxazin-6-ones
-
The Vilsmeier-Haack reaction on isoxazolin-5-ones gives 2-(dialkylamino)-1,3-oxazin-6-ones, and a reaction path is proposed depending on substitution pattern of the isoxazolin-5-ones studied.A thermal equilibrium between the oxazinones, imino ketenes, and vinyl isocyanates is hypothesized to explain most of the chemical reactivity of the 2-(dialkylamino)-1,3-oxazin-6-ones.
- Beccalli, Egle M.,Marchesini, Alessandro
-
p. 3426 - 3434
(2007/10/02)
-
- HYDROGEN BONDED COMPLEXES IV; UREA-PHENOL COMPLEXES
-
A number of crystalline, hydrogen-bonded complexes of ureas and phenols are reported.The most commonly observed urea-phenol ratio is 1:1, but some complexes with ratios of 2:1, 1:2 and 1:3 were encountered.The structures of these complexes are discussed and one degradative reaction is described.
- Barry, John E.,Finkelstein, Manuel,Hutchins, Gudrun A.,Ross, Sidney D.
-
p. 2151 - 2156
(2007/10/02)
-
- Organic compounds substituted heptadeca-5,9- and 5,10-dienoic acid
-
The present invention provides novel substituted heptadeca-5,9- and 5,10-dienoic acid and similar fatty acid compounds which are derivatives of certain prostaglandins and are potent thromboxane A2 inhibitors. By virtue of this pharmacological property, they represent useful pharmacological agents for a wide variety of purposes.
- -
-
-
- Antibacterially active amides
-
Carboxylic acid amides of formula (II): STR1 where R1 and R2 represent a variety of hydrocarbon or heterocyclic groups, possess antibacterial activity and antimycoplasmal activity and are therefore of value in the treatment of human and veterinary bacterial and mycoplasmal infections.
- -
-
-