- Redox-Neutral Coupling between Two C(sp3)?H Bonds Enabled by 1,4-Palladium Shift for the Synthesis of Fused Heterocycles
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The intramolecular coupling of two C(sp3)?H bonds to forge a C(sp3)?C(sp3) bond is enabled by 1,4-Pd shift from a trisubstituted aryl bromide. Contrary to most C(sp3)?C(sp3) cross-dehydrogenative couplings, this reaction operates under redox-neutral conditions, with the C?Br bond acting as an internal oxidant. Furthermore, it allows the coupling between two moderately acidic primary or secondary C?H bonds, which are adjacent to an oxygen or nitrogen atom on one side, and benzylic or adjacent to a carbonyl group on the other side. A variety of valuable fused heterocycles were obtained from easily accessible ortho-bromophenol and aniline precursors. The second C?H bond cleavage was successfully replaced with carbonyl insertion to generate other types of C(sp3)-C(sp3) bonds.
- Rocaboy, Ronan,Anastasiou, Ioannis,Baudoin, Olivier
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p. 14625 - 14628
(2019/09/16)
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- Pharmaceutical preparation containing copolyvidone
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A stabilized preparation which comprises: a unstable drug in a polyethylene glycol-containing preparation; and a coating agent comprising a copolyvidone instead of polyethylene glycol with which the drug is coated.
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Page/Page column 38
(2018/11/06)
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- Dihydrofuran and yinyin alkane - imidazole salt compound and its preparation method
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The invention discloses a series of dihydrofuran indenoane-imidazole salts compounds and a preparation method thereof. The preparation method comprises the following steps of: carrying out Vilsmeier reaction and Perskin reaction on 2,3-dihydrobenzofuran taken as a raw material; reducing palladium/carbon in an acetic acid to 5-propionic acid dihydrobenzofuran and forming acyl chloride with thionyl chloride; carrying out intramolecular Friedel-Crafts reaction and reducing in an alcohol solution by using sodium borohydride to obtain dihydrofuran indenoanol; forming a chloride in a toluene solution with the thionyl chloride; and reflowing and reacting with imidazole or 2-methyl imidazole or 2-ethyl imidazole or benzimidazole in acetonitrile or a toluene solvent to synthesize 1-(dihydrofuran indenoane) imidazole, and reacting with a halide on the above basis to synthesize the compound. According to the dihydrofuran indenoane-imidazole salts compounds and the preparation method thereof, pharmacophores with obvious tumor resisting activity in natural products are used as precursors to carry out designing and synthesizing on anti-tumor medicine molecule, and when an imidazole structure unit in a synthesized compound is the benzimidazole, particularly a naphthoyl methyl imidazole salts compound, the compound has very good in-vitro anticancer physiological activity.
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Paragraph 0035-0036
(2017/08/02)
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- Method for recovering and utilizing byproduct of chlorination of phosphorus pentachloride
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The invention relates to a technology for comprehensively utilizing the byproduct of chlorination of phosphorus pentachloride, and mainly relates to a post treatment, which scientifically utilizes the excess phosphorus pentachloride reagent. The byproduct is converted into an organic synthesis reagent with a wide application range. The wastes are converted into a valuable resource. The discharge of waste water, waste gas, and waste solid is reduced. The obtained reagent is an excellent active reagent, which is widely used in the chemical industry, pharmacy industry, and material industry. The production cost is reduced, and the environment is protected.
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Paragraph 0032-0033
(2017/08/28)
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- Selective reduction of carboxylic acids to aldehydes with hydrosilane: Via photoredox catalysis
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The direct reduction of carboxylic acids to aldehydes with hydrosilane was achieved through visible light photoredox catalysis. The combination of both single electron transfer and hydrogen atom transfer steps offers a novel and convenient approach to selective reduction of carboxylic acids to aldehydes. The method also features mild conditions, high yields, broad substrate scope, and good functional group tolerance, such as alkyne, ester, ketone, amide and amine groups.
- Zhang, Muliang,Li, Nan,Tao, Xingyu,Ruzi, Rehanguli,Yu, Shouyun,Zhu, Chengjian
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supporting information
p. 10228 - 10231
(2017/09/22)
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- Nucleophilicity Parameters of Stabilized Iodonium Ylides for Characterizing Their Synthetic Potential
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Kinetics and mechanisms of the reactions of the β-dicarbonyl-substituted iodonium ylides 1(a-d) with several π-conjugated carbenium and iminium ions have been investigated. All reactions proceed with rate-determining attack of the electrophile at the nucleophilic carbon center of the ylides to give iodonium ions, which rapidly expel iodobenzene and undergo different subsequent reactions. The second-order rate constants k2 for the reactions of the iodonium ylides with benzhydrylium ions correlate linearly with the electrophilicity parameters E of the benzhydrylium ions and thus follow the linear free energy relationship log k(20 °C) = sN(N + E) (eq 1), where electrophiles are characterized by one parameter (E), while nucleophiles are characterized by two parameters: the nucleophilicity N and the susceptibility sN. The nucleophilicity parameters 4 + at the carbanionic center of Meldrum's acid or dimedone, respectively, reduces the nucleophilicity by approximately 10 orders of magnitude. The iodonium ylides 1(a-d) thus have nucleophilicities similar to those of pyrroles, indoles, and silylated enol ethers and, therefore, should be suitable substrates in iminium-activated reactions. Good agreement of the measured rate constant for the cyclopropanation of the imidazolidinone-derived iminium ion 10a with the iodonium ylide 1a with the rate constant calculated by eq 1 suggests a stepwise mechanism in which the initial nucleophilic attack of the iodonium ylide at the iminium ion is rate-determining. The reaction of cinnamaldehyde with iodonium ylide 1a catalyzed by (5S)-5-benzyl-2,2,3-trimethyl-imidazolidin-4-one (11a, MacMillan's first-generation catalyst) gives the corresponding cyclopropane with an enantiomeric ratio of 70/30 and, thus, provides proof of principle that iodonium ylides are suitable substrates for iminium-activated cyclopropanations.
- Chelli, Saloua,Troshin, Konstantin,Mayer, Peter,Lakhdar, Sami,Ofial, Armin R.,Mayr, Herbert
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supporting information
p. 10304 - 10313
(2016/09/03)
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- Novel tricyclic indeno[5,6-b]furan-imidazole hybrid compounds: Design, synthesis and antitumor activity
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A series of novel hybrid compounds between tricyclic indeno[5,6-b]furan and imidazole has been prepared and evaluated in vitro against a panel of human tumor cell lines. The results suggest that the existence of benzimidazole ring and substitution of the imidazolyl-3-position with a naphthylacyl group were vital for modulating cytotoxic activity. In particular, hybrid compound 26 was found to be the most potent compound against 5 strains human tumor cell lines and more active than cisplatin (DDP), while compound 18 was more selective towards breast carcinoma (MCF-7) and colon carcinoma (SW480) with IC50 value 3.4-fold and 4.3-fold more sensitive to DDP.
- Chen, Wen,Yang, Li-Juan,Li, Yan,Wang, Xue-Quan,Wang, Shao-Jie,Wan, Wei-Chao,Zhang, Hong-Bin,Yang, Xiao-Dong
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p. 561 - 571
(2013/08/23)
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- PROCESS FOR PREPARATION OF (S)-N-[2-(1,6,7,8-TETRAHYDRO-2H-INDENO[5,4-B]FURAN-8-YL)ETHYL] PROPIONAMIDE AND NOVEL INTERMEDIATES THEREOF
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Disclosed herein process for preparation of (S)-Ramelteon and intermediates thereof.
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Page/Page column 28
(2010/04/28)
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- PROCESS FOR THE SYNTHESIS OF RAMELTEON AND ITS INTERMEDIATES
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The present invention provides processes and intermediates for the synthesis of ramelteon.
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Page/Page column 45
(2009/01/24)
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- PROCESS OF MAKING RAMELTEON AND RELATED SUBSTANCES
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The present patent application provides a process for the preparation of compounds of the Formula (I) Wherein represents a single bond or a double bond. R represents ethyl, vinyl or ethynyl.
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Page/Page column 29
(2009/01/24)
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- PROCESS FOR PRODUCTION OF OPTICALLY ACTIVE AMINE DERIVATIVES
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An industrial process for production of high-purity optically active amine derivatives in high yield while inhibiting the formation of by-products, which comprises subjecting (E)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-ylidene)ethylamine to asymmetric reduction, catalytically reducing the obtained product at a reaction temperature of 40 to 100°C and a pH of 3 to 9, subjecting the obtained (S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine to propionylation, and then crystallizing the reaction mixture.
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Page/Page column 11
(2008/06/13)
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- Condensed indoline derivatives and their use as 5HT, in particular 5HT2c, receptor ligands
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A chemical compound of formula (I) wherein R1 and R2 are independently selected from hydrogen and alkyl; R3 is alkyl; R4 and R5 are selected from hydrogen and alkyl; R6 and R7 are independently selected from hydrogen, halogen, hydroxyl, alkyl, aryl, amino, alkylamino, dialkylamino, alkoxy, aryloxy, alkylthio, alkylsulfoxyl, nitro, carbonitrile, carbo-alkoxy, carbo-aryloxy and carboxyl; and A is a 5- or 6-membered ring optionally containing one or more heteroatoms wherein the atoms of the ring A, other than the unsaturated carbon atoms of the phenyl ring to which the ring A is fused, are saturated or unsaturated, and pharmaceutically acceptable salts, addition compounds and prodrugs thereof; and the use thereof in therapy, particularly as an agonist or antagonist of a 5HT receptor, particularly a 5HT2C receptor, for instance in the treatment of disorders of the central nervous system; damage to the central nervous system; cardiovascular disorders; gastrointestinal disorders; diabetes insipidus, and sleep apnea, and particularly for the treatment of obesity.
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Page/Page column 8
(2010/02/13)
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- Pharmaceutical preparation containing copolyvidone
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A stabilized preparation which comprises: a unstable drug in a polyethylene glycol-containing preparation; and a coating agent comprising a copolyvidone instead of polyethylene glycol with which the drug is coated.
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- C17,20-lyase inhibitors. Part 2: Design, synthesis and structure-activity relationships of (2-naphthylmethyl)-1H-imidazoles as novel C17,20-lyase inhibitors
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A series of 1- and 4-(2-naphthylmethyl)-1H-imidazoles (3 and 4) has been synthesized and evaluated as C17,20-lyase inhibitors. Several 6-methoxynaphthyl derivatives showed potent C17,20-lyase inhibition, suppression of testosterone biosynthesis in rats and reduction in the weight of prostate and seminal vesicles in rats, whereas most of these compounds increased the liver weight after consecutive administrations. The effect on the liver weight was removed by incorporation of a hydroxy group and an isopropyl group at the methylene bridge, as seen in (S)-28d and (S)-42. Selectivity for C 17,20-lyase over 11β-hydroxylase is also discussed, and (S)-42 was found to be a more than 260-fold selective inhibitor. Furthermore, (S)-42 showed a potent suppression of testosterone biosynthesis after a single oral administration in monkeys. These data suggest that (S)-42 may be a promising agent for the treatment of androgen-dependent prostate cancer.
- Matsunaga, Nobuyuki,Kaku, Tomohiro,Ojida, Akio,Tanaka, Toshimasa,Hara, Takahito,Yamaoka, Masuo,Kusaka, Masami,Tasaka, Akihiro
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p. 4313 - 4336
(2007/10/03)
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- Imidazol-4-ylmehanols and their use as inhibitors of steroid C17-20 lyase
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Imidazol-4-ylmethanols and their uses for preventing and treating primary tumors, metastasis and recurrence of tumors, various symptoms accompanying tumors, prostatic hypertrophy, virilism, hirsutism, male pattern alopecia, precocious puberty, endometriosis, uterine myoma, mastopathy and polycystic ovary syndrome are disclosed.
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- PHARMACEUTICAL PREPARATION CONTAINING COPOLYVIDONE
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A stabilized preparation which comprises: a unstable drug in a polyethylene glycol-containing preparation; and a coating agent comprising a copolyvidone instead of polyethylene glycol with which the drug is coated.
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- Method for treating or preventing sleep disorders
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The present invention provides a pharmaceutical composition for treating or preventing sleep disorders which comprises (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide in combination with at least one active component selected from zolpidem, zopiclone, triazolam and brotizolam.
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- Synthesis of a novel series of tricyclic indan derivatives as melatonin receptor agonists
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To develop a new therapeutic agent for sleep disorders, we synthesized a novel series of tricyclic indan derivatives and evaluated them for their binding affinity to melatonin receptors. In our previous paper, we proposed a conformation of the methoxy group favorable for the binding of the MT1 receptor. To fix the methoxy group in an active conformation, we decided to synthesize conformationally restricted tricyclic indan analogues with the oxygen atom in the 6-position incorporated into a furan, 1,3-dioxane, oxazole, pyran, morpholine, or 1,4-dioxane ring system. Among these compounds, indeno[5,4-b]furan analogues were found to be the most potent and selective MT1 receptor ligands and to have superior metabolic stability. The optimization of substituents led to (S)-(-)-22b, which showed very strong affinity for human MT1 (Ki = 0.014 nM), but no significant affinity for hamster MT3 (Ki = 2600 nM) or other neurotransmitter receptors. The pharmacological effects of (S)-(-)-22b were studied in experimental animals, and it was found that a dose of 0.1 mg/kg, po promoted a sleep in freely moving cats, as demonstrated by a decrease in wakefulness and increases in slow wave sleep and rapid eye movement sleep, which lasted for 6 h after administration. Melatonin (1 mg/kg, po) also had a sleep-promoting effect, though it lasted only 2 h. A new chiral method for the synthesis of (S)-(-)-22b starting from 60, which was prepared from 59 employing asymmetric hydrogenation with the (S)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl-Ru complex, was developed. (S)-(-)-22b (TAK-375) is currently under clinical trial for the treatment of insomnia and circadian rhythm disorders.
- Uchikawa, Osamu,Fukatsu, Kohji,Tokunoh, Ryosuke,Kawada, Mitsuru,Matsumoto, Kiyoharu,Imai, Yumi,Hinuma, Shuji,Kato, Koki,Nishikawa, Hisao,Hirai, Keisuke,Miyamoto, Masaomi,Ohkawa, Shigenori
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p. 4222 - 4239
(2007/10/03)
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- Bicyclic compounds and pharmaceutical composition containing tricyclic compound for treating or preventing sleep disorders
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A compound having the following general fomula: wherein R1 is an optionally substituted hydrocarbon, amino or heterocyclic group; R2 is H or an optionally substituted hydrocarbon group; R3 is H or an optionally substituted hydrocarbon or heterocyclic group; X is CHR4, NR4, O or S in which R4 is H or an optionally substituted hydrocarbon group; R5 is H, a halogen atom, C1-6 alkyl group, a C1-6 alkoxy group, a hydroxy group, a nitro group, a cyano group or an amino group wherein the C1-6 alkyl group, the C1-6 alkoxy group and the amino group may be substituted by 1 to 5 substituents, Y is C or N; ring B is an optionally substituted benzene ring; m = 1 to 4 and n = 0 to 2; L represents a leaving group such as a halogen atom, an alkylsulfonyl group, an alkylsulfonlyoxy group and arylsulfonyloxy group; or a salt thereof.
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Referential example 1
(2010/11/29)
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- A practical approach to highly functionalized benzodihydrofurans
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A number of aromatic dibromides have been treated with 2-3 equivalents of n-butyllithium in order to initiate two sequential chemical events, a Parham cyclization and an intermolecular reaction with DMF. (C) 2000 Elsevier Science Ltd.
- Plotkin, Michael,Chen, Sanyou,Spoors, P. Grant
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p. 2269 - 2273
(2007/10/03)
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- Tricyclic compounds, their production and use
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A compound of the formula: STR1 wherein R1 is an optionally substituted hydrocarbon, amino or heterocyclic group; R2 is H or an optionally substituted hydrocarbon group; R3 is H or an optionally substituted hydrocarbon or heterocyclic group; X is CHR4, NR4, O or S in which R4 is H or an optionally substituted hydrocarbon group; Y is C, CH or N; ring A is optionally substituted 5- to 7-membered ring; ring B is an optionally substituted benzene ring; and m is 1 to 4, or a salt thereof, a process for producing it, an intermediate for the production and a pharmaceutical composition comprising it are provided.
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- Endothelin antagonists
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A compound of the formula (I): or a pharmaceutically acceptable salt thereof is disclosed, as well as processes for and intermediates in the preparation thereof, and a method of antagonizing endothelin.
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- ENDOTHELIN ANTAGONISTS
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A compound of the formula (I): STR1 or a pharmaceutically acceptable salt thereof is disclosed, as well as processes for and intermediates in the preparation thereof, and a method of antagonizing endothelin.
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- Potent and selective non-benzodioxole-containing endothelin-A receptor antagonists
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The benzodioxole ((methylenedioxy)benzene) group is present in a number of endothelin (ET) receptor antagonists thus far reported. As part of our own endothelin antagonist program we have developed (2R*,3R*,4S*)-1-(N,N- dibutylacetamido)-4-(1,3-benzodioxol-5-yl)-2-(4-methoxyphenyl)pyrrolidine-3- carboxylic acid (A-127722). This is a potent antagonist, binding to the ET(A) and ET(B) receptor subtypes with affinities (IC50) of 0.4 and 520 nM, respectively, and also contains the aforementioned benzodioxole. While this compound was seemingly optimized at its N-terminus, no effort had been directed toward understanding the contributions to binding affinity or receptor subtype selectivity conferred by the benzodioxole. Substitution by 1- or 2-naphthyl yielded weak antagonists. Oxygenated benzenes, such as p- anisyl, were potent compounds with IC50s in the low-nanomolar range. Simple deletion of either of the two oxygen atoms (dihydrobenzofurans) yielded extremely potent agents, possessing subnanomolar affinity for the ET(A) receptor. Additionally, the compounds showed enhanced selectivity, binding to the ET(B) receptor subtype in the micromolar range. This paper describes the development of this novel class of compounds.
- Tasker, Andrew S.,Sorensen, Bryan K.,Jae, Hwan-Soo,Winn, Martin,Von Geldern, Thomas W.,Dixon, Douglas B.,Chiou, William J.,Dayton, Brian D.,Calzadila, Samuel,Hernandez, Lisa,Marsh, Kennan C.,WuWong, J. Ruth,Opgenorth, Terry J.
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p. 322 - 330
(2007/10/03)
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- ENDOTHELIN ANTAGONISTS
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A compound of the formula (I): STR1 or a pharmaceutically acceptable salt thereof is disclosed, as well as processes for and intermediates in the preparation thereof, and a method of antagonizing endothelin.
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- UROKINASE INHIBITORS
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Disclosed are benzothiophene and thienothiophene derivatives useful for inhibiting urokinase activity.
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- Synthesis and Pharmacological Examination of Benzofuran, Indan, and Tetralin Analogues of 3,4-(Methylenedioxy)amphetamine
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Benzofuran, indan and tetrahydronaphthalene analogs of 3,4-(methylenedioxy)amphetamine (MDA) were prepared in order to examine the role of the dioxole ring oxygen atoms of MDA in interacting with the serotonin and catecholamine uptake carriers.The series of compounds was evaluated for discriminative stimulus effects in rats trained to discriminate saline from the training drugs (S)-(+)-MBDB (1c), MMAI (3), and (S)-(+)-amphetamine and for the ability to inhibit the uptake of 3H>serotonin, 3H>dopamine, and 3H>norepinephrine into crude synaptosome preparations.Behaviorally, the benzofuran and indan analogs 4-6 produced similar discriminative cues, whereas the tetralin derivative 7 did not fully substitute for the training drugs.The results in the in vitro pharmacology studies indicate that selectivity for 5-HT versus catecholamine uptake carriers may be modulated by the position and orientation of ring oxygen atoms.However, the nonoxygenated isostere 6 possessed high potency at all uptake sites examined.Enlargement of the saturated ring by one methylene unit to give the tetralin derivative resulted in a large (3-4-fold) reduction in activity at catecholamine sites.
- Monte, Aaron P.,Marona-Lewicka, Danuta,Cozzi, Nicholas V.,Nichols, David E.
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p. 3700 - 3706
(2007/10/02)
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- Carbon-13 Nuclear Magnetic Resonance Studies of Carbocations. 10. Variation of Cationic Carbon Chemical Shifts with Increasing Electron Demand in 1,1-Diaryl-1-methyl (Benzhydryl) Carbocations
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A series of 28 1-X-phenyl-1-Z-phenyl-1-methyl (benzhydryl) carbocations, where the X and Z substituents have been varied over the range of electron demand (3,4-CH2CH2O, 11; 4-OCH3, 12; 4-CH3, 13; 4-F, 14; 4-H, 1; 4-CF3, 15; 3,5-(CF3)2, 16), have been prepared from the corresponding alcohols by ionization in superacids and their 13C NMR spectra recorded at low temperatures (-70 to -10 deg C).Plots of the substituent chemical shifts of the cationic carbons (ΔδC+) at -70 deg C against ?C+ are linear for the electron donors (Z = 3,4-CH2CH2O to Z = H) of 13 - 16 and 1 but deviate upward from this correlation line (relative shielding) for the electron acceptors (Z = H to Z = 3,5-(CF3)2).The plots of the highly stabilized cations 11 and 12 approximate shallow curves where groups more electron demanding than 4-CH3 cause relative shielding of the cationic carbon.All these plots are interpreted in terms of competing resonance and localized inductive ?-polarization effects.
- Kelly, David P.,Jenkins, Margot J.
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p. 409 - 413
(2007/10/02)
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