- Synthesis of propiolamide and 1H, 13C and 15N NMR spectra of formamide, acetamide and propiolamide
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A high-yield synthesis and purification of propiolamide is described. The structure and purity of the compound were confirmed by 1H, 13C and 15N NMR studies. Natural abundance 13C and 15N chemical shift measurements in 3.0 M acetonitrile solutions are reported along with 1H-1H, 1H-15N and 1H-13C spin coupling constants. Polarization transfer techniques were used for the 15N and 13C measurements. The propiolamide NMR parameters were compared with those for 3.0 M solutions of formamide and acetamide in acetonitrile solution. Measurements at 298 and 278 K indicated that for all three compounds there is still significant rotation about the carbon-nitrogen bond at room temperature.
- Ferris, Thomas D.,Lee, Peter T.,Farrar, Thomas C.
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Read Online
- Thiol-yne click reaction: an interesting way to derive thiol-provided catechols
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The hydrothiolation of activated alkynes is presented as an attractive and powerful way to functionalize thiols bearing catechols. The reaction was promoted by a heterogeneous catalyst composed of copper nanoparticles supported on TiO2 (CuNPs/TiO2) in 1,2-dichloroethane (1,2-DCE) under heating at 80 °C. The catalyst could be recovered and reused in three consecutive cycles, showing a slight decrease in its catalytic activity. Thiol derivatives bearing catechol moieties, obtained through a versatile Michael addition, were reacted with different activated alkynes, such as methyl propiolate, propiolic acid, propiolamide or 2-ethynylpyridine. The reaction was shown to be regio- and stereoselective towards anti-Markovnikov Z-vinyl sulfide in most cases studied. Finally, some catechol derivatives obtained were tested as ligands in the preparation of coordination polymer nanoparticles (CNPs), by taking the advantage of their different coordination sites with metals such as iron and cobalt.
- Nador, Fabiana,Mancebo-Aracil, Juan,Zanotto, Duham,Ruiz-Molina, Daniel,Radivoy, Gabriel
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p. 2074 - 2082
(2021/01/29)
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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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supporting information
p. 2677 - 2685
(2019/06/13)
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- Advanced Continuous Flow Platform for On-Demand Pharmaceutical Manufacturing
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As a demonstration of an alternative to the challenges faced with batch pharmaceutical manufacturing including the large production footprint and lengthy time-scale, we previously reported a refrigerator-sized continuous flow system for the on-demand production of essential medicines. Building on this technology, herein we report a second-generation, reconfigurable and 25 % smaller (by volume) continuous flow pharmaceutical manufacturing platform featuring advances in reaction and purification equipment. Consisting of two compact [0.7 (L)×0.5 (D)×1.3 m (H)] stand-alone units for synthesis and purification/formulation processes, the capabilities of this automated system are demonstrated with the synthesis of nicardipine hydrochloride and the production of concentrated liquid doses of ciprofloxacin hydrochloride, neostigmine methylsulfate and rufinamide that meet US Pharmacopeia standards.
- Zhang, Ping,Weeranoppanant, Nopphon,Thomas, Dale A.,Tahara, Kohei,Stelzer, Torsten,Russell, Mary Grace,O'Mahony, Marcus,Myerson, Allan S.,Lin, Hongkun,Kelly, Liam P.,Jensen, Klavs F.,Jamison, Timothy F.,Dai, Chunhui,Cui, Yuqing,Briggs, Naomi,Beingessner, Rachel L.,Adamo, Andrea
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p. 2776 - 2784
(2018/02/06)
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- Samarium-mediated intramolecular cross-couplings of an α,β-unsaturated N-acylpyrrole
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The first example of an α,β-unsaturated N-acylpyrrole undergoing a SmI2-mediated cyclization is reported. In contrast to other unsaturated units, the intermediate samarium enolate readily engages in aldol-type reactions, necessitating careful control of the reaction conditions.
- Law, Katherine R.,McErlean, Christopher S.P.
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supporting information
p. 3113 - 3116
(2016/07/06)
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- ANTI-FIBROTIC PYRIDINONES
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This application relates to polycyclic compounds with a pyridinone or pyridinone derivative core including, substituted pyridinones, 5,6- and 6,6- bicyclic heterocycles and substituted pyridine-thiones. This application also discloses methods of preparing these polycyclic compounds, pharmaceutical compositions and medicaments comprising said compounds and methods to treat, prevent or diagnose diseases, disorders or conditions associated with fibrosis.
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Paragraph 0337
(2015/11/02)
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- PROCESS FOR PREPARING N-H OR N-ALKYL 2-PROPYNAMIDE
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Disclosed is a method for the synthesis of N—H or N-alkyl 2-propynamides useful as intermediate in the manufacture of pharmaceutically active ingredients.
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Paragraph 0043; 0044
(2014/03/25)
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- PROCESS FOR PREPARING N-H OR N-ALKYL 2-PROPYNAMIDE
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Disclosed is a method for the synthesis of N-H or N-alkyl 2-propynamides useful as intermediate in the manufacture of pharmaceutically active ingredients.
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Page/Page column 7
(2014/03/26)
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- ANTI-FIBROTIC PYRIDINONES
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Disclosed are pyridinone compounds, method for preparing these compounds, and methods for treating fibrotic disorders.
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Paragraph 0586-0587
(2014/04/17)
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- Continuous flow total synthesis of rufinamide
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Small molecules bearing 1,2,3-triazole functionalities are important intermediates and pharmaceuticals. Common methods to access the triazole moiety generally require the generation and isolation of organic azide intermediates. Continuous flow synthesis provides the opportunity to synthesize and consume the energetic organoazides, without accumulation thereof. In this report, we described a continuous synthesis of the antiseizure medication rufinamide. This route is convergent and features copper tubing reactor-catalyzed cycloaddition reaction. Each of the three chemical steps enjoys significant benefits and has several advantages by being conducted in flow. The total average residence time of the synthesis is approximately 11 min, and rufinamide is obtained in 92% overall yield.
- Zhang, Ping,Russell, M. Grace,Jamison, Timothy F.
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p. 1567 - 1570
(2015/02/19)
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- Racemization-free chemoenzymatic peptide synthesis enabled by the ruthenium-catalyzed synthesis of peptide enol esters via alkyne-addition and subsequent conversion using alcalase-cross-linked enzyme aggregates
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The C-terminal activation of peptides as prerequisite for the formation or ligation of peptide fragments is often associated with the problem of epimerization. We report that ruthenium-catalyzed alkyne addition with (+)-2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane as ligand allows the racemization-free synthesis of peptide enol esters tolerating a wide range of functional groups. The transformation can be performed in a variety of different solvents addressing the solubility issues imposed by peptides with varying amino acid side chain patterns. We show that peptide enol esters with an amide motif in the enol moiety are excellent acyl donors for the peptide condensation with other peptide fragments in organic solvents using serine endopeptidase subtilisin A as catalyst. The reported combination of transition metal catalysis with enzymatic peptide ligations adds an important tool for the racemization-free synthesis and ligation of peptides which is compatible even with unprotected amino acid side chains. Copyright
- Schroeder, Hilmar,Strohmeier, Gernot A.,Leypold, Mario,Nuijens, Timo,Quaedflieg, Peter J. L. M.,Breinbauer, Rolf
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supporting information
p. 1799 - 1807
(2013/07/19)
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- PHOSPHOGLYCERATE KINASE INHIBITORS
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Disclosed are compounds of formula (I) or pharmaceutical acceptable salts thereof, wherein R1, R2, R3 and R4 are as defined in the description. Disclosed are also the methods of making said compounds, and compositions containing said compounds which are useful for inhibiting kinases such as phosphoglycerate kinase.
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Page/Page column 77
(2012/04/23)
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- I2-TEMPO as an efficient oxidizing agent for the one-pot conversion of alcohol to amide using FeCl3 as the catalyst
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A high yield one-pot method for the synthesis of amides from alcohols is described. The aldehyde was generated in situ using iodine-TEMPO as oxidizing agent followed by intermediate oxime formation through reaction with NH 2OH?HCl and finally rearrangement of oxime catalyzed by FeCl3.
- Das, Rima,Chakraborty, Debashis
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experimental part
p. 48 - 53
(2012/08/28)
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- Stetter reactions of unsaturated 1-acyl-1H-pyrroles
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α,β-Unsaturated 1-acyl-1H-pyrroles are employed as enabling units for the construction of 1,4-dicarbonyl systems using the organocatalytic Stetter reaction. The enhanced electrophilicity of the 1-acyl-1H-pyrrole unit allows for the catalytic construction of fused and non-fused pyranones from aliphatic aldehydes, is compatible with aromatic aldehydes, and also facilitates an intermolecular variant of the reaction involving both aromatic and aliphatic aldehydes.
- Phippen, Christopher B. W.,Goldys, Anna M.,McErlean, Christopher S. P.
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experimental part
p. 6957 - 6964
(2012/01/13)
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- Highly efficient desilylation of 3-trimethylsilylprop-2-ynamides by the action of KF-Al2O3
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A highly effective procedure has been developed for desilylation of 3-trimethylsilylprop-2-ynamides in the presence of KF-Al2O 3 as catalyst. The corresponding terminal prop-2-ynamides were obtained in high yield in methanol at 25°C using 5 mol % of the catalyst (reaction time 20 min). Rise in temperature leads to the formation of Z,E-3-methoxyprop-2-enamides or 3,3-dimethoxypropanamides as a result of tandem desilylation-addition of methanol, depending on the conditions.
- Andreev,Safronova,Medvedeva
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experimental part
p. 1797 - 1801
(2012/03/10)
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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 3-4
(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 6
(2010/10/03)
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- SUBSTITUTE 1, 6-NAPHTHYRIDINES FOR USE AS SCD INHIBITORS
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The present invention relates to substituted tetrahydronaphthyridine (THN) compounds of the formula (I) and salts thereof, to pharmaceutical compositions containing them and their use in medicine. In particular, the invention relates to compounds for inhibiting SCD activity.
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Page/Page column 43
(2009/06/27)
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- TETRAHYDRONAPHTHYRIDINES AND AZA DERIVATIVES THEREOF AS HISTAMINE H3 RECEPTOR ANTAGONISTS
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The invention relates to compounds of formula (I), wherein X1a, X1 to X5, Ra, Rb, n and R have the meaning as cited in the description and the claims. Said compounds are useful as Histamine H3 receptor antagonists. The invention also relates to pharmaceutical compositions, the preparation of such compounds as well as the production and use as medicament.
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Page/Page column 75
(2009/10/30)
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- Synthesis and evaluation of electron-rich curcumin analogues
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The natural product curcumin has long been recognized for its medicinal properties and is utilized for the treatment of many diseases. However, it remains unknown whether this activity is based on its presumably promiscuous scaffold, or if it results from the Michael acceptor properties of the α,β-unsaturated 1,3-diketone moiety central to its structure. To probe this issue, electron-rich pyrazole and isoxazole analogues were prepared and evaluated against two breast cancer cell lines, which resulted in the identification of several compounds that exhibit low micromolar to mid nanomolar anti-proliferative activity. A conjugate addition study was also performed to compare the relative electrophilicity of the diketone, pyrazole and isoxazole analogues.
- Amolins, Michael W.,Peterson, Laura B.,Blagg, Brian S.J.
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experimental part
p. 360 - 367
(2011/02/26)
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- COMPOUNDS WITH ACTIVITY AT THE 5-HT2C RECEPTOR
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A compound of Formula (I): wherein R1 is a substituted or unsubstituted heterocycloalkyl containing at least two rings, wherein said rings are fused rings, bridged fused rings and/or spiro rings. A method for treating a 5-HT2C receptor-mediated disorder in a mammal using the same.
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Page/Page column 65
(2009/07/25)
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- TETRAHYDRO-5H-PYRIDO[2,3-D]AZEPINES AS 5-HT2C LIGANDS
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Compounds according to Formula (I); wherein the radical R7 preferably represents a hetereocycle of 6 or 7 members and R4, R9-12 all preferably represent hydrogen atoms. These compounds and their pharmaceutical acceptable salts are used in pharmaceutical compositions and are useful for treating serotonin 5HT2C receptor mediated diseases. Processes to make such derivatives are as well disclosed therein.
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Page/Page column 55
(2008/06/13)
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- AMIDE COMPOUND
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There is provided a FAAH inhibitor and a prophylactic or therapeutic agent for cerebrovascular disorders or sleep disorders comprising it. The prophylactic or therapeutic agent comprises a compound of the formula (I0): wherein Z is oxygen or sulfur; R1 is aryl which may be substituted, or a heterocyclic group which may be substituted; R1a is a hydrogen atom, a hydrocarbon group which may be substituted, hydroxyl, etc.; R2 is piperidin-1,4-diyl which may be substituted, or piperazin-1,4-diyl which may be substituted; R3 is a group formed by eliminating two hydrogen atoms from a 5-membered aromatic heterocyclic group having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, which may be further substituted, -CO-, etc.; and R4 is a hydrocarbon group which may be substituted, or a heterocyclic group which may be substituted; or a salt thereof.
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Page/Page column 88
(2008/06/13)
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- Antitumor agents 247. New 4-ethoxycarbonylethyl curcumin analogs as potential antiandrogenic agents
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4-Ethoxycarbonylethyl curcumin (ECECur) (3) is a current drug candidate for the treatment of prostate cancer. Due to problems inherent in the tautomerism of ECECur, 4-fluoro-4-ethoxycarbonylethyl curcumin (4) and 4- ethoxycarbonylethylenyl curcumin (5) were designed and synthesized. These two target compounds and their synthetic intermediates (4-9) were evaluated for their inhibitory activity against androgen receptor transcription in LNCaP and PC-3 prostate cancer cell lines. While the enol-keto analogs showed varying anti-androgen potencies, the di-keto analogs showed no activity. Tetrahydropyranylation of the phenoxy groups had a positive impact on the anti-AR activity of 4-ethoxycarbonylethylenyl curcumin, but a negative impact on the activity of ECECur. With potent anti-AR activity, di-tetrapyranylated 4-ethoxycarbonylethylenyl curcumin (9), which exists in only one form, is a good drug lead for further structural modification. Based on the SAR information obtained from the above study, five new compounds were designed and subsequently synthesized. Among them, compound 10 was found to be the most potent anti-AR agent and is considered to be a promising drug candidate for the treatment of prostate cancer.
- Lin, Li,Shi, Qian,Su, Ching-Yuan,Shih, Charles C.-Y.,Lee, Kuo-Hsiung
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p. 2527 - 2534
(2007/10/03)
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- Tetrahydronaphthyridine derivates useful as histamine H3 receptor ligands
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The invention relates to tetrahydronaphthyridine derivatives having formula (I) and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives. Said tetrahydronaphthyridine derivatives are H3 ligands and are useful in numerous diseases, disorders and conditions, in particular inflammatory, allergic and respiratory diseases, disorders and conditions.
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Page/Page column 49
(2008/06/13)
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- Imidazolo-5-YL-2anilino-pyrimidines as agents for the inhibition of the cell proliffration
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Compounds of the formula (I): wherein R1, R2, R3, R4, R5, R6, p, q, and n are as defined within and a pharmaceutically acceptable salts and in vivo hydrolysable esters are described. Also described are processes for their preparation and their use as medicaments, particularly medicaments for producing a cell cycle inhibitory (anti-cell-proliferation) effect in a warm-blooded animal, such as man.
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Page/Page column 38
(2010/02/05)
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- Synthesis of enamides from aldehydes and amides
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A range of double unsaturated amides (15, 19, and 21), obtained by cross-coupling reactions was reacted with aldehydes to hemiaminals. Heating the hemiaminals in the presence of Ac2O and pyridine affected clean conversion to the corresponding enamides, such as 42, 45, and 47. Alternatively, N,S-acetals were prepared which were oxidized to the sulfones. Treatment with base also gave the enamides, favoring the cis-isomer. However, this method is less general. Application of these methods led to the natural products lansiumamide-A (30_cis), lansiumamide-I (31) and lansiumamide-B (32).
- Bayer, Alexander,Maier, Martin E.
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p. 6665 - 6677
(2007/10/03)
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- ANTIMICROBIAL COMPOUNDS
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A compound having a formula: R-SOn-Z-CO-Y, wherein: R is an alkyl group having 6-20 carbon atoms or an alkyl group having 6-20 carbon atoms interrupted by at least one aromatic ring; Z is a radical selected from the group consisting of -CH2-, -O-, -NH-, two of these radicals coupled together, and -CH=CH-; Y is selected from -NH2, O-CH2-C6H5, and -CO-CO-O-CH3; and n is 1 or 2. The compound may be used in the preparation of a medicament for inhibiting the growth of a microbial cell wherein the cell synthesises alpha -substituted beta -hydroxy fatty acids.
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- DERIVATIVES OF 4- (IMIDAZOL-5-YL)-2-(4-SULFOANILINO) PYRIMIDINE WITH CDK INHIBITORY ACTIVITY
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Compounds of the formula (I): wherein R1, R2, R3, R4, R5 and p are as defined within and a pharmaceutically acceptable salts and in vivo hydrolysable esters are described. Also described are processes for their preparation and their use as medicaments, particularly medicaments for producing a cell cycle inhibitory (anti-cell-proliferation) effect in a warm-blooded animal, such as man.
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Page/Page column 69
(2008/06/13)
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- Microwave spectra and molecular structures of (Z)-pent-2-en-4-ynenitrile and maleonitrile
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Accurate equilibrium structures have been determined for (Z)-pent-2-en-4-ynenitrile (8) and maleonitrile (9) by combining microwave spectroscopy data and ab initio quantum chemistry calculations. The microwave spectra of 10 isotopomers of 8 and 5 isotopomers of 9 were obtained using a pulsed nozzle Fourier transform microwave spectrometer. The ground-state rotational constants were adjusted for vibration-rotation interaction effects calculated from force fields obtained from ab initio calculations. The resultant equilibrium rotational constants were used to determine structures that are in very good agreement with those obtained from high-level ab initio calculations (CCSD(T)/cc-pVTZ). The geometric parameters in 8 and 9 are very similar; they also do not differ significantly from the all-carbon analogue, (Z)-hex-3-ene-1,5-diyne (7), the parent molecule for the Bergman cyclization. A small deviation from linearity about the alkyne and cyano linkages is observed for 7-9 and several related species where accurate equilibrium parameters are available. The data on 7-9 should be of interest to radioastronomy and may provide insights on the formation and interstellar chemistry of unsaturated species such as the cyanopolyynes.
- Halter,Fimmen,McMahon,Peebles,Kuczkowski,Stanton
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p. 12353 - 12363
(2007/10/03)
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- Palladium-catalyzed hydroarylation of propiolamides. A regio- and stereocontrolled method for preparing 3,3-diarylacrylamides
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A general regio- and stereoselective synthesis of 3,3-diarylacrylamides is reported. Palladium-catalyzed coupling reactions of propiolamides with aryl provides arylpropiolamides. A subsequent hydroarylation reaction of these arylpropiolamides with aryl halides, catalytic palladium, an amine base, and formic acid in refluxing ethyl acetate provides 3,3- diarylacrylamides regio- and stereoselectively. The unique stereo- and regiocontrol is presumed to proceed through careful reaction parameters that allow intramolecular coordination of the propiolamide amide functionality to the transient palladium-alkyne complex. Palladium-catalyzed hydroarylation of propiolamides has not been studied; however, preliminary results from related systems suggest that regioselective addition can be achieved. The methodology as a synthesis tool is demonstrated in an efficient route to previously difficult-to-prepare potent, benzimidazole antiviral targets. In addition, the synthesis scope is explored where, by judicious choice of reaction sequence and aryl iodide, either the Z- or E-geometric isomer of a given pair of 3,3-diarylacrylamides is independently prepared.
- Hay, Lynne A.,Koenig, Thomas M.,Ginah, Francis O.,Copp, James D.,Mitchell, David
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p. 5050 - 5058
(2007/10/03)
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- OXAZOLES AND THIAZOLES FOR THE TREATMENT OF SENILE DEMENTIA
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1,3-Oxazole and 1,3-thiazole compounds of formula I, and their pharmaceutically acceptable salts and prodrugs: STR1 wherein X represents oxygen or sulphur;R 1 represents a non-aromatic azacyclic or azabicyclic ring system.
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- Reaction of (E)-β-Enamino Amides with Dimethyl Acetylenecarboxylate (DMAD): Formation of Benzene Derivatives, Enamino Esters, and 2-Pyridones
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An investigation of the additions of (E)-enamino amides (1a-d) with DMAD has shown that they are influenced by the stereochemistry of the intermediates and the amine component of the enamine system.In dry acetonitrile (E)- benzyl(methyl)amino- (1b), (E)-pyrrolidin-1-ylamino-(1c), and (E)-piperidin-1-ylamino-(1d) acrylamides, following a known mechanism, yielded tetramethyl benzene-1,2,3,4-tetracarboxylate (5), the (E)-aminobutenedioates (6a-d), and the 3,4-bismethoxycarbonylpyridin-2(1H)-one (8).Dimethylamino-(1a) and morpholin-1-ylamino-(1e)-acrylamides, owing to the different nucleophilicity of the β-carbon, formed a zwitterion (11) which eliminated propiolamide to give only the (E)-aminobutenedioates (6a,e).
- Nuvole, Antonio,Paglietti, Giuseppe
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p. 1007 - 1011
(2007/10/02)
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- Pyrazolo(1,5-c)quinazoline derivatives and related compounds
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Compounds are provided having the structure STR1 wherein R1 is hydrogen, alkyl of 1-3 carbons, phenyl optionally substituted by R4 ; R2 is cyano; STR2 (wherein Z is a single bond or STR3 X is O or S); STR4 (wherein R9 is hydrogen or alkyl, Q is CH or N); STR5 wherein R6 is amino, alkylamino, dialkylamino, haloalkyl or STR6 and R4 and R5 are the same or different and represent hydrogen, lower alkyl, lower alkoxy, alkanoyloxy, benzyloxy, substituted benzyloxy, hydroxy, halogen (Cl, Br and F), nitro and trifluoromethyl; and R7, R8, m and n are defined hereinafter.
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