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Efficient synthesis of decahydroacridine-1,8-diones and polyhydroquinolines using the step-wise method
Various symmetrical and unsymmetrical decahydroacridine-1,8-dione and polyhydroquinoline derivatives were synthesized via two-step cyclocondensation reactions. The advantages of this step-wise addition of reactants in comparison with other one-pot reactions are avoiding the formation of 2 or 3 undesired by-products, therefore allowing cleaner work up of reaction. The important factor of this effective cyclocondensation method is that the prepared β-enaminone component was added dropwise to the solution, in which the Knoevenagel condensation product is slowly being formed by reaction of aldehyde molecule and 1,3-dicarbonyl compounds. The results of the proposed step-wise method are compared and discussed with those obtained in the one-pot reactions.
Hosseininasab, Fatemeh Sadat,Memarian, Hamid Reza
(2022/01/11)

On the enantioselective phosphoric-acid-catalyzed hantzsch synthesis of polyhydroquinolines
A reinvestigation of a chiral phosphoric-acid-catalyzed four-component Hantzsch enantioselective synthesis of polyhydroquinolines reported in 2009 is presented. In our hands, when the reaction was performed with fidelity to the original report using a chiral enantiopure phosphoric acid catalyst, no enantioselectivity was observed. Unlike in the original report, enantioselectivity results are backed by baseline separation of the enantiomers by HPLC analyses on chiral stationary phase with UV and chiroptical detection.
Bonne, Damien,Bressy, Cyril,Bugaut, Xavier,Constantieux, Thierry,Jean, Marion,Lemaitre, Clément,Quinonero, Ophélie,Rodriguez, Jean,Roussel, Christian,Vanthuyne, Nicolas
supporting information
p. 3394 - 3398
(2021/05/29)

HISTONE ACETYLTRANSFERASE (HAT) INHIBITOR AND USE THEREOF
The present invention relates to a histone acetyltransferase (HAT) inhibitor. Provided are a compound represented by general formula I, a pharmaceutically acceptable salt, a stereoisomer, an enantiomer, a diastereomer, an atropisomer, a racemate, a polymorph, a solvate or an isotope-labeled compound (including deuterium substitution) thereof, a preparation method therefor, a pharmaceutical composition comprising the same, and use thereof in the treatment of various HAT-related diseases or conditions.
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Paragraph 0859-0860

(2021/02/25)

Tetrasubstituted 1,3-Enynes by Gold-Catalyzed Direct C(sp2)-H Alkynylation of Acceptor-Substituted Enamines
A gold-catalyzed synthesis of tetrasubstituted 1,3-enynes from hypervalent iodine(III) reagents and activated alkenes is reported. This reaction involves an in situ formed alkynyl Au(III) species and a subsequent direct C(sp2)-H functionalization of alkenes, offering 26 enynes in 62-92% yield with excellent functional group tolerance.
Han, Chunyu,Tian, Xianhai,Zhang, Huili,Rominger, Frank,Hashmi, A. Stephen K.
supporting information
p. 4764 - 4768
(2021/06/30)

Synthesis and Biological Activities of Nicotinaldehyde Based 1,4-Dihydropyridinedicarboxylates
Abstract: 1,4-Dihydropyridinecarboxylates were prepared by the reaction of nicotinaldehydes with aminocrotonoates in the presence of p-TsOH at room temperature. The prepared compounds were evaluated for their anti-microbial, free-radical scavenging and α-glucosidase inhibitory activities. Compounds diethyl 2,6-diphenyl-4-(pyridin-3-yl)-1,4-dihydropyridine-3,5-dicarboxylate and diethyl 4-(2-chloro-5-(4-fluorophenyl)pyridin-3-yl)-2,6-diphenyl-1,4-dihydropyridine-3,5-dicarboxylate were identified as potent anti-fungal agents. The compounds diethyl 2,6-dimethyl-4-(pyridin-3-yl)-1,4-dihydropyridine-3,5-dicarboxylate, dimethyl 4-(2-chloropyridin-3-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate and diethyl 2,6-dimethyl-4-(pyridin-4-yl)-1,4-dihydropyridine-3,5-dicarboxylate were identified as ABT?+ free radical scavengers. The compounds diethyl 4-(2-chloro-5-phenylpyridin-3-yl)-2,6-diphenyl-1,4-dihydropyridine-3,5-dicarboxylate and diethyl 4-(2-chloro-5-phenylpyridin-3-yl)-2,6-diphenyl-1,4-dihydropyridine-3,5-dicarboxylate denoted α-glucosidase inhibitory activity.
Hariprasad, K. S.,Prakasham, R. S.,Praveena, G.,Raju, B. China,Ramya, S.,Suchitra Rani, K.,Tiwari, A. K.,Zehra, A.
p. 1335 - 1340
(2021/12/23)

Chiral diphosphine ligand rhodium complex containing tetra (3, 5-bis (trifluoromethylphenyl) boron anions and preparation method and application thereof
The invention relates to a chiral diphosphine ligand rhodium complex containing tetra (3, 5-bis (trifluoromethylphenyl) boron anions and a preparation method and application thereof. Specifically, the high-stability chiral diphosphine ligand rhodium complex containing BArF anions can be obtained by complexing a chiral diphosphine ligand with a rhodium salt and then carrying out anion exchange with NaBArF. The complex can efficiently catalyze an asymmetric catalytic hydrogenation reaction of beta-dehydroamino acid ester to prepare a beta-amino acid ester derivative with high optical purity, so that a synthetic method suitable for industrialization is provided for optically pure beta-amino acid and beta-amino alcohol, and the complex has a good application prospect.
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Paragraph 0056-0065

(2021/10/27)

Copper-Catalyzed Thiolation of Terminal Alkynes Employing Thiocyanate as the Sulfur Source Leading to Enaminone-Based Alkynyl Sulfides under Ambient Conditions
A highly efficient protocol for copper-catalyzed thio-alkynylation of enaminone-based thiocyanates with terminal alkynes under mild conditions has been developed. This scalable amino group-directed thio-alkynylation proceeds in the open air with a broad substrate scope and an excellent yield. The demonstrated synthetic transformation creates the opportunity for a wide variety of sulfur-containing useful materials. Gram-scale synthesis and further synthetic transformations of alkynyl sulfides highlight the potential utility of the method.
Chandran,Pise, Ashwini,Shah, Suraj Kumar,Rahul,Suman,Tiwari, Keshri Nath
supporting information
p. 6557 - 6561
(2020/08/24)

Preparation method of 2-methoxy-6, 7-dihydro-5H-cyclopenta [b] pyridine-5-one
The invention relates to a preparation method of 2-methoxy-6,7-dihydro-5H-cyclopenta[b]pyridine-5-one. According to the preparation method, ethyl acetoacetate is used as a starting raw material, and anovel target product 2-methoxy-6, 7-dihydro-5H-cyclopenta[b]pyridine-5-one is prepared through nine steps of reactions including dehydration, addition, cyclization, chlorination, bromination, substitution, cyclization again, decarboxylation and etherification. The preparation method of the novel target product is simple and efficient. The purity of the novel target product prepared by the methoddisclosed by the invention reaches over 99.0%.
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Paragraph 0006; 0040-0046; 0080-0085; 0119-0124; 0158-0163

(2020/08/22)

Preparation method of herbicide 3-tert-butyl-5-chloro-6-methyluracil
The invention discloses a preparation method of herbicide 3-tert-butyl-5-chloro-6-methyluracil. The method comprises the steps that a compound acetoacetic ester is taken as a raw material to react with an ammonia source to generate 3-amino-2-butenoic acid ethyl ester, the 3-amino-2-butenoic acid ethyl ester is reacted with tert-butylisocyanate to generate an intermediate, and the 3-tert-butyl-5-chloro-6-methyluracil is obtained after chlorination is conducted on the intermediate. The method has the advantages that the obtaining of the raw material is easy, the technology is brief, the method is economical and environmentally friendly, and the method is suitable for industrial production.
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Paragraph 0010; 0024-0027

(2019/05/02)

Unsymmetric dihydropyridines bearing 2-pyridyl methyl carboxylate as modulators of P-glycoprotein; Synthesis and biological evaluation in resistant and non-resistant cancer cells
Multi-drug resistance (MDR) in cancer cells is often associated with overexpression of P-glycoprotein (P-gp or ABCB1 or MDR1); therefore, modulators of this transporter might be helpful in overcoming MDR. In this study, 16 novel unsymmetrical dihydropyridine (DHP) derivatives bearing 2-pyridyl methyl carboxylate at C3 and a nitroimidazole or nitrophenyl ring at C4 positions of the DHP ring were synthesized. Their cytotoxicity was tested against four human cancer cells by MTT assay. The reversal capacity of MDR was examined in P-gp overexpressing cells (MES-SA/DX5) by measuring the alteration of doxorubicin's IC50 and performing flow cytometric determination of intracellular rhodamine 123 accumulation. The calcium channel blocking (CCB) activity, as a side effect of DHPs, was tested on the ileum of a guinea pig. Molecular docking was performed to explain the binding mode of compounds. Two derivatives, 4a and 4c, containing 4-nitrophenyl at C4 and possessing methyl (4a) and iso-propyl (4c) carboxylates at the C5 position of DHP core demonstrated superior cytotoxic and MDR reversal activities and lower CCB effect. Docking analysis confirmed the importance of the 4-nitrophenyl ring for P-gp inhibitory activity. Some of the synthesized DHP derivatives with considerable MDR reversal capacity could be promising compounds for further discovery of useful agents for management of drug resistant cancer.
Nejati, Maryam,Sadeghpour, Hossein,Ranjbar, Sara,Javidnia, Katayoun,Edraki, Najmeh,Saso, Luciano,Firuzi, Omidreza,Miri, Ramin
p. 603 - 614
(2019/08/06)

Condensation of 4-chloro-2H-chromene-3-carbaldehydes and ethyl-3-aminocrotonates with p-TsOH: a facile approach for the synthesis of chromenyldihydropyridines
The investigated reaction of 4-chloro-2H-chromene-3-carbaldehyde 1a with ethyl 3-oxobutanoate 2a in the presence of ammonium acetate provided two compounds, 2H-chromenyldihydropyridine dicarboxylate 3a and chromenopyridine carboxylate 4a. However, the reaction of 1a with ethyl-3-aminocrotonate 5a in the presence of p-TsOH provided selectively 2H-chromenyldihydropyridine dicarboxylate 3a with very good yield. The established method was applied for the preparation of series of 2H-chromenyldihydropyridine dicarboxylates 3a–q.
Madhunala, Shravani,Kurma, Siva Hariprasad,Etikala, Varsha Reddy,Bhimapaka, China Raju
p. 2538 - 2545
(2019/07/15)

Divergent Synthesis of Multisubstituted Unsymmetric Pyrroles and Pyrrolin-4-ones from Enamino Esters via Copper-Catalyzed Aerobic Dimerization
A facile synthetic method to access multisubstituted unsymmetric pyrrole and pyrrolin-4-one derivatives is disclosed. In the presence of Cu(OAc)2 and KOAc, substituted pyrrole derivatives are produced in good yields (up to 93 %) through oxidative cyclization of enamino esters. Meanwhile, using CuCl2 and TFA (trifluoroacetic acid), pyrrolin-4-one derivatives are obtained in excellent yields (up to 94 %) through 1,2-aryl migration. A wide range of functional groups have been tolerated, and a reliable method for the synthesis of valuable multisubstituted pyrroles and pyrrolin-4-ones has been developed.
Chen, Zhi-Wei,Zheng, Lei,Liu, Jin
p. 3051 - 3060
(2019/05/24)

Structural insight into the optimization of ethyl 5-hydroxybenzo[g]indol-3-carboxylates and their bioisosteric analogues as 5-LO/m-PGES-1 dual inhibitors able to suppress inflammation
The release of pro-inflammatory mediators, such as prostaglandines (PGs) and leukotrienes (LTs), arising from the arachidonic acid (AA) cascade, play a crucial role in initiating, maintaining, and regulating inflammatory processes. New dual inhibitors of 5-lipoxygenase (5-LO) and microsomal prostaglandin E2 synthase-1 (mPGES-1), that block, at the same time, the formation of PGE2 and LTs, are currently emerged as a highly interesting drug candidates for better pharmacotherapie of inflammation-related disorders. Following our previous studies, we here performed a detailed structure-based design of benzo[g]indol-3-carboxylate derivatives, disclosing several new key factors that affect both enzyme activity. Ethyl 2-(3,4-dichlorobenzyl)-5-hydroxy-1H-benzo[g]indole-3-carboxylate (4b, RAF-01) and ethyl 2-(3,4-dichlorophenyl)-5-hydroxy-1H-benzo[g]indole-3-carboxylate (7h, RAF-02) emerged as the most active compounds of the series. Additionally, together with selected structure based analogues, both derivatives displayed significant in vivo anti-inflammatory properties. In conclusion, modeling and experimental studies lead to the discovery of new candidate compounds prone to further developments as multi-target inhibitors of the inflammatory pathway.
Bruno, Ferdinando,Errico, Suann,Pace, Simona,Nawrozkij, Maxim B.,Mkrtchyan, Arthur S.,Guida, Francesca,Maisto, Rosa,Olga?, Abdurrahman,D'Amico, Michele,Maione, Sabatino,De Rosa, Mario,Banoglu, Erden,Werz, Oliver,Fiorentino, Antonio,Filosa, Rosanna
p. 946 - 960
(2018/07/24)

Copper-Catalyzed Tandem Reaction of Enamino Esters with ortho-Halogenated Aromatic Carbonyls: One-Pot Approach to Functionalized Quinolines
An efficient and practical approach for the synthesis of functionalized quinolines has been developed by using the copper-catalyzed tandem C–C bond formation and C–N coupling reaction of enamino esters and ortho-halogenated aromatic carbonyl compounds. Various functional groups were tolerated under the reaction conditions, and a series of quinolines were easily obtained in moderate to good yields. A gram-scale reaction was also performed to demonstrate a further application of this synthetic method.
Peng, Fei,Liu, Jin,Li, Lili,Chen, Zhiwei
supporting information
p. 666 - 672
(2018/02/14)

Lewis Acid-Mediated [3+3] Annulation for the Construction of Substituted Pyrimidine and Pyridine Derivatives
A direct and single-step procedure towards substituted pyrimidine and pyridine derivatives via Lewis acid-promoted [3+3] annulation between 3-ethoxycyclobutanones and enamines or amidines is presented. Diverse substituted pyrimidine and pyridine derivatives were obtained in good to high yields with a wide substrate scope. (Figure presented.).
Zhou, Yao,Tang, Zhonghe,Song, Qiuling
supporting information
p. 952 - 958
(2017/03/27)

Synthesis of Indoles and Pyrroles Utilizing Iridium Carbenes Generated from Sulfoxonium Ylides
Metal carbenes can undergo a myriad of synthetic transformations. Sulfur ylides are potential safe precursors of metal carbenes. Herein, we report cascade reactions that involve carbenoids derived from sulfoxonium ylides for the efficient and regioselective synthesis of indoles and pyrroles. The tandem action of iridium and Br?nsted acid catalysts enables rapid assembly of the heterocycles from unmodified anilines or readily accessible enamines under microwave irradiation. The key mechanistic steps are the catalytic transformation of the sulfoxonium ylide into an iridium–carbene complex, followed by N?H or C?H functionalization of an aniline or enamine, respectively, and a final acid-catalyzed cyclization. The present method was successfully applied to the synthesis of the densely functionalized pyrrole subunit of atorvastatin.
Vaitla, Janakiram,Bayer, Annette,Hopmann, Kathrin H.
supporting information
p. 4277 - 4281
(2017/04/03)

Nickel-catalyzed enantioselective hydrogenation of β-(acylamino)acrylates: Synthesis of chiral β-amino acid derivatives
The nickel-catalyzed asymmetric hydrogenation of β-(acylamino)acrylates has been developed, affording chiral β-amino acid derivatives with excellent yields (95-99% yield) and enantioselectivities (97-99% ee). With the Ni-Binapine system, high enantioselectivities (98-99% ee) have also been obtained in the hydrogenation of Z/E isomeric mixtures of β-alkyl and β-aryl β-(acylamino)acrylates. The synthesis of chiral β-amino acid derivatives on a gram scale has also been achieved with 0.2 mol % catalyst loading.
Li, Xiuxiu,You, Cai,Li, Shuailong,Lv, Hui,Zhang, Xumu
supporting information
p. 5130 - 5133
(2017/11/06)

SUBSTITUTED ISOXAZOLOPYRIDAZINONES AND ISOTHIAZOLOPYRIDAZINONES AND METHODS OF USE
Compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein R1, R2 and R3 are as defined in the specification, are useful in treating conditions or disorders prevented by or ameliorated by positive allosteric modulation of the γ-aminobutyric acid B (GABA-B) receptor. Methods for making the compounds are described. Also described are pharmaceutical compositions of compounds of formula (I), and methods for using such compounds and compositions.
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Paragraph 0455

(2017/04/04)

SPIROCYCLIC HAT INHIBITORS AND METHODS FOR THEIR USE
Compounds having a structure of Formula (IX) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R1, R2a, R2b, R3a, R3b, R4a, R4b, Q1----Q2, R6, R7, A, B, W, x, and y are as defined herein and are provided. Pharmaceutical compositions comprising such compounds and methods for treating various HAT-related conditions or diseases, including cancer, by administration of such compounds are also provided.
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Page/Page column 604; 605

(2016/04/10)

Three-component access to 2-pyrrolin-5-ones and their use in target-oriented and diversity-oriented synthesis
The Hantzsch-type microwave-assisted, solvent-free sequential three-component reaction between primary amines, β-dicarbonyl compounds and α-bromoesters in the presence of indium trichloride afforded 2-pyrrolin-5-ones, which are difficult to access by alternative methods. Ready access to these compounds allowed their use as synthetic building blocks in a target-oriented project aimed at the synthesis of a compound that had previously been postulated as a candidate for HIV integrase inhibition on the basis of computational studies. The versatility of 2-pyrrolin-5-ones was further verified by their use in a diversity-oriented synthesis context, leading to a library of highly functionalized bispiro compounds. The overall process leading to these compounds involved the generation of six bonds and two cycles over three steps, two of which are multicomponent, and the fully controlled generation of up to four stereocenters, including two quaternary ones.
Cores, ángel,Estévez, Verónica,Villacampa, Mercedes,Menéndez, J. Carlos
p. 39433 - 39443
(2016/06/01)

One-Pot Synthesis of Hantzsch Pyridines via NH4I Promoted Condensation of 1,3-Dicarbonyl Compounds with DMSO and NH4OAc
A one-pot synthesis of Hantzsch pyridines was achieved through NH4I-promoted condensation of 1,3-dicarbonyl compounds with DMSO and NH4OAc, in which the C4 of the pyridine rings was derived from DMSO and the nitrogen atom resulted from NH4OAc and NH4I. The target product could be obtained in moderate to excellent yields.
Chang, Liming,Lai, Junyi,Yuan, Gaoqing
p. 887 - 894
(2016/09/20)

Cytotoxic and multidrug resistance reversal activities of novel 1,4-dihydropyridines against human cancer cells
Multidrug resistance (MDR) caused by P-glycoprotein (P-gp, ABCB1, MDR-1) transporter over-expression in cancer cells substantially limits the effectiveness of chemotherapy. 1,4-Dihydropyridines (DHPs) derivatives possess several pharmacological activities. In this study, 18 novel asymmetrical DHPs bearing 3-pyridyl methyl carboxylate and alkyl carboxylate moieties at C3 and C5 positions, respectively, as well as nitrophenyl or hetero aromatic rings at C4 were synthesized and tested for MDR reversal with the aim of establishing a structure-activity relationship (SAR) for these agents. Effect of these compounds on P-gp mediated MDR was assessed in P-gp over-expressing MES-SA/DX5 doxorubicin resistant cells by flow cytometric detection of rhodamine 123 efflux. MDR reversal was further examined as the alteration of doxorubicin's IC50 in MES-SA/DX5 cells in the presence of DHPs by MTT assay and was compared to nonresistant MES-SA cells. Direct anticancer effect was examined against 4 human cancer cells including HL-60, K562, MCF-7 and LS180. Calcium channel blocking (CCB) activity was also measured as a potential side effect. Most DHPs, particularly compounds bearing 3-nitrophenyl (A2B2 and A3B2) and 4-nitrophenyl (A3B1 and A4B1) moieties at C4 significantly inhibited rhodamine 123 efflux at 5-25 μM, showing that the mechanism of MDR reversal by these agents is P-gp transporter modulation. Same derivatives were also able to selectively lower the resistance of MES-SA/DX5 to doxorubicin. A2B2 bearing ethyl carboxylate at C5 had also high direct antitumoral effect (IC50 range: 3.77-15.60 μM). Our findings suggest that SAR studies of DHPs may lead to the discovery of novel MDR reversal agents.
Shekari, Farnaz,Sadeghpour, Hossein,Javidnia, Katayoun,Saso, Luciano,Nazari, Farhad,Firuzi, Omidreza,Miri, Ramin
p. 233 - 244
(2015/04/16)

Three-component synthesis of cyclic β-aminoesters using CeO2 nanoparticles as an efficient and reusable catalyst
CeO2 nanoparticles were used as an efficient catalyst for the preparation of cyclic β-aminoesters by three-component reaction between primary amines, ethyl acetoacetate, and chalcones in ethanol. Atom economy, low catalyst loading, reusable catalyst, and high yields of products are some of the important features of this protocol.
Safaei-Ghomi, Javad,Kalhor, Sima,Shahbazi-Alavi, Hossein,Asgari-Kheirabadi, Mehrnoosh
p. 843 - 849
(2015/08/06)

Synthesis of functionalized pyridinium salts bearing a free amino group
Tetrasubstituted N-methylpyridinium salts bearing a free tertiary amino group have been synthesized by a straightforward procedure starting from inexpensive starting materials. The key feature of the synthesis is the use of a proton as a simple effective protecting group to achieve selective N-methylation of the pyridine ring without attacking the amino group. ARKAT-USA, Inc.
Auth, Johanna,Mauleon, Pablo,Pfaltz, Andreas
p. 154 - 169
(2014/03/21)

Ionic liquid promoted synthesis of β-Enamino ketones and esters under microwave irradiation
A facile amination of 1,3-dicarbonyl compounds with amines or ammonium salts has been achieved under microwave irradiation in the presence of acidic ionic liquid 1-butyl-3-methylimidazolium hydrogen sulphate. The method has the advantage of solvent free reactions, short reaction time and mild conditions.
Singh, Ashima,Gupta, Neeru,Sharma,Singh, Jasvinder
p. 900 - 906
(2014/08/05)

Synthesis of oxazolidin-2-ones and imidazolidin-2-ones directly from 1,3-diols or 3-amino alcohols using iodobenzene dichloride and sodium azide
A general and efficient method for the synthesis of oxazolidin-2-ones and imidazolidin-2-ones directly from 1,3-diols and 3-amino alcohols has been developed using the same reagent combination of iodobenzene dichloride (PhICl2) and sodium azide (NaN3).
He, Tian,Gao, Wen-Chao,Wang, Wei-Kun,Zhang, Chi
supporting information
p. 1113 - 1118
(2014/04/03)

The multicomponent Hantzsch reaction: Comprehensive mass spectrometry monitoring using charge-tagged reagents
A novel strategy for the ESI-MS monitoring of reaction solutions involving the alternate use of permanently charge-tagged reagents has been used for comprehensive mass spectrometry monitoring of the multicomponent Hantzsch 1,4-dihydropyridine reaction. By placing a charge tag on either, or both, of the two key reactants, ion suppression effects for ESI were eliminated or minimized, and comprehensive detection of charge-tagged intermediates was achieved. The strategy allowed the trapping and characterization of the important intermediates in the mechanism for 1,4-dihydropyridine formation.
Santos, Vanessa G.,Godoi, Marla N.,Regiani, Thaís,Gama, Fernando H. S.,Coelho, Mirela B.,De Souza, Rodrigo O. M. A.,Eberlin, Marcos N.,Garden, Simon J.
supporting information
p. 12808 - 12816
(2015/03/30)

Reversal of multidrug resistance in cancer cells by novel asymmetrical 1,4-dihydropyridines
Multidrug resistance (MDR) is an important obstacle that limits the efficacy of chemotherapy in many types of cancer. In this study, 14 novel asymmetrical DHPs possessing pyridyl alkyl carboxylate substitutions at C 3 and alkyl carboxylate groups at C5 in addition to a nitroimidazole or nitrophenyl moiety at C4 position were synthesized. Calcium channel blocking (CCB) activity was measured in guinea pig ileal longitudinal smooth muscle. Cytotoxicity was tested on 4 human cancer cell lines, while MDR reversal capacity was examined on P-glycoprotein overexpressing doxorubicin resistant MES-SA-DX5 and compared with non-resistant MES-SA cells. Compounds showed different CCB (IC50: 29.3 nM-4.75 μM) and cytotoxic activities (IC50: 6.4 to more than 100 μM). Several compounds having nitrophenyl moiety at C4, could significantly reverse resistance to doxorubicin at 0.5 and 1 μM. The most active ones were 7e and 7g containing ethyl carboxylate and isopropyl carboxylate at C 5, respectively. CCB activity, which is considered an undesirable effect for these agents, of 7e and 7g were 33 and 20 times lower than nifedipine, respectively. In conclusion, the newly synthesized asymmetrical DHP compounds showed promising MDR reversal and antitumoral activities with low CCB effects and could be of therapeutic value in drug resistant cancer.
Firuzi, Omidreza,Javidnia, Katayoun,Mansourabadi, Elham,Saso, Luciano,Mehdipour, Ahmad Reza,Miri, Ramin
p. 1392 - 1402
(2013/12/04)

IBX mediated reaction of β-enamino esters with allylic alcohols: A one pot metal free domino approach to functionalized pyridines
IBX facilitated the reaction of β-enamino esters with allylic alcohols affording a direct, one-pot and metal free synthesis of functionalized pyridines including 2-substituted nicotinic acids, densely substituted pyridines and precursors of azafluorenones. The methodology also afforded the racemic pyridine core of cyclothiazomycin.
Gade, Narendar Reddy,Devendram,Pal, Manojit,Iqbal, Javed
supporting information
p. 7926 - 7928
(2013/09/02)

Identification of fused-ring alkanoic acids with improved pharmacokinetic profiles that Act as G protein-coupled receptor 40/free fatty acid receptor 1 agonists
The G protein-coupled receptor 40 (GPR40)/free fatty acid receptor 1 (FFA1) has emerged as an attractive target for a novel insulin secretagogue with glucose dependency. We previously identified phenylpropanoic acid derivative 1 (3-{4-[(2′,6′-dimethylbiphenyl-3-yl)methoxy]-2-fluorophenyl} propanoic acid) as a potent and orally available GPR40/FFA1 agonist; however, 1 exhibited high clearance and low oral bioavailability, which was likely due to its susceptibility to β-oxidation at the phenylpropanoic acid moiety. To identify long-acting compounds, we attempted to block the metabolically labile sites at the phenylpropanoic acid moiety by introducing a fused-ring structure. Various fused-ring alkanoic acids with potent GPR40/FFA1 activities and good PK profiles were produced. Further optimizations of the lipophilic portion and the acidic moiety led to the discovery of dihydrobenzofuran derivative 53 ((6-{[4′-(2-ethoxyethoxy)-2′,6′-dimethylbiphenyl-3-yl]methoxy} -2,3-dihydro-1-benzofuran-3-yl)acetic acid), which acted as a GPR40/FFA1 agonist with in vivo efficacy during an oral glucose tolerance test (OGTT) in rats with impaired glucose tolerance.
Negoro, Nobuyuki,Sasaki, Shinobu,Ito, Masahiro,Kitamura, Shuji,Tsujihata, Yoshiyuki,Ito, Ryo,Suzuki, Masami,Takeuchi, Koji,Suzuki, Nobuhiro,Miyazaki, Junichi,Santou, Takashi,Odani, Tomoyuki,Kanzaki, Naoyuki,Funami, Miyuki,Tanaka, Toshimasa,Yasuma, Tsuneo,Momose, Yu
supporting information; experimental part
p. 1538 - 1552
(2012/04/10)

PROCESS FOR CONTINUOUS FLOW SYNTHESIS OF β-ΑΜΙΝΟ CROTONATE
Beta aminocrotonates are important intermediates for the synthesis of Ca channel blockers. The processes available in the art are batch processes with yields about 85%. There are no continuous processes available for the synthesis of such compounds. This gap in the art is addressed by the invention by disclosing a continuous process resulting in high yields of beta amino crotonates.
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Page/Page column 7

(2012/11/13)

One-pot multi-component synthesis of polyhydroquinolines at ambient temperature
An efficient and eco-friendly one-pot synthesis of polyhydroquinolines at ambient temperature from the multi-component reaction of aldehyde, 1,3-diketone, β-keto ester and ammonium acetate in ethanol medium is described. The probable mechanism of transformation is suggested. The features of this procedure are mild reaction conditions, no need of external catalyst, good yields and the operational simplicity at ambient temperature.
Undale,Shaikh,Gaikwad,Pore
scheme or table
p. 511 - 515
(2012/03/08)

Synthesis of unsymmetrical 1, 4-dihydropyridine derivatives in ionic liquid and inference on the formation mechanism of furopyridines
Aromatic aldehydes, methyl acetoacetate, ethyl acetoacetate, ammonium acetate, ethyl 4-chloroacetoacetate as materials, eight unsymmetrical 1, 4-dihydropyridine derivatives were synthesized in ionic liquid [Bmim]OH in short time with the 60%-90% yield, and the ionic liquid could be utilized for 5 times repeatedly with the no decrease of the yield, four of products [3(a-d)] (see in Table-1) were synthesized through Knoevenagel and Michael addition reaction, and another four Furopyridines [3(e-h)] (see in Table-2) through one-pot synthesis whose formation mechanism being different from that of [3(a-d)] was first inferred.
Zhang, Jian,Jin, Long Fei
experimental part
p. 916 - 921
(2012/02/16)

Synthesis of β-amino acid derivatives via copper-catalyzed asymmetric 1,4-reduction of β-(acylamino)acrylates
A new set of reaction conditions has been established to facilitate the copper-catalyzed enantioselective 1,4-reduction of β-(acylamino)acrylates toward a selection of β-alkyl-β-amino acid derivatives in high yields and with uniformly high ee values (up to 99%) irrespective of the use of (E)- or (Z)-substrates.
Wu, Yan,Qi, Shan-Bin,Wu, Fei-Fei,Zhang, Xi-Chang,Li, Min,Wu, Jing,Chan, Albert S. C.
supporting information; experimental part
p. 1754 - 1757
(2011/05/12)

A green solventless protocol for the synthesis of β-Enaminones and β -Enamino esters using silica sulfuric acid as a highly efficient, heterogeneous and reusable catalyst
Silica sulfuric acid is utilized as a green, highly efficient, heterogeneous and recyclable catalyst for the preparation of β-enaminones and β -enamino esters from amines and β -dicarbonyl compounds under solvent-free conditions at 80 °C. Using this method, the title compounds are produced in high to excellent yields and in short reaction times.
Hasaninejad, Alireza,Zare, Abdolkarim,Mohammadizadeh, Mohammad Reza,Shekouhy, Mohsen,Moosavi-Zare, Ahmad Reza
experimental part
p. 1546 - 1554
(2011/12/05)

Pyrrole synthesis via allylic sp3 C-H activation of enamines followed by intermolecular coupling with unactivated alkynes
A conceptually novel pyrrole synthesis is reported, efficiently merging enamines and (unactivated) alkynes under oxidative conditions. In an intermolecular Rh catalyzed process, the challenging allylic sp3 C-H activation of the enamine substrates is followed by the cyclization with the alkyne (R3 = CO2R). Alternatively, in some cases (R 3 = CN), the enamine can be utilized for a vinylic sp2 C-H activation. A total of 17 examples with yields above 60% is presented, together with the results of an initial mechanistic investigation.
Rakshit, Souvik,Patureau, Frederic W.,Glorius, Frank
supporting information; experimental part
p. 9585 - 9587
(2010/09/10)

Bohlmann-Rahtz cyclodehydration of aminodienones to pyridines using N-iodosuccinimide
Cyclodehydration of Bohlmann-Rahtz aminodienone intermediates using N-iodosuccinimide as a Lewis acid proceeds at low temperature under very mild conditions to give the corresponding 2, 3,6-trisubstituted pyridines in high yield and with total regiocontrol.
Bagley, Mark C.,Glover, Christian
scheme or table
p. 3211 - 3227
(2010/09/04)

4-phenyl-1,4-dihydropyridines by aqueous hantzsch reactions
A family of biologically active 4-phenyl-l,4-dihydropyridines were synthesized in a two-step one-pot aqueous Hantzsch protocol. The yields ranged from 44% to 93%. This method provides a particular ecological advantage as it replaces the need for organic solvents with water.
Da Silva,Goncalves,Ferre,Sena,Coelho,Junior, J. Jones
experimental part
p. 57 - 59
(2010/03/03)

Synthesis and biological evaluation of some new 1,4-dihydropyridines containing different ester substitute and diethyl carbamoyl group as anti-tubercular agents
Tuberculosis is a leading infectious cause of death worldwide. Because of the concern of the resistance to most of the commonly used drugs displayed by the considered mycobacteria, most efforts have been done to introduce new anti-tubercular agents. Recent studies showed that 1,4-dihydropyridine-3,5-dicarbamoyl derivatives with lipophilic groups have significant anti-tubercular activity. In this study, we synthesized new derivatives of 1,4-dihydropyridines in which different alkyl and aryl esters and diethyl carbamoyl are substituted in C-3 and C-5 of the DHP ring. In addition nitroimidazole ring is substitutes at C-4 position. These asymmetric analogues were synthesized by a modified Hantzsh reaction using procedure reported by Meyer. The in vitro anti-tubercular activity of compounds against Mycobacterium tuberculosis was evaluated. The results indicate that the compounds containing aromatic esters are more potent than alkyl ones. The most potent aromatic compound (R = 3-phenylpropyl) exhibits comparable anti-tubercular activity (MIC = 1 μmol/ml) with reference compound isoniazide (INH) (MIC = 1 μmol/ml). Conformational analysis, SAR studies of these compounds showed that increasing in lipophilicity and rotable bonds of these compounds resulted in increasing anti-tubercular activity.
Khoshneviszadeh, Mehdi,Edraki, Najmeh,Javidnia, Katayoun,Alborzi, Abdolvahab,Pourabbas, Bahman,Mardaneh, Jalal,Miri, Ramin
experimental part
p. 1579 - 1586
(2009/07/11)

Structure-activity relationships of 1,4-dihydropyridines that act as enhancers of the vanilloid receptor 1 (TRPV1)
Vanilloid agonists such as capsaicin activate ion flux through the TRPV1 channel, a heat- and ligand-gated cation channel that transduces painful chemical or thermal stimuli applied to peripheral nerve endings in skin or deep tissues. We have probed the SAR of a variety of 1,4-dihydropyridine (DHP) derivatives as novel 'enhancers' of TRPV1 activity by examining changes in capsaicin-induced elevations in 45Ca2+-uptake in either cells ectopically expressing TRPV1 or in cultured dorsal root ganglion (DRG) neurons. The enhancers increased the maximal capsaicin effect on 45Ca2+-uptake by typically 2- to 3-fold without producing an action when used alone. The DHP enhancers contained 6-aryl substitution and small alkyl groups at the 1 and 4 positions, and a 3-phenylalkylthioester was tolerated. Levels of free intracellular Ca2+, as measured by calcium imaging, were also increased in DRG neurons when exposed to the combination of capsaicin and the most efficacious enhancer 23 compared to capsaicin alone. Thus, DHPs can modulate TRPV1 channels in a positive fashion.
Roh, Eun Joo,Keller, Jason M.,Olah, Zoltan,Iadarola, Michael J.,Jacobson, Kenneth A.
scheme or table
p. 9349 - 9358
(2009/04/06)

Iridium-catalyzed hydrogenation of β-dehydroamino acid derivatives using monodentate phosphoramidites
The iridium-catalyzed asymmetric hydrogenation of 13 different β-dehydroamino acid derivatives to give optically active β-amino acid esters has been examined. Readily accessible monodentate octahydrobinaphthol- based phosphoramidites were used as chiral ligands. Good to excellent enantioselectivities and yields were obtained for the E isomers, whereas poorer catalyst performance was found for the Z isomers. Importantly, to obtain high enantioselectivity, substitution at the 3,3′-positions of the ligands was necessary. Enantioselectivities of up to 94% ee were achieved under optimized conditions. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.
Enthaler, Stephan,Erre, Giulia,Junge, Kathrin,Schroeder, Kristin,Addis, Daniele,Michalik, Dirk,Hapke, Marko,Redkin, Dmitry,Beller, Matthias
experimental part
p. 3352 - 3362
(2009/04/07)

Development of practical rhodium phosphine catalysts for the hydrogenation of β-dehydroamino acid derivatives
The rhodium-catalyzed asymmetric hydrogenation of various β-dehydroamino acid derivatives to give optically active β-amino acids has been examined. Chiral monodentate 4,5-dihydro-3H-dinaphthophosphepines, which are easily tuned and accessible in a multi-10-g scale, have been used as ligands. The enantioselectivity is largely dependent on the nature of the substituent at the phosphorous atom and on the structure of the substrate. Applying optimized conditions up to 94% ee was achieved.
Enthaler, Stephan,Erre, Giulia,Junge, Kathrin,Holz, Jens,Boerner, Armin,Alberico, Elisabetta,Nieddu, Ilenia,Gladiali, Serafino,Beller, Matthias
p. 568 - 577
(2012/12/31)

Synthesis of some new unsymmetrically substituted 1,4-dihydropyridines
A series of some new 3,5-unsymmetrically substituted 1,4-dihydropyridines have been synthesized, which have ethoxycarbonyl and acetyl groups on 3- and 5-positions, respectively. A three-step procedure has been examined to increase the yield of the desired products, by suppressing the formation of the symmetrically substituted 3,5-diacetyl-1,4-dihydropyridines and 3,5-diethoxycarbonyl-1,4-dihydropyridines.
Memarian, Hamid R.,Abdoli-Senejani, Masumeh,D?pp, Dietrich
p. 50 - 56
(2008/02/10)

New method for the synthesis of 2-aza-1,3-butadienes
2-Aza-1,3-butadienes have been synthesized from carbonyl compounds and 1,1,1,3,3,3-hexamethyl-disilazane in the presence of cobalt-containing catalysts. The best yields (up to 95%) were achieved in the case of aldehydes branched in the α-position and 2-methylcyclohexanone. In the case of two α,β-unsaturated ketones, pyridine derivatives were found as the main products. Copyright Taylor & Francis Group, LLC.
Sisak, Attila
p. 3693 - 3702
(2007/10/03)

A Convenient and Effective Method for Synthesizing β-Amino-α ,β-Unsaturated Esters and Ketones
A convenient and effective method for the preparation of β-amino-α, β-unsaturated esters and ketones has been developed through silica gel-catalyzed and solvent-free reactions of β-dicarbonylic compounds with ammonia and primary amines.
Gao, Yuanhe,Zhang, Qihan,Xu, Jiaxi
p. 909 - 916
(2007/10/03)

A mechanistic study of the ammonolysis of alkyl acetoacetates in water. Formation of 1,5-dimethyl-2,6,9-triaza-bicyclo[3.3.1]nonane-3,7-dione as the main product
Ammonolysis of alkyl acetoacetates with 15% NH3 in water at room temperature initially lead to formation of alkyl β-aminocrotonates which slowly converted into 1,5-dimethyl-2,6,9-triaza-bicyclo[3.3.1]nonane-3,7-dione as the main product.
Paredes, Rodrigo,Abonia, Rodrigo,Cadavid, John,Moreno-Fuquen, Rodolfo,Jaramillo, Alonso,Hormaza, Angelina,Ramirez, Alfonso,Kennedy, Allan
p. 55 - 60
(2007/10/03)

Discovery of 5-Hydroxyalkyl-4-phenylpyridines as a new class of glucagon receptor antagonists
5-Hydroxyalkyl-4-phenylpyridines have been identified as a novel class of glucagon antagonists with potential utility for the treatment of diabetes. A lead structure with moderate activity was discovered through a high throughput screening assay. Structure-activity relationships led to the discovery of a potent antagonist, IC50=0.11 μM, more than 60-fold improvement over the lead structure.
Ladouceur, Gaetan H.,Cook, James H.,Doherty, Elizabeth M.,Schoen, William R.,MacDougall, Margit L.,Livingston, James N.
p. 461 - 464
(2007/10/03)

Highly enantioselective rhodium-catalyzed hydrogenation of β-dehydroamino acid derivatives using monodentate phosphoramidites
New and very easily accessible monodentate phosphoramidite ligands have been developed that lead to excellent ee's and full conversions in the hydrogenation of (E)- and (Z)-β-dehydroamino acid derivatives with both aliphatic and aromatic side chains. Particularly, two different catalytic systems were established for (E)-β-(acylamino)acrylates (98-99% ee) and (Z)-β-(acylamino)acrylates (92-95% ee) based on phosphoramidites 2 and 3, respectively. Copyright
Pena, Diego,Minnaard, Adriaan J.,De Vries, Johannes G.,Feringa, Ben L.
p. 14552 - 14553
(2007/10/03)

Rh(I)-catalyzed enantioselective hydrogenation of (E)- and (Z)-beta-(acylamino)acrylates using 1,4-bisphosphine ligands under mild conditions.
[reaction: see text] Rh-Me-BDPMI (1a) complex can be an effective catalyst for the hydrogenations of (E)- and (Z)-beta-(acylamino)acrylates, in which the Z-isomers hydrogenated with the same or even higher ee values than the corresponding E-isomers. The conversion yield and enantioselectivity of E- and Z-isomers were largely dependent on the solvent, and thus, the E-isomers were hydrogenated more effectively in CH(2)Cl(2), whereas the Z-isomers were hydrogenated more effectively in polar MeOH solvent.
Lee, Sang-gi,Zhang, Yong Jian
p. 2429 - 2431
(2007/10/03)

A new modification of the Bohlmann-Rahtz pyridine synthesis
A range of highly functionalised pyridines is prepared from enamino esters and alkynones in a single synthetic step by the use of acetic acid or amberlyst 15 ion exchange resin at 50°C.
Bagley,Dale,Bower
p. 1149 - 1151
(2007/10/03)