- Practical Synthesis of (3a R, 9b R)-8-Fluoro-7-(perfluoropropan-2-yl)-9b-(phenylsulfonyl)-2,3,3a,4,5,9b-hexahydro-1 H-benzo[e]indole: An Advanced Intermediate to Access the RORγt Inverse Agonist BMT-362265
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A practical and scalable route to (3aR, 9bR)-8-fluoro-7-(perfluoropropan-2-yl)-9b-(phenylsulfonyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indole 10, an advanced intermediate en route to the synthesis of the RORγt inverse agonist, BMT-362265, is described starting from fluorobenzene. The synthesis involved the screening of multiple synthetic routes for their feasibility and scalability. We also demonstrate the utility of an annulating reagent, (R)-N-(2-chloroethyl)-2-methylpropane-2-sulfinamide, for the diastereoselective synthesis of tricyclic pyrrolidine intermediates 24 and 36 on a multigram scale.
- Karmakar, Ananta,Nimje, Roshan Y.,Silamkoti, Arundutt,Pitchai, Manivel,Basha, Mushkin,Singarayer, Christuraj,Ramasamy, Duraisamy,Babu, G. T. Venkatesh,Samikannu, Ramesh,Subramaniam, Srinath,Anjanappa, Prakash,Vetrichelvan, Muthalagu,Kumar, Hemantha,Dikundwar, Amol G.,Gupta, Anuradha,Gupta, Arun Kumar,Rampulla, Richard,Dhar, T. G. Murali,Mathur, Arvind
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p. 1001 - 1014
(2021/04/12)
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- Synthesis of Enantiopure ω-(4-Fluorophenyl)-6,11-Methylene Lipoxin B 4Methyl Ester
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The synthesis of Lipoxin B 4analogues (LXB 4) to gain access to stabilized inflammation-resolving compounds is an active field of research. Focusing on variation and stabilization of the conjugated E, Z, E, E C6-C13 tetraene moiety of natural LXB 4, a methylene bridge introduced between C6 and C11 suppresses any Z / E isomerization of the C8-C9 olefin. Furthermore, rapid ω-oxidation (C20) should be avoided by replacing the C18-C20 segment by an aromatic moiety. Optically active C1-C12 building blocks were accessed from methyl cycloheptatriene-1-carboxylate (C6-C11, C21) and glutaryl chloride (C1-C5) as described earlier. The ω-segment was generated via a five-step sequence starting from 4-arylbutanoic acid. Horner key olefination enabled assembly of the carbon backbone. A final five-step sequence including a chelate Cram reduction of the unsaturated ketone moiety afforded the target ω-aryl 6,11-methylene-LXB 4methyl ester.
- Trippe, Lukas,Nava, Analuisa,Frank, Andrea,Schollmeyer, Dieter,Nubbemeyer, Udo
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supporting information
p. 3760 - 3768
(2021/06/28)
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- Ligand-Controlled Regiodivergence in Nickel-Catalyzed Hydroarylation and Hydroalkenylation of Alkenyl Carboxylic Acids**
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A nickel-catalyzed regiodivergent hydroarylation and hydroalkenylation of unactivated alkenyl carboxylic acids is reported, whereby the ligand environment around the metal center dictates the regiochemical outcome. Markovnikov hydrofunctionalization products are obtained under mild ligand-free conditions, with up to 99 % yield and >20:1 selectivity. Alternatively, anti-Markovnikov products can be accessed with a novel 4,4-disubstituted Pyrox ligand in excellent yield and >20:1 selectivity. Both electronic and steric effects on the ligand contribute to the high yield and selectivity. Mechanistic studies suggest a change in the turnover-limiting and selectivity-determining step induced by the optimal ligand. DFT calculations reveal that in the anti-Markovnikov pathway, repulsion between the ligand and the alkyl group is minimized (by virtue of it being 1° versus 2°) in the rate- and regioselectivity-determining transmetalation transition state.
- Deng, Ruohan,Engle, Keary M.,Fu, Yue,Gao, Yang,Li, Zi-Qi,Liu, Peng,Tran, Van T.
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supporting information
p. 23306 - 23312
(2020/10/19)
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- Synthesis of Novel Pterocarpen Analogues via [3?+?2] Coupling-Elimination Cascade of α,α-Dicyanoolefins with Quinone Monoimines
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By employing triethylamine as a catalyst, [3?+?2] coupling-elimination cascade of α,α-dicyanoolefins with quinone monoimines was realized. The reactions afforded various novel pterocarpen analogues with generally moderate yields (up to 75%). In addition, a plausible reaction mechanism was proposed.
- Chen, Hui,Zhao, Sihan,Cheng, Shaobing,Dai, Xingjie,Xu, Xiaoying,Yuan, Weicheng,Zhang, Xiaomei
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p. 1672 - 1683
(2019/04/08)
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- Cooperative iodine and photoredox catalysis for direct oxidative lactonization of carboxylic acids
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A new method for the formation of γ- and δ-lactones from carboxylic acids through direct conversion of benzylic C-H to C-O bonds is described. The reaction is conveniently induced by visible light and relies on a mild cooperative catalysis by the combination of molecular iodine and an organic dye.
- Duhamel, Thomas,Mu?iz, Kilian
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p. 933 - 936
(2019/01/23)
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- Visible-light-induced oxidation/[3 + 2] cycloaddition/oxidative aromatization to construct benzo[ a]carbazoles from 1,2,3,4-tetrahydronaphthalene and arylhydrazine hydrochlorides
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An efficient synthesis of benzo[a]carbazoles via visible-light-induced tandem oxidation/[3 + 2] cycloaddition/oxidative aromatization reactions was reported. The benzylic C(sp3)-H of tetrahydronaphthalene was activated through visible-light photoredox catalyst with oxygen as the clean oxidant under mild reaction conditions. This protocol proceeds efficiently with broad substrate scope, and the mechanism study was performed.
- Shen, Jiaxuan,Li, Nannan,Yu, Yanjiang,Ma, Chunhua
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p. 7179 - 7183
(2019/09/30)
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- Strategic Approach to the Metamorphosis of γ-Lactones to NH γ-Lactams via Reductive Cleavage and C-H Amidation
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A new approach has elaborated on the conversion of γ-lactones to the corresponding NH γ-lactams that can serve as γ-lactone bioisosteres. This approach consists of reductive C-O cleavage and an Ir-catalyzed C-H amidation, offering a powerful synthetic tool for accessing a wide range of valuable NH γ-lactam building blocks starting from γ-lactones. The synthetic utility was further demonstrated by the late-stage transformation of complex bioactive molecules and the asymmetric transformation.
- Jung, Hoi-Yun,Chang, Sukbok,Hong, Sungwoo
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supporting information
p. 7099 - 7103
(2019/09/07)
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- Highly enantioselective [3+2] coupling of cyclic enamides with quinone monoimines promoted by a chiral phosphoric acid
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Enantioselective [3+2] coupling of cyclic enamides with quinone monoimines was realised using a chiral phosphoric acid as a catalyst. This transformation allowed for the synthesis of highly enantioenriched polycyclic 2,3-dihydrobenzofurans (up to 99.9% ee). The absolute configuration of one product was determined by an X-ray crystal structural analysis. We also found a possible mechanism for this reaction.
- Zhang, Minmin,Yu, Shuowen,Hu, Fangzhi,Liao, Yijun,Liao, Lihua,Xu, Xiaoying,Yuan, Weicheng,Zhang, Xiaomei
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supporting information
p. 8757 - 8760
(2016/07/15)
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- Metal-Free Enantioselective Oxidative Arylation of Alkenes: Hypervalent-Iodine-Promoted Oxidative C?C Bond Formation
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The enantioselective oxyarylation of (E)-6-aryl-1-silyloxylhex-3-ene was achieved using a lactate-based chiral hypervalent iodine(III) reagent in the presence of boron trifluoride diethyl etherate. The silyl ether promotes the oxidative cyclization, and enhances the enantioselectivity. In addition, the corresponding aminoarylation was achieved.
- Shimogaki, Mio,Fujita, Morifumi,Sugimura, Takashi
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supporting information
p. 15797 - 15801
(2016/12/16)
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- INHIBITORS OF HISTONE LYSINE SPECIFIC DEMETHYLASE (LSD1) AND HISTONE DEACETYLASES (HDACS)
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A series of phenelzine analogs comprising a phenelzine scaffold linked to an aromatic moiety and their use as inhibitors of lysine-specific demethylase 1 (LSD1) and/or one or more histone deacetylases (HDACs) is provided. The presently disclosed phenelzine analogs exhibit potency and selectivity for LSD1 versus MAO and LSD2 enzymes and exhibit bulk, as well as, gene specific histone methylation changes, anti-proliferative activity in several cancer cell lines, and neuroprotection in response to oxidative stress. Accordingly, the presently disclosed phenelzine analogs can be used to treat diseases, conditions, or disorders related to LSD1 and/or HDACs, including, but not limited to, cancers and neurodegenerative diseases.
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Page/Page column 98
(2015/09/28)
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- Discovery of a highly orally bioavailable c-5-[6-(4-Methanesulfonyloxyphenyl)hexyl]-2-methyl-1,3-dioxane-r-2-carbo xylic acid as a potent hypoglycemic and hypolipidemic agent
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A series of novel 1,3-dioxane-2-carboxylic acid derivatives containing alkyl chain tether and substituted phenyl group as a lipophilic tail have been prepared as agonists of PPARα and γ. c-5-[6-(4-Methanesulfonyloxyphenyl)hexyl]-2-methyl-1,3-dioxane-r-2-carbo xylic acid 13c exhibited potent hypoglycemic and lipid lowering activity with high oral bioavailability in animal models.
- Pingali, Harikishore,Jain, Mukul,Shah, Shailesh,Basu, Sujay,Makadia, Pankaj,Goswami, Amitgiri,Zaware, Pandurang,Patil, Pravin,Godha, Atul,Giri, Suresh,Goel, Ashish,Patel, Megha,Patel, Harilal,Patel, Pankaj
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scheme or table
p. 5586 - 5590
(2009/06/18)
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- AMINO ALCOHOL COMPOUND
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A pharmaceutical composition is provided that has a low toxicity, demonstrates superior physicochemical properties and pharmacokinetics, and has superior peripheral blood lymphocyte count lowering activity. The pharmaceutical composition contains a compound having general formula (I): (wherein R 1 represents a methyl group or an ethyl group, R 2 represents a methyl group or an ethyl group, and R 3 represents a phenyl group substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkyl group, a cycloalkyl group, a lower alkoxy group, a halogeno lower alkyl group, a lower aliphatic acyl group and a cyano group), a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof.
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Page/Page column 56
(2010/11/25)
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- 4,5-DIHYDRONAPHTHO [1,2-b] THIOPHENE DERIVATIVE
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A 4,5-dihydronaphtho[1,2-b]thiophene derivative expressed by the formula: (wherein R1 is a C1 to C10 1-hydroxyalkyl group or a C1 to C10 acyl group, and R2 and R3 separately substitute in the 6-, 7-, 8-, or 9-positions, and are each independently a hydrogen atom, a halogen atom, a C1 to C10 alkyl group, a hydroxy group, a C1 to C10 alkoxy group, a C1 to C5 alkenyloxy group, a C1 to C5 alkynyloxy group, a benzyloxy group, or the like, provided that when R1 is an acyl group and R2 is a hydrogen atom, then R3 is neither a hydrogen atom nor an acetyl group), or a pharmaceutically acceptable salt thereof. This is a novel compound that is effective in reducing triglyceride levels in the liver and reducing blood glucose levels.
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Page/Page column 12-13
(2010/11/08)
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- Synthesis of 1-tetralone derivatives using a Stille cross coupling/friedel crafts acylation sequence
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An efficient method of synthesis of 1-tetralones has been achieved featuring a Stille cross-coupling reaction as the key step.
- Vercouillie, Johnny,Abarbri, Mohamed,Parrain, Jean-Luc,Duchene, Alain,Thibonnet, Jerome
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p. 3751 - 3762
(2007/10/03)
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- FUSED IMIDAZOLE DERIVATIVE
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According to the present invention, fused imidazole derivatives of the general formula: wherein R1 is a hydrogen atom, a halogen atom, hydroxy group, a lower alkyl group or a lower alkoxy group, R2 is an aryl group, benzodioxanyl group, or 5-6 membered, monocyclic, unsaturated, heterocyclic group containing nitrogen atom(s) which may be substituted with lower alkyl, trityl or oxo, R3 is a hydrogen atom or hydroxy group, A is a group represented by the formula : -(CH2)m - or -O-(CH2)m- [wherein m is an integer of 1-3] and their salts are provided.
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- Indoles
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A 1,4-substituted cyclic amine derivative represented by the following formula or a pharmacologically acceptable salt thereof: wherein A, B, C, D, T, Y, and Z each represent a methine or a nitrogen linkage; R1, R2, R3, R4, and R5 each represent a substituent; n represents 0 or an integer of 1 to 3; m represents 0 or an integer of 1 to 6; and p represents an integer of 1 to 3. The compounds have serotonin antagonism. They are therefore clinically useful as medicaments, in particular, for treating, ameliorating, and preventing spastic paralysis. They are also useful as central muscle relaxants for ameliorating myotonia.
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- Imidazole compounds
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A novel class of imidazo heterocyclic compounds, pharmaceutical compositions comprising them and use thereof in the treatment and/or prevention of diseases and disorders related to the histamine H3 receptor. More particularly, the compounds are useful for the treatment and/or prevention of diseases and disorders in which an interaction with the histamine H3 receptor is beneficial.
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- Bicyclic amide derivatives and their use as muscle relaxants
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Novel compounds of formula (1) together with their salts and solvates have a number of uses in medicine, in particular as central muscle relaxants.
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- Bicyclic amide derivatives and their use as muscle relaxants
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Novel compounds of formula (I) STR1 wherein R1, R2, R3 and R4 are each selected from hydrogen and fluoro and at least one and not more than two is fluoro; R5 is selected from hydrogen and C1 -C4 alkyl; R6 is selected from hydrogen, C1 -C4 ally and hydroxy; or R5 and R6 together with the ring carbon form a carbonyl group; R7 is selected from hydrogen and hydroxy, R8 and R9 are each selected from hydrogen, C1 -C4 alkyl and cyclo(C3 or C4) alkyl or together with the nitrogen form a morpholino group; and X is selected from a bond, methylene and --O-- and is always a bond or --O-- when any of R5, R6 and R7 is other than hydrogen and is always a bond when R5 and R6 together with the ring carbon form a carbonyl group; and their salts and solvates have a number of uses as central muscle relaxants. In particular, treatment of conditions associated with abnormally raised skeletal muscle tone. They are of special value in the relaxation of skeletal muscle in spastic, hypertonic and hyperkinetic conditions.
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- Amide derivatives and their therapeutic use
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Novel carbocyclic amides together with their salts, solvates and physiologically active derivatives which have a number of uses in medicine, in particular as central muscle relaxants, and in the treatment or prophylaxis of anxiety, inflammation, arthritis and pain.
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- Synthesis of potent non-imidazole histamine H3-receptor antagonists
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Histamine has been converted into a non-imidazole H3-receptor histamine antagonist by addition of a 4-phenylbutyl group at the N(α)-position followed by removal of the imidazole ring. The resulting compound, N-ethyl- N-(4-phenylbutyl)amine, remarkably has a Ki = 1.3 μM as an H3 antagonist. Using this as a lead compound, a novel series of homologous O and S isosteric tertiary amines was synthesised and structure-activity studies furnished N- (5-phenoxypentyl)pyrrolidine (Ki = 0.18 ± 0.10 μM, for [3H]histamine release from rat cerebral cortex synaptosomes) which, more importantly, was active in vivo. Substitution of NO2 into the para position of the phenoxy group gave N-(5-p-nitrophenoxypentyl)pyrrolidine, UCL 1972 (Ki= 39 ± 11 nM), ED50 = 1.1 ± 0.6 mg/kg per os in mice on brain tele-methylhistamine levels.
- Ganellin, C. Robin,Leurquin, Fabien,Piripitsi, Antonia,Arrang, Jean-Michel,Garbarg, Monique,Ligneau, Xavier,Schunack, Walter,Schwartz, Jean-Charles
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p. 395 - 404
(2007/10/03)
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- Synthesis of 6/7-halotetralones
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The title compounds were prepared from halobromobenzenes via a palladium catalysed coupling followed by cyclisation.
- Owton,Brunavs
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p. 981 - 987
(2007/10/02)
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