- tert-Amino effect in heterocyclic chemistry. Synthesis of hydrogenated spiro derivatives of quinolines
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A new method was developed for the one-step synthesis of spiro derivatives of fused quinolines by the reactions of ortho-amino derivatives of benzaldehyde with Meldrum's acid, cyclohexane-1,3-dione, or N,N′-disubstituted barbituric acids.
- D'yachenko,Glukhareva,Nikolaenko,Tkachev,Morzherin
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Read Online
- Double Capture of Difluorocarbene by 2-Aminostyrenes Enables the Construction of 3-(2,2-Difluoroethyl)-2-fluoroindoles
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We report herein an efficient strategy to construct 3-(2,2-difluoroethyl)-2-fluoroindoles from activated o-aminostyrenes with ethyl bromodi-fluoroacetate as a difluorocarbene source. Through double capture of a difluorocarbene, two different types of fluo
- Sheng, Heyun,Su, Jianke,Li, Xin,Li, Xue,Song, Qiuling
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supporting information
p. 7781 - 7786
(2021/10/25)
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- Hexafluoroisopropanol-Mediated Redox-Neutral α-C(sp3)-H Functionalization of Cyclic Amines via Hydride Transfer
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Hexafluoroisopropanol has been demonstrated as the versatile promoter for redox-neutral α-C(sp3)-H functionalization of cyclic amines via the cascade [1,5]-hydride transfer/cyclization strategy. A wide range of cyclic amines are functionalized
- Shen, Yao-Bin,Wang, Lin-Xuan,Sun, Yun-Ming,Dong, Feng-Ying,Yu, Liping,Liu, Qing,Xiao, Jian
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p. 1915 - 1926
(2020/02/04)
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- Development of TsDPEN based imine-containing ligands for the copper-catalysed asymmetric Kinugasa reaction
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A novel class of chiralN,N,Nimine-containing ligands derived from TsDPEN (N-(p-tosyl)-1,2-diphenylethylene-1,2-diamine) has been developed and applied to the copper-catalyzed asymmetric Kinugasa reaction. The copper(ii) salt proved to be an efficient catalyst precursor, and it provides an efficient way to synthesize enantioenrichedcis-β-lactam. The pathway is air-tolerant and easily manipulated, and the ligands are easy to synthesize. A working model is proposed in which the stereocontrolling step is the [2 + 2] cycloaddition between ketene and imine to explain the observed stereoselectivities.
- Deng, Ping,He, Feilong,He, Huakang,Wu, Yue,Xu, Chuanlong,Yang, Yuchen,Zhou, Hui
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p. 18107 - 18114
(2020/06/08)
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- Catalyst-free photodecarbonylation ofortho-amino benzaldehyde
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It is almost a consensus that decarbonylation of the aldehyde group (-CHO) needs to not only be mediated by transition metal catalysts, but also requires severe reaction conditions (high temperature and long reaction time). In this work, inspired by the “conformational-selectivity-based” design strategy, we broke this consensus and discovered a catalyst-free photodecarbonylation of the aldehyde group. It revealed that decarbonylation can be easily achieved with visible light irradiation by introducing a tertiary amine into theortho-position of the aldehyde group. A diverse array of tertiary amines is tolerated by our photodecarbonylation under mild conditions. Furthermore, the (QM) computations of the mechanism and the experiments on well-designed special substrates revealed that our photodecarbonylation depends on the conformational specificity of the aldehyde group and tertiary amine, and occurs through an unusual [1,4]-H shift and a subsequent [1,3]-H shift.
- Li, Lamei,Wang, Songping,Wei, Wentao,Yan, Ming,Zhou, Jingwei
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supporting information
p. 3421 - 3426
(2020/06/25)
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- Synthesis method of repaglinide
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The invention discloses a synthesis method of repaglinide, and belongs to the technical field of medicine synthesis. The method comprises the following steps that ortho-halogenated benzaldehyde is taken as a raw material, a 2-piperidine-1-benzaldehyde compound 1 is obtained through piperidine substitution and reacts with (R)-methylpropane-2-sulfinamide to obtain an imine compound 2, then the iminecompound 2 reacts with a 2-methyl-1-propylene Grignard reagent lithium chloride, and through reduction, an S-(+)-1-(2-piperidine phenyl)-3-methyl n-butylamine compound 3 is obtained; then the S-(+)-1-(2-piperidine phenyl)-3-methyl n-butylamine compound 3 and 4-carboxyl methyl-2-ethoxy benzoate are condensed to obtain an S-(+)-2-oxethyl-4-[N-{1-(2-piperidine phenyl)-3-methyl-1-butyl}amine carbonylmethyl]benzoate compound 4; finally, the repaglinide 5 is obtained through hydrolysis. Compared with other technologies, the synthesis method has the advantages that operation is simple, the raw materials are easy to obtain, the yield is high, the cost is low, and the method is environmentally friendly; the product repaglinide has very high optical purity and is suitable for industrial production.
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Paragraph 0067-0069
(2019/07/16)
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- N-Alkylation-Initiated Redox-Neutral [5 + 2] Annulation of 3-Alkylindoles with o-Aminobenzaldehydes: Access to Indole-1,2-Fused 1,4-Benzodiazepines
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Described herein is an unprecedented N-Alkylation-initiated redox-neutral [5 + 2] annulation of 3-Alkylindoles with o-Aminobenzaldehydes via a cascade N-Alkylation/dehydration/[1,5]-hydride transfer/Friedel-Crafts alkylation sequence. A series of indole-1,2-fused 1,4-benzodiazepines are facilely constructed in moderate to good yields in one step. This protocol features excellent regioselectivity, metal-free conditions, high step economy, and wide substrate scope.
- Wang, Shuai,Shen, Yao-Bin,Li, Long-Fei,Qiu, Bin,Yu, Liping,Liu, Qing,Xiao, Jian
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supporting information
p. 8904 - 8908
(2019/11/19)
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- Alkyl Radical Addition to Aliphatic and Aromatic N-Acylhydrazones Using an Organic Photoredox Catalyst
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Increased versatility of intermolecular radical addition to imino acceptors via photoredox catalysis is reported. Primary and secondary radicals, generated via visible-light photocatalysis from alkyl biscatecholatosilicates with organocatalyst 4CzIPN, add
- Cullen, Stephen T. J.,Friestad, Gregory K.
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supporting information
p. 8290 - 8294
(2019/10/21)
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- Spirocyclic Tetramates by Sequential Knoevenagel and [1,5]-Prototropic Shift
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Highly functionalized spirocyclic tetramates were prepared via a sequential Knoevenagel reaction and [1,5]-prototropic shift (T-reaction) of bicyclic tetramates. While these compounds isomerize in solution, stable analogues can be prepared via an appropri
- Josa-Culleré, Laia,Hirst, Michael G.,Lockett, Jonathan P.,Thompson, Amber L.,Moloney, Mark G.
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p. 9671 - 9683
(2019/09/06)
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- BF3·OEt2-Promoted Propargyl Alcohol Rearrangement/[1,5]-Hydride Transfer/Cyclization Cascade Affording Tetrahydroquinolines
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An efficient BF3·OEt2-mediated propargyl alcohol rearrangement/[1,5]-hydride transfer/cyclization cascade for the synthesis of tetrahydroquinoline derivatives has been described. The substituents adjacent to triple bonds play an important role in the formation of ketones (via [1,3]-hydroxyl shift) or alkenyl fluorides which are products of formal trans-carbofluorination of internal alkynes. This method provides a rapid access to diverse heterocycles in moderate to excellent yields.
- Zhao, Shuang,Wang, Xiaoyang,Wang, Pengfei,Wang, Guangwei,Zhao, Wentao,Tang, Xiangyang,Guo, Minjie
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supporting information
p. 3990 - 3993
(2019/06/14)
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- Investigation of the [1,5]-hydride shift as a route to nitro-Mannich cyclisations
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Conditions were found for the [1,5]-hydride shift nitro-Mannich reaction that led to the synthesis of 2,3-disubstituted tetrahydroquinolines. Two simple cyclic amine substrates gave diastereomerically pure rearranged products in 65 and 90% yields by refluxing in HFIP. A more general procedure used Gd(OTf)3 as a catalyst and successfully rearranged other cyclic and acyclic amines in 42–84% yield with diastereomeric ratios of 75:25 to >95:5 in favour of the anti-diastereoisomer (9 examples). Two examples of sulphur containing heterocycles gave lower yields of 9 and 25%. Electron withdrawing substituents were shown to have a deleterious effect on the success of the reaction. The results indicated the limitation of the [1,5]-hydride shift nitro-Mannich reaction with respect to the stability of the intermediate iminium ion.
- Anderson, James C.,Chang, Chia-Hao,Corpinot, Mérina K.,Nunn, Michael,Ware, Oliver J.
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- NOVEL IMIDAZOLE COMPOUND AND USE THEREOF AS MELANOCORTIN RECEPTOR AGONIST
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The present invention relates to a novel imidazole compound or a pharmaceutically acceptable salt thereof having a melanocortin receptor agonistic activity, and medical use thereof. The present invention relates to an imidazole compound represented by general formula [I] [wherein: Ring A represents an optionally substituted aryl group or the like; R1 represents a hydrogen atom, an optionally substituted alkyl group, or the like; R2 represents a hydrogen atom, a halogen atom, or the like; and R3 represents an optionally substituted alkyl group] or a pharmaceutically acceptable salt thereof.
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Paragraph 0496
(2018/10/04)
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- Pharmaceutical compositions (by machine translation)
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[Problem] imidazole compound or its pharmacologically acceptable salt in the melanocortin receptor activity that operates as an active ingredient of a pharmaceutical composition comprising. "I" general formula [a]" Formula, the aryl group may be substituted A ring represents a; R1 Represents a hydrogen atom, or an alkyl group which may be substituted represented; R2 Represents a hydrogen atom, a halogen atom or represents a; R3 The alkyl group may be substituted " represented by the imidazole compound, its pharmacologically acceptable salt as an active ingredient in a pharmaceutical composition. [Drawing] no (by machine translation)
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Paragraph 0170
(2019/01/31)
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- Direct Intermolecular C-H Functionalization Triggered by 1,5-Hydride Shift: Access to N-Arylprolinamides via Ugi-Type Reaction
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A novel Ugi-type reaction triggered by 1,5-hydride shift has been established, giving access to N-arylprolinamides and related compounds in high atom economy and good yields. This is an example of a two starting material-three component reaction. The benz
- Zhen, Le,Wang, Jiankun,Xu, Qing-Long,Sun, Hongbin,Wen, Xiaoan,Wang, Guangji
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supporting information
p. 1566 - 1569
(2017/04/13)
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- First Application of Heterogeneous Cobalt Catalysis in Csp2-N Cross-Coupling of Activated Chloroarenes under Ligand-Free Conditions
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A heterogeneous CoII/Al2O3 catalyst efficiently catalyses the N-arylation of N-heterocycles and open-chain secondary amines by activated chloroarenes and chloroheteroarenes under ligand-free conditions in water to give a series of functionalized tertiary amines. The catalyst was prepared by immobilizing CoBr2 onto the surface of Al2O3, and was characterized by X-ray diffraction, X-ray photoelectron spectroscopy, scanning electron microscopy, and energy-dispersive X-ray analysis. This catalyst could be recycled up to six times without any appreciable loss of catalytic activity. A heterogeneous CoII/Al2O3 catalyst efficiently catalyses the N-arylation of N-heterocycles and open- or closed-chain secondary amines by activated chloroarenes and chloroheteroarenes under ligand-free conditions in water to give a series of functionalized tertiary amines.
- Mukherjee, Nirmalya,Chatterjee, Tanmay,Ranu, Brindaban C.
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p. 4018 - 4023
(2015/06/30)
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- Asymmetric tandem 1,5-hydride shift/ring closure for the synthesis of chiral spirooxindole tetrahydroquinolines
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The direct functionalization of sp3 C-H bonds through a tandem 1,5-hydride shift/ring closure is described. Various optically active spirooxindole tetrahydroquinoline derivatives bearing contiguous quaternary or tertiary stereogenic carbon centers were readily synthesized. A chiral scandium complex of N,N'-dioxide promoted the reactions in good yields (up to 97%) with excellent diastereoselectivities (>20:1) and enantioselectivities (up to 94% ee). Kinetic isotope effect (KIE) experiments and internal redox reactions of chiral substrates were conducted, and the results provided intriguing information that helped clarify the mechanism of the reaction.
- Cao, Weidi,Liu, Xiaohua,Guo, Jing,Lin, Lili,Feng, Xiaoming
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supporting information
p. 1632 - 1636
(2015/01/30)
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- Aluminum complexes with bidentate amido ligands: Synthesis, structure and performance on ligand-initiated ring-opening polymerization of rac-lactide
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A series of mononuclear aluminum dimethyl complexes bearing bidentate N-[2-(1-piperidinyl)benzyl]anilino or N-(2-morpholinobenzyl)anilino ligands were synthesized via reactions of the corresponding proligands with trimethylaluminum upon heating, while at ambient temperature two trimethylaluminum adducts with neutral N-[2-(1-piperidinyl)benzyl]aniline proligands were obtained. These complexes were well characterized by NMR spectroscopy, elemental analysis and occasionally by EI-HRMS. The molecular structures of the typical trimethylaluminum adduct 2b and aluminum dimethyl complex 3b were further confirmed by X-ray diffraction studies. All the aluminum dimethyl complexes could effectively initiate the ring-opening polymerization (ROP) of rac-lactide in a well-controlled manner to afford PLAs with narrow molecular weight distributions (PDI = 1.06-1.18). The polymer samples obtained are systematically end-capped with the bidentate ancillary ligands as characterized by 1H NMR and ESI-TOF mass spectroscopy. Moreover, the introduction of substituent(s) at the ortho-position(s) of the anilino moiety in the ligand results in an obvious decrease in the catalytic activity of the corresponding aluminum complex, and complexes with meta-chloro substituted anilino units show higher activities likely due to the enhanced electrophilicity of the metal centers induced by the anilino groups. the Partner Organisations 2014.
- Liu, Junpeng,Ma, Haiyan
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p. 9098 - 9110
(2014/06/10)
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- Chemo-, Regio-, and stereoselective trifluoromethylation of styrenes via visible light-driven single-electron transfer (SET) and triplet-triplet energy transfer (TTET) processes
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A process for tunable and chemo-, regio-, and stereoselective photocatalytic trifluoromethylation of styrenes was developed. Thermodynamically stable E-trifluoromethylated alkenes were prepared using Tognis reagent in the presence of Ru(bpy)3Cl2·6H2O under visible light irradiation, whereas less thermodynamically stable Z-trifluoromethylated alkenes were obtained by employing Umemotos reagent and photocatalyst Ir(ppy)3.
- Lin, Qing-Yu,Xu, Xiu-Hua,Qing, Feng-Ling
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p. 10434 - 10446
(2015/02/19)
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- Lewis acid catalyzed formation of 3-amino-3-carboxy-tetrahydroquinoline derivatives via tandem 1,5-hydride transfer/cyclization process
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A Sc(OTf)3-catalyzed intramolecular tandem 1,5-hydride transfer/cyclization process to construct 3-amino-3-carboxy-tetrahydroquinoline derivatives has been developed. The methodology gives access to a range of relatively complex tetrahydroquinolines (tetracyclic and pentacyclic heterocycles bearing spirocyclic skeleton and two stereogenic centers) in good to excellent yields with diastereoselectivities ranging from 57:43 to 73:27. The synthetic utility of the method was also demonstrated by an efficient ring opening derivatization reaction.
- Han, Wen-Yong,Zuo, Jian,Wu, Zhi-Jun,Zhang, Xiao-Mei,Yuan, Wei-Cheng
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p. 7019 - 7025
(2013/07/26)
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- N-fused indolines through non-carbonyl-stabilized rhodium carbenoid C-H insertion of N-aziridinyl imines
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Under rhodium catalysis, N-aziridinyl imines provided access to N-fused indolines through non-carbonyl-stabilized rhodium carbenoid C-H insertion. The utility of this methodology for the synthesis of architecturally complex heterocycles was further demonstrated by an expedient total synthesis of ( ±)-cryptaustoline (see scheme). Copyright
- Mahoney, Stuart J.,Fillion, Eric
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supporting information; experimental part
p. 68 - 71
(2012/02/04)
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- Intramolecular redox-triggered C-H functionalization
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Sacrifice for the team: A one-pot method achieves remote functionalization at the α-position of an amine moiety through the sacrificial reduction of a neighboring group. The process takes advantage of an intramolecular redox reaction, thereby avoiding the need for any external oxidants. This method was applied to a concise five-step total synthesis of indolizidine 167B.
- Jurberg, Igor D.,Peng, Bo,Woestefeld, Eckhard,Wasserloos, Maximilian,Maulide, Nuno
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supporting information; experimental part
p. 1950 - 1953
(2012/04/04)
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- Synthesis of novel chiral tetraaza ligands and their application in enantioselective transfer hydrogenation of ketones
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Novel chiral tetraaza ligands (R)-N, N′-bis[2-(piperidin-1-yl) benzylidene]propane-1, 2-diamine 6 and (S)-N-[2-(piperidin-1-yl)benzylidene]-3- {[2-(piperidin-1-yl)benzylidene]amino}-alanine sodium salt 7 have been synthesized and fully characterized by NM
- Yu, Shen Luan,Li, Yan Yun,Dong, Zhen Rong,Gao, Jing Xing
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scheme or table
p. 395 - 398
(2012/06/18)
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- Platinum/scandium-cocatalyzed cascade cyclization and ring-opening reaction of tertiary amines with substituted salicylaldehydes to synthesize 3-(aminoalkyl)coumarins
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The synthesis of 3-(aminoalkyl)coumarins starting with a platinum/scandium-cocatalyzed oxidative dehydrogenation of α,β- C(sp3)-H bonds of tertiary amines in the presence of ambient oxygen followed by reactions with substituted salicylaldehydes is revealed. The in situ formed enamines reacted with various salicylaldehydes, which resulted in the development of a one-pot synthetic protocol involving aldol reaction, cyclization, and then ring-opening.
- Xia, Xiao-Feng,Shu, Xing-Zhong,Ji, Ke-Gong,Shaukat, Ali,Liu, Xue-Yuan,Liang, Yong-Min
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supporting information; experimental part
p. 342 - 345
(2011/03/19)
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- Novel, versatile three-step synthesis of 1,2,3,4,10,10a-hexahydro- pyrazino[1,2- a ]indoles by intramolecular carbene-mediated C-H insertion
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A new convenient three-step synthesis of the privileged CNS scaffold 1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles has been developed. The method makes use of an intramolecular carbene-mediated C-H insertion in phenylpiperazine-derived tosyl-hydrazones m
- Krogsgaard-Larsen, Niels,Begtrup, Mikael,Herth, Matthias M.,Kehler, Jan
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experimental part
p. 4287 - 4299
(2011/02/22)
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- Platinum-catalyzed michael addition and cyclization of tertiary amines with nitroolefins by dehydrogenation of α,β-sp3 C-H bonds
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A mild platinum-catalyzed oxidative dehydrogenation of α,β- C(sp3)-H bonds of tertiary amines in the presence of ambient oxygen is revealed, and the in situ formed enamines subsequently reacting with various nitroolefins resulted in the development of two one-pot synthetic protocols involving Michael addition-elimination and Michael addition-cyclization. By using different functionalized nitroolefins compatible with the current oxidative conditions, two types of structurally divergent products, trisubstituted enamines and chromano[2,3-b]piperidines, could be expediently accessed, respectively.
- Xia, Xiao-Feng,Shu, Xing-Zhong,Ji, Ke-Gong,Yang, Yan-Fang,Shaukat, Ali,Liu, Xue-Yuan,Liang, Yong-Min
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supporting information; experimental part
p. 2893 - 2902
(2010/07/09)
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- Platinum-catalyzed cross-dehydrogenative coupling reaction in the absence of oxidant
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A third strategy for cross-dehydrogenative coupling reaction has been reported via platinum-catalyzed sp3 C-H and sp3 C-H coupling reaction in the absence of oxidant. Nitroalkanes as well as dialkyl malonate derivatives, β-keto esters and malononitrile are active participants in this coupling reaction. Both cyclic and acyclic non-activated simple ketones are good reactants in this reaction.
- Shu, Xing-Zhong,Yang, Yan-Fang,Xia, Xiao-Feng,Ji, Ke-Gong,Liu, Xue-Yuan,Liang, Yong-Min
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supporting information; experimental part
p. 4077 - 4079
(2010/10/21)
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- Product-selectivity control by the nature of the catalyst: Lewis acid-catalyzed selective formation of ring-fused tetrahydroquinolines and tetrahydroazepines via intramolecular redox reaction
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Selective synthesis of ring-fused tetrahydroquinolines and tetrahydroazepines from the same starting materials was achieved by subtle use of the oxophilic Sc(OTf)3 or carbophilic IPrAuOTf as the catalyst.
- Zhou, Guanghua,Zhang, Junliang
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supporting information; scheme or table
p. 6593 - 6595
(2010/10/21)
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- NOVEL CURCUMIN DERIVATIVE
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The present invention provides a novel compound that is structurally similar to curcumin and has a suppressive effect on Aβ aggregation, a degradative effect on Aβ aggregates, an inhibitory effect on β-secretase, and a protective effect on neurons. The novel compound is a compound represented by the following general formula (Ia) or a salt thereof: wherein R1 represents a 4-hydroxy-3-methoxyphenyl group or the like, and R2 represents a 1H-indol-6-yl group or the like.
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Page/Page column 100-101
(2009/12/07)
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- Selective functionalization of sp3 C - H bonds adjacent to nitrogen using (diacetoxyiodo)benzene (DIB)
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(Chemical Equation Presented) A PhI(OAc)2 mediated selective functionalization of sp3C - H bonds adjacent to a nitrogen atom has been reported. When piperidine derivates were used, direct diacetoxylation of α and β sp3 C - H adjacent to a nitrogen atom were observed to afford various cis-2,3-diacetoxylated piperidines. On the other hand, tetrahydroisoquinoline derivatives gave various α-C - H functionalized products in the presence of PhI(OAc)2. Nitroalkanes, dialkyl malonates, and β-keto ester are active participants in this coupling reaction. Meanwhile, α-amino nitriles can also be obtained by oxidative coupling of amineswithmalononitrile. 2009 American Chemical Society.
- Shu, Xing-Zhong,Xia, Xiao-Feng,Yang, Yan-Fang,Ji, Ke-Gong,Liu, Xue-Yuan,Liang, Yong-Min
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supporting information; experimental part
p. 7464 - 7469
(2010/01/06)
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- Scope and limitations of the T-reaction employing some functionalized C-H-acids and naturally occurring secondary amines
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Scope and limitations of the T-reaction with emphasis on using chiral, natural products as starting materials to prepare novel chiral heterocycles is studied and the diastereoselective introduction of newly formed stereocenters is explained via proposed mechanisms.
- Rabong, Constantin,Hametner, Christian,Mereiter, Kurt,Kartsev, Victor G.,Jordis, Ulrich
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p. 799 - 838
(2008/09/21)
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- Stereoselective synthesis of new spiro-fused heterocyclic systems, 2,3,4,4a,5.6-hexahydro-6H-spiro[benzo[c]quinolizine-5,4′-pyrazol] -5′-ones
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The synthesis of 2,3,4,4a,5,6-hexahydro-6H-spiro[benzo[c]quinolizine-5, 4′-pyrazol]-5′-ones has been achieved by the reaction of 2-piperidinobenzaldehydes with 2-aryl-5-methyl-2,4-dihydropyrazol-3-one via the "tert-amino effect" mechanism.
- Glukhareva,Kropotina,Kosterina,Nein,Deeva,Morzherin
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- INHIBITORS OF PAPILLOMA VIRUS
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The use of a compound of formula (II): or its enantiomers or diastereoisomers thereof, or salts or pharmaceutically-acceptable esters thereof, in the treatment or prevention of a papilloma virus infection, particularly human papilloma virus in a mammal, wherein R11; X4; X5; X6; R13; R14; W; Z; Y; T; and R18 are defined herein. The present invention also provides novel compounds, pharmaceutical compositions and methods for using these compounds and compositions in the treatment or prevention of papilloma virus infection. More particularly, the present invention provides compounds, compositions and methods for inhibiting papilloma virus DNA replication by interfering with the E1-E2 protein-protein interaction essential for viral DNA replication.
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- Process for preparing (RS) 3-methyl-1-(2-piperidinyl phenyl) butyl amine
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The Present invention relates to a process for the preparation of (RS) 3-methyl-1-(2-piperidinyl phenyl) butyl amine of formula 1. (RS) 3-Methyl-1-(2-piperidinyl phenyl butyl amine having formula 1 is an important key intermediate for the synthesis of repaglinide of formula 2 an oral hypoglycemic agent.
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- METHOD FOR THE PRODUCTION OF PHENYLACETIC ACID DERIVATIVES
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Disclosed is a method for producing (S) (+) phenylacetic acid derivatives of general formula (I), wherein R1 represents a linear or branched alkyl radical with 1 to 6 carbon atoms or optionally substituted benzyl while R2 represents methyl, ethyl, or propyl. The inventive method is characterized in that a compound of general formula (II), wherein R1 has the meaning indicated above and R3 represents a nucleofuge, or a suitable salt of a compound of general formula (II) is reacted with a compound of general formula (III), wherein R2 has the meaning indicated above and R4 represents hydrogen or a hydrolytically cleavable nucleofuge, whereupon the optionally provided protective group R4 is eliminated.
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Page/Page column 11-13
(2010/02/09)
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- Repaglinide and related hypoglycemic benzoic acid derivatives
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The structure-activity relationships in two series of hypoglycemic benzoic acid derivatives (5, 6) were investigated. Series 5 resulted from meglitinide (3) when the 2-methoxy was replaced by an alkyleneimino residue. Maximum activity was observed with the cis-3,5-dimethylpiperidino (5h) and the octamethyleneimino (5l) residues. Series 6 resulted from the meglitinide analogon 4 bearing an inversed amido function when the 2-methoxy, the 5- fluoro, and the α-methyl residue were replaced by a 2-piperidino, a 5- hydrogen, and a larger α-alkyl residue, respectively. An alkoxy residue ortho to the carboxy group further increased activity and duration of action in the rat. The most active racemic compound, 6al (R4 = isobutyl; R = ethoxy), turned out to be 12 times more active than the sulfonylurea (SU) glibenclamide (1). Activity was found to reside predominantly in the (S)- enantiomers. Compared with the SUs 1 and 2 (glimepiride), the most active enantiomer, (S)-6al (AG-EE 623 ZW; repaglinide; ED50 = 10 μg/kg po), is 25 and 18 times more active. Repaglinide turned out to be a useful therapeutic for type 2 diabetic patients; approval was granted recently by the FDA and the EMEA. From investigations on the pharmacophoric groups in compounds of type 5 and 6, it was concluded that in addition to the two already known - the acidic group (COOH; S02NH) and the amidic spacer (CONH; NHCO) - the ortho residue R1 (alkyleneimino; alkoxy; oxo) must be regarded as a third one. A general pharmacophore model suitable for hypoglycemic benzoic acid derivatives, SUs, and sulfonamides is proposed (Figure 6). Furthermore, from superpositions of low-energy conformations (LECs) of 1, 2, and (S)-6al, it was concluded that a common binding conformation (LEC II; Figure 10B) may exist and that differences in binding to the SU receptor and in the mechanism of insulin release between repaglinide and the two SUs may be due to specific hydrophobic differences.
- Grell, Wolfgang,Hurnaus, Rudolf
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p. 5219 - 5246
(2007/10/03)
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