- A New Electrosynthesis of 2,2-Dimethylchromenes from 2-(1-Bromo-1-methylethyl)benzofurans
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Electrolytic reduction of 2-(1-bromo-1-methylethyl)benzofurans in acetonitrile affords the corresponding 2,2-dimethylchromenes in good yields even in the absence of a proton donor and comprises the cleavage of a carbon-bromine bond followed by ring expansion.
- Tsukayama, Masao,Utsumi, Hideyuki,Kunugi, Akira
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- Continuous processing to control a potentially hazardous process: Conversion of aryl 1,1-dimethylpropargyl ethers to 2,2-dimethylchromenes (2,2-dimethyl-2H-1-benzopyrans)
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The thermal Claisen rearrangement of 4-cyanophenyl 1,1-dimethylpropargyl ether (4) to 6-cyano-2,2-dimethylchromene (5), (6-cyano-2,2-dimethyl-2H-1-benzopyran), which is used in the synthesis of a potassium channel activator drug candidate, BMS-180448, created a significant process development issue. The resulting large heat release in this conversion posed not only a safety risk but could also cause product degradation if done in a batch-wise manner. The solution was to exploit the high surface-to-volume ratio of a plug-flow reactor that would maximize the heat transfer, thereby permitting tight and responsive temperature with better reaction control. In the course of successfully testing the plug-flow concept on "micro"-flow scale (gram quantity) and "kilo"-flow scale (～10 kg), a generalized mathematical model capable of predicting the reaction performance based on the physical properties of any given plug-flow reactor was generated. The model provides requisite information to design and operate a plug-flow reactor of any size for this reaction. This model would optimize reaction conditions for an acquired reactor system capable of producing ～7 kg/h of the dimethylchromene. Application of plug-flow reactor technology enabled production of high quality 2,2-dimethylchromenes in good yield (>98 mol %) without the use of solvents and with virtually no waste streams.
- Bogaert-Alvarez, Ricardo J.,Demena, Paul,Kodersha, Gus,Polomski, Robert E.,Soundararajan,Wang, Steve S. Y.
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- Identification of anticancer agents based on the thieno[2,3-b]pyridine and 1H-pyrazole molecular scaffolds
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Structural similarity search of commercially available analogues of thieno[2,3-b]pyridine and 1H-pyrazole derivatives, known anticancer agents, resulted in 717 hits. These were docked into the phosphoinositide specific-phospholipase C (PLC) binding pocket, the putative target of the compounds, to further focus the selection. Thirteen derivatives of the thieno[2,3-b]pyridines were identified and tested against the NCI60 panel of human tumour cell lines. The most active derivative 1 was most potent against the MDA-MB-435 melanoma cell line with GI50at 30?nM. Also, it was found that a piperidine moiety is tolerated on the thieno[2,3-b]pyridine scaffold with GI50?=?296?nM (MDA-MB-435) for derivative 10 considerably expanding the structure activity relationship for the series. For the 1H-pyrazoles four derivatives were identified using the in silico approach and additionally ten were synthesised with various substituents on the phenyl moiety to extend the structural activity relationship but only modest anticancer activity was found.
- Eurtivong, Chatchakorn,Reynisdóttir, Inga,Kuczma, Stephanie,Furkert, Daniel P.,Brimble, Margaret A.,Reynisson, Jóhannes
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supporting information
p. 3521 - 3526
(2016/07/20)
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- NOVEL COMPOUND OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, AND PHARMACEUTICAL COMPOSITION CONTAINING SAME AS ACTIVE INGREDIENT
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The present invention relates to a novel compound inhibiting Hsp 90 and to a pharmaceutical composition including same as an active ingredient. Compounds of formula 1 and formula 2 according to the present invention inhibit the accumulation of HIF-1α protein, which is an Hsp90 client protein, by suppressing Hsp90 expression, and effectively inhibit the activity of vascular endothelial growth factor (VEGF). Furthermore, said compounds have low cytotoxicity and can thus be used as an active ingredient for the treatment of diabetic retinopathy and arthritis.
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Paragraph 0216-0219
(2015/05/26)
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- NOVEL COMPOUND OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, AND PHARMACEUTICAL COMPOSITION CONTAINING SAME AS ACTIVE INGREDIENT
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The present invention relates to a compound inhibiting Hsp90 and a pharmaceutical composition comprising the same as an active ingredient. The compounds represented by formula 1 and formula 2 of the present invention suppress the expression of Hsp90 so that they can inhibit the accumulation of HIF-1α, the Hsp90 client protein, and also efficiently inhibit the activation of VEGF. In addition, these compounds display low cytotoxicity, so that they can be effectively used as an active ingredient of an anti-cancer agent, a diabetic retinopathy treating agent, and an anti-arthritic agent.
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Paragraph 0315; 0316
(2015/07/15)
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- Identification of small molecule inhibitors of the STAT3 signaling pathway: Insights into their structural features and mode of action
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A series of novel STAT3 inhibitors consisting of Michael acceptor has been identified through assays of the focused in-house library. In addition, their mode of action and structural feature responsible for the STAT3 inhibition were investigated. In parti
- Kim, Kyeojin,Kim, Su-Jung,Han, Young Taek,Hong, Sung-Jun,An, Hongchan,Chang, Dong-Jo,Kim, Taewoo,Lim, Bumhee,Lee, Jeeyeon,Surh, Young-Joon,Suh, Young-Ger
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p. 5444 - 5448
(2015/11/09)
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- Natural product-like combinatorial libraries based on privileged structures. 1. General principles and solid-phase synthesis of benzopyrans
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Herein we report a novel strategy for the design and construction of natural and natural product-like libraries based on the principle of privileged structures, a term originally introduced to describe structural motifs capable of interacting with a variety of unrelated molecular targets. The identification of such privileged structures in natural products is discussed, and subsequently the 2,2-dimethylbenzopyran moiety is selected as an inaugural template for the construction of natural product-like libraries via this strategy. Initially, a novel solid-phase synthesis of the benzopyran motif is developed employing a unique cycloloading strategy that relies on the use of a new, polystyrene-based selenenyl bromide resin. Once the loading, elaboration, and cleavage of these benzopyrans was established, this new solid-phase method was then thoroughly validated through the construction of six focused combinatorial libraries designed around natural and designed molecules of recent biological interest.
- Nicolaou,Pfefferkorn,Roecker,Cao,Barluenga,Mitchell
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p. 9939 - 9953
(2007/10/03)
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- Process for the production of 2H-1-benzopyrans
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There is provided a 2-stage process for making 2H-1-benzopyrans wherein an alpha,beta-unsaturated aldehyde is reacted with an alkanol or an alkane-diol in the presence of a dehydrating compound which is an orthoformate and an aluminum oxide/silicon oxide catalyst to form an aliphatic acetal, which is then condensed in a second stage with a phenol in the presence of base in an organic solvent.
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- Cyclization of o-(3-hydroxy-3-methylbutynyl)-phenols with boron tribromide to 4-bromo-2,2-dimethylchromenes and their electroreduction to 2,2-dimethylchromenes
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Cyclization of o-(3-hydroxy-3-methylbutynyl)phenols (2) with boron tribromide gave easily 4-bromo-2,2-dimethylchromenes (3). Electrolytic reduction of 3 at a Hg-pool electrode afforded the corresponding 2,2-dimethylchromenes (6) in high yields.
- Tsukayama, Masao
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p. 1131 - 1142
(2007/10/03)
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- Synthesis of 6-Cyano-2,2-dimethyl-2H-1-benzopyran and Other Substituted 2,2-dimethyl-2H-1-benzopyrans
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A practical synthesis of 6-cyano-2,2-dimethyl-2H-1-benzopyran (1) has been developed.This process involves the pyridine-catalyzed condensation of 1,1-diethoxy-3-methyl-2-butene (6) with 4-cyanophenol (3) in toluene or xylene at elevated temperatures.The development of this process, including an evaluation of solvents, bases, acid catalysts, and alterantive acetals, along with an improved synthesis of 1,1-diethoxy-3-methyl-2-butene, is discussed.Using this method, a variety of other substituted 2,2-dimethyl-2H-1-benzopyrans were synthesized.
- North, Jeffrey T.,Kronenthal, David R.,Pullockaran, Annie J.,Real, Sharon D.,Chen, Helen Y.
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p. 3397 - 3400
(2007/10/02)
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- Bentonitic Earth Catalyzed Rearrangement of Aryl 1,1-Dimethyl-propargyl Ethers. Synthesis of 2,2-Dimethyl-2H-1-benzopyrans
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Mexican Bentonitic earth (Tonsil) catalyzed the Claisen rearrangement of aryl 1,1-dimethylpropargyl ethers under mild conditions to provide 2,2-dimethyl-2H-1-benzopyrans.The synthesis of encecalin 2f and desmethoxyencecalin 2i, two biologically active products among other natural products (2b, 2e) was performed by this procedure.
- Cruz-Almanza, Raymundo,Perez-Flores, Francisco,Brena, Leonardo,Tapia, Eva,Ojeda, Reyna,Fuentes, Aidee
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p. 219 - 222
(2007/10/02)
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- Copper(I) iodide: A catalyst for the improved synthesis of aryl propargyl ethers
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Copper(I) iodide catalyses the reaction between phenols and dialkylpropargyl chlorides to give aryl 1,1-dialkylpropargyl ethers 5 a-k and 7a-e in good yields and purity. These ethers are important as precursors to the 2H-1-benzopyrans 8a-l and 9a-e.
- Bell,Davies,Geen,Mann
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p. 707 - 712
(2007/10/02)
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- REGIOSELECTIVE PRENYLATION OF PHENOLS BY PALLADIUM CATALYST: SYNTHESES OF PRENYLPHENOLS AND CHROMANS
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The palladium-catalyzed coupling reaction of iodophenols (1) with 2-methyl-3-butyn-2-ol gave alkynylphenols (2).Catalytic hydrogenation of 2 over Raney nickel and the subsequent dehydration of the resultant alkylphenols (3) gave regioselectively the desired prenylphenols (4).Dehydration of alkylphenols (3f-h) gave chromans (7).
- Tsukayama, Masao,Kikuchi, Makoto,Kawamura, Yasuhiko
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p. 1487 - 1490
(2007/10/02)
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- A new synthesis of desmethoxyencecalin
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A new synthesis of the title compound using aryllithium salts as key intermediates is described. The synthetic approach is mainly based on a cyclization reaction that mimics the process by which is believed benzopyran rings are formed in nature.
- Cruz-Almanza,Perez-Flores,Cardenas,Vazquez,Fuentes
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p. 1009 - 1018
(2007/10/02)
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- Benzopyran derivatives and processes for preparation thereof
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Benzopyrene derivatives effective for the treatment of hypertension have been prepared.
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- Acylation of 2,2-Dimathyl-2H-chromenes
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Orientation in acylation reactions of 2,2-dimethyl-2H-chromenes was studied.Five acetylchromenes were obtained with two methods and six formylchromenes were obtained with a third method.Demethylation of four acyl-methoxy-substituted chromenes gave the corresponding acylchromenols. 2,2-Dimethyl-2H-chromene-6-carboxylic acid (anofinic acid) was also obtained by oxidation of 6-formylchromene.
- Yamaguchi, Seiji,Yamamoto, Satoru,Abe, Shoichi,Kawase, Yoshiyuki
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p. 442 - 445
(2007/10/02)
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- Synthesis of 6-(1-Hydroxyethyl)-2,2-dimethyl-2H--benzopyrans: Eupatoriachromene-C and Desmethoxyencecalinol
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6-Acetyl-5,8-dimethoxy-2,2-dimethyl-2H--benzopyran (2) on reduction with potassium borohydride gives eupatoriochromene-C (1).Condensation of 4-Hydroxyacetophenone with isoprene in the presence of orthophosphoric acid gives the chroman (5) which on dehydrogenation with NBS furnishes desmethoxyencecalin (4). 4 on reduction with potassium borohydride affords desmethoxyencecalinol (3).Alternatively, 4-hydroxybenzaldehyde on condensation with isoprene gives the monochroman (6) which is also obtained by a similar condensation of 4-methylphenol with isoprene followed by reaction with DDQ.Dehydrogenation of 6 with NBS affords 6-formyl-2,2-dimethyl-2H--benzopyran (8) and 6-phenacyl bromide derivative (9). 8 on reaction with methylmagnesium iodide furnishes 3.
- Ahluwalia, V. K.,Mukherjee, Irani,Mukherjee, Keya
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p. 1124 - 1125
(2007/10/02)
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- Synthesis and antihypertensive activity of substituted trans-4-amino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ols
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A series of novel substituted trans-4-amino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ols was prepared and tested for antihypertensive activity in the conscious deoxycorticosterone acetate (DOCA)/saline treated hypertensive rat. Optimum blood pressure lowering activity requires 6-substitution by a strong electron-withdrawing group, together with a pyrrolidino or piperidino group at the 4 position. Exceptions to this were the 7-nitro-4-pyrrolidine analogue and the 6-nitro-3-chloropropylamine, which retained marked antihypertensive activity. All of these compounds were direct vasodilators and had comparable antihypertensive activity to hydralazine and to the calcium antagonist, nifedipine. The synthetic route to these compounds involves cyclization of propargyl ethers to 2H-1-benzopyrans, followed by conversion via bromohydrins to 3,4-epoxides, which were ring opened with the appropriate amines. Meta-substituted propargyl ethers gave both 5- and 7-substituted benzopyrans on thermal cyclization, the former predominating. A new route to 2,2-dimethyl-7-nitrobenzopyran is described.
- Evans, John M.,Fake, Charles S.,Hamilton, Thomas C.,Poyser, Robert H.,Watts, Eric A.
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p. 1582 - 1589
(2007/10/02)
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- Hypotensive 3,4-dihydro-2,2-dimethyl-4-amino-2H-benzo[b]pyran-3-ols
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Amino chromanols, their preparation and anti-hypertensive compositions containing the compounds in hypotensive amounts with a pharmaceutically acceptable carrier for oral or parenteral administration. Pharmaceutically acceptable salts and O-acyl, particularly O-acetyl, derivatives are described. The compounds exist as racemates and optically active isomers.
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