- Exploring the synthetic potential of a marine transaminase including discrimination at a remote stereocentre
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The marine transaminase, P-ω-TA, can be employed for the transamination from 1-aminotetralins and 1-aminoindanes with differentiation of stereochemistry at both the site of reaction and at a remote stereocentre resulting in formation of ketone products with up to 93% ee. While 4-substituents are tolerated on the tetralin core, the presence of 3- or 8-substituents is not tolerated by the transaminase. In general P-ω-TA shows capacity for remote diastereoselectivity, although both the stereoselectivity and efficiency are dependent on the specific substrate structure. Optimum efficiency and selectivity are seen with 4-haloaryl-1-aminotetralins and 3-haloaryl-1-aminoindanes, which may be associated with the marine origin of this enzyme. This journal is
- Schwarz, Maria,Murphy, Edel J.,Foley, Aoife M.,Woods, David F.,Castilla, Ignacio Abreu,Reen, F. Jerry,Collins, Stuart G.,O'gara, Fergal,Maguire, Anita R.
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supporting information
p. 188 - 198
(2021/01/18)
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- Sertraline derivative and preparation method and application thereof
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The invention discloses a sertraline derivative or a medicinal salt thereof. The structural general formula of the sertraline derivative is shown in the specification. The sertraline derivative has a good inhibition effect on cryptococcus neoformans, particularly, the compound D16 disclosed by the invention has a relatively good inhibition effect on candida glabrata 9073, candida tropicalis 10186, cryptococcus neoformans, candida albicans 5314, candida albicans 904, candida tropicalis 10186, drug-resistant candida albicans 103 and cryptococcus gottii.
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Paragraph 0084-0088
(2021/04/14)
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- Metal free decarboxylative aminoxylation of carboxylic acids using a biphasic solvent system
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The smooth oxidative radical decarboxylation of carboxylic acids with TEMPO and other derivatives as radical scavengers is reported. The key to success was the use of a two-phase solvent system to avoid otherwise predominant side reactions such as the oxidation of TEMPO by persulfate and enabled the selective formation of synthetically useful alkoxyamines. The method does not require transition metals and was successfully used in a new synthetic approach for the antidepressant indatraline.
- Schulz, G?ran,Kirschning, Andreas
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supporting information
p. 273 - 278
(2021/01/14)
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- Synthesis of 2-sulfonyl indenes and indanes
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In this paper, we developed facile and high-yield synthetic routes for the preparation of 2-sulfonyl indenes and indanes, including: (i) Amberlyst-15-promoted Knoevenagel reaction of β-ketosulfones and arylaldehydes in refluxing toluene; (ii) Grignard reagent (R′MgBr) or reducing reagent (NaBH4) promoted regio-and/or stereocontrolled 1,4-Addition or 1,4-/1,2-reduction of the resulting sulfonyl chalcones in THF or MeOH/THF at 25 °C; and then (iii) Amberlyst-15 mediated intramolecular Friedel-Crafts annulation of the corresponding β-ketosulfones or β-hydroxysulfones in toluene at reflux. This present method describes a highly efficient (3 + 2) annulation via the formation of two carbon-carbon (C-C) bonds. The DFT calculations were utilized to rationalize the regioselectivity of the addition reaction.
- Chang, Meng-Yang,Wu, Yan-Shin,Tsai, Yu-Lin,Chen, Hsing-Yin
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p. 11699 - 11723
(2019/10/02)
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- Palladium Nanoparticles-Catalyzed Synthesis of Indanone Derivatives via Intramolecular Reductive Heck Reaction
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An efficient protocol for the straightforward, single-step synthesis of 3-aryl-1-indanones from 2′-iodochalcone via reductive Heck reaction using phosphine free, stable and reusable binaphthyl stabilized palladium nanoparticle (Pd-BNP) as a catalyst has been described. An immense array of substrate scope with electron-rich and deficient 2′-iodochalcones have been synthesized. Further derivatization of product indanones have been achieved successfully. The heterogeneous nature of the Pd-BNP has been validated by centrifugation test and mercury poisoning experiment. Pd-BNP has been successfully recycled up to 5 cycles without any significant loss in reaction yield and particle size of nanoparticles, confirmed by TEM analysis. (Figure presented.).
- Parveen, Naziya,Sekar, Govindasamy
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p. 4581 - 4595
(2019/09/03)
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- Synthesis of 3-aryl-1-indanones via CsF-promoted coupling of arylboronic acids with N-tosylhydrazones
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A series of 17 3-aryl-1-indanones, four of which are novel, were prepared in good yield via a CsF-promoted reductive cross-coupling of the monotosylhydrazone of a 1,3-indanedione with an arylboronic acid. The method demonstrates wide substrate scope and good functional group tolerance. Moreover, the 3-aryl-1-indanones could also be prepared on a multi-gram scale.
- Liu, Yueqiang,Chen, Lingjuan,Liu, Yan,Liu, Ping,Dai, Bin
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- A Weinreb Amide Based Building Block for Convenient Access to β,β-Diarylacroleins: Synthesis of 3-Arylindanones
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Towards the synthesis of symmetrical and unsymmetrical β,β-diarylacroleins for assembling diarylmethine fragments present in biologically important molecules, we have developed a new Weinreb amide (WA) based building block, derived from propiolic acid. The WA functionality present in this compound allowed the sequential addition of various arylmagnesium bromide reagents in a controlled manner. The developed methodology for the access to β,β-diarylacroleins has been utilised for the synthesis of biologically important 3-arylindanone molecules. Synthesis of both symmetrical and unsymmetrical β,β-diarylacrolein and diarylmethine fragments, have been achieved via easily accessible and hitherto unknown Weinreb Amide (WA) based building block 11. The WA functionality allowed the sequential addition of nucleophiles such as arylmagnesium bromide in a controlled manner, which has enabled the synthesis of an important 3-arylindanone molecule.
- Tiwari, Praveen Kumar,Aidhen, Indrapal Singh
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p. 2637 - 2646
(2016/06/08)
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- Enantiopurity determination of the enantiomers of the triple reuptake inhibitor indatraline
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The present study describes the development of two approaches for the determination of the enantiopurity of both enantiomers of indatraline. Initially, a method was developed using different chiral solvating agents (CSAs) for diastereomeric discrimination regarding signal separation in 1H nuclear magnetic resonance (NMR) spectroscopy, revealing MTPA as a promising choice for the differentiation of the indatraline enantiomers. This CSA was also tested for its ideal molar ratio, temperature, and solvent. Optimized conditions could be achieved that made determination of enantiopurity for (1R,3S)-indatraline up to 98.9% enantiomeric excess (ee) possible. To quantify even higher enantiopurities, a high-performance liquid chromatography (HPLC) method based on a modified β-cyclodextrine phase was established. The influence of buffer type, concentration, pH value, percentage and kind of organic modifier, temperature, injection volume as well as sample solvent on chromatographic parameters was investigated. Afterwards, the reliability of the established HPLC method was demonstrated by validation according to the ICH guideline Q2(R1) regarding specificity, accuracy, precision, linearity, and quantitation limit. The developed method proved to be strictly linear within a concentration range of 1.25-1000 μM for the (1R,3S)-enantiomer and 1.25-750 μM for its mirror image that enables a reliable determination of enantiopurities up to 99.75% ee for the (1R,3S)-enantiomer and up to 99.67% ee for the (1S,3R)-enantiomer.
- Grimm, Stefanie H.,Allmendinger, Lars,Hoefner, Georg,Wanner, Klaus T.
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p. 923 - 933
(2014/01/06)
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- Asymmetric total synthesis of (+)-indatraline via diastereoselective amination of chiral ethers using chlorosulfonyl isocyanate
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A concise asymmetric total synthesis of (+)-indatraline from readily available cinnamic acid is described. The key steps include Corey's oxazaborolidine-catalyzed asymmetric carbonyl reduction and a highly stereoselective amination of chiral benzylic ether with retention of stereochemistry using chlorosulfonyl isocyanate.
- Lee, Sang Hwi,Park, Sook Jin,Kim, In Su,Jung, Young Hoon
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p. 1877 - 1880
(2013/03/13)
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- AROMATIC KETONE SYNTHESIS WITH AMIDE REAGENTS AND RELATED REACTIONS
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A method of preparing an aryl carbonyl or aryl thiocarbonyl compound, comprises reacting an N-(nitroaryl)-amide or N-(nitroaryl)-thioamide with an aromatic ring, with a superacid catalyst, to produce the aryl carbonyl or aryl thiocarbonyl compound. The superacid is present in an amount of at most 8 equivalents in proportion to the N-(nitroaryl)-amide or N-(nitroaryl)-thioamide. A method of preparing aryl amide or aryl thioamide, comprises reacting an N-(nitroaryl)-carbamide or N-(nitroaryl)-thiocarbamide with an aromatic ring, with a superacid catalyst, to produce the aryl amide or aryl thioamide.
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Paragraph 0038; 0040
(2013/10/22)
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- Friedel-crafts acylation with amides
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Friedel-Crafts acylation has been known since the 1870s, and it is an important organic synthetic reaction leading to aromatic ketone products. Friedel-Crafts acylation is usually performed with carboxylic acid chlorides or anhydrides, while amides are generally not useful substrates in these reactions. Despite being the least reactive carboxylic acid derivative, we have found a series of amides capable of providing aromatic ketones in good yields (55-96%, 17 examples). We propose a mechanism involving diminished C-N resonance through superelectrophilic activation and subsequent cleavage to acyl cations.
- Raja, Erum K.,Deschepper, Daniel J.,Nilsson Lill, Sten O.,Klumpp, Douglas A.
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experimental part
p. 5788 - 5793
(2012/07/30)
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- Synthesis of optically pure 1-amino-3-aryl indanes exemplified by (+)-indatraline
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A versatile procedure for the synthesis of optically pure 1-amino-3-aryl indanes is presented, exemplified by the synthesis of the triple uptake inhibitor (+)-indatraline (1). Georg Thieme Verlag Stuttgart · New York.
- N?rager, Niels Gr?n,Lorentz-Petersen, Linda Luise Reeh,Lyngs?, Lars Ole,Kehler, Jan,Juhl, Karsten
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p. 1753 - 1755
(2011/09/16)
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- TREATMENT OF NEURODEGENERATIVE DISEASES USING INDATRALINE ANALOGS
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Methods and compositions useful in the treatment or prevention of synucleinopathies, such as Parkinson''s disease, diffuse Lewy body disease, and multiple system atrophy, or other neurodegenerative diseases (e.g., amyotrophic lateral sclerosis, Huntington''s disease, and Alzheimer''s disease) are provided. The treatment including administering to a subject an indatraline derivative that inhibits the aggregation of a-synuclein.
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- Remarkable electronic effect on the diastereoselectivity of the Heck reaction of methyl cinnamate with arenediazonium salts: Formal total synthesis of (±)-indatraline and (±)-sertraline
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An efficient and stereoselective protocol for the preparation of β,β-disubstituted acrylates in good to high yields by means of a Heck-Matsuda arylation was accomplished. The method employs a base- and ligand-free Heck arylation reaction of methyl cinnamate using both electron-deficient and electron-rich arenediazonium salts as electrophiles. The Heck reaction displays a remarkable electronic dependence regarding the diastereoselectivity of the arylation process, which correlates with the electronic nature of the arenediazonium salts employed. A rationale for the observed diastereoselectivity is presented. The overall methodology provides a convenient route to 3-arylindanones and 4aryltetralones allowing the concise formal total syntheses of the therapeutically important psychoactive compounds (± )-indatraline and (± )-sertraline.
- Pastre, Julio Cezar,Correia, Carlos Roque Duarte
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supporting information; experimental part
p. 1217 - 1223
(2009/12/24)
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- Versatile synthesis of 3-arylindan-1-ones by palladium-catalyzed intramolecular reductive cyclization of bromochalcones
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We have developed a novel and versatile synthesis of racemic 3-arylindan-1-ones by palladium-catalyzed intramolecular reductive cyclization of bromochalcones. This method is especially attractive because it avoids strong acidic conditions and consequently a larger number of sensitive functional groups are accepted during synthesis compared with existing methods.
- Pueschl, Ask,Rudbeck, Hans Christian,Faldt, Andre,Confante, Allesia,Kehler, Jan
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p. 291 - 295
(2007/10/03)
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- Superacid-Catalyzed Reactions of Cinnamic Acids and the Role of Superelectrophiles
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The chemistry of cinnamic acids and related compounds has been studied. In superacid-catalyzed reactions with arenes, two competing reaction mechanisms are proposed. Both mechanisms involve the formation of dicationic intermediates (superelectrophiles), and the reactions can lead to either chalcone-type products or indanone products. The direct observation of a dicationic species (by low-temperature 13C NMR) is reported. We provide clear evidence that protonated carboxylic acid groups (or the corresponding acyl cation) can enhance the reactivity of an adjacent electrophilic center. Triflic acid is also found to be an effective acid catalyst for the direct synthesis of some electron-deficient chalcones and heterocyclic chalcones from cinnnamic acids.
- Rendy, Rendy,Zhang, Yun,McElrea, Aaron,Gomez, Alma,Klumpp, Douglas A.
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p. 2340 - 2347
(2007/10/03)
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- Synthesis of indatraline using a Suzuki cross-coupling reaction and a chemoselective hydrogenation: A versatile approach
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Indatraline and its derivatives can be obtained in five steps from indanone by using a Suzuki cross-coupling reaction and a chemoselective hydrogenation catalyzed by Wilkinson's catalyst.
- Cossy, Janine,Belotti, Damien,Maguer, Aude
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p. 1515 - 1517
(2007/10/03)
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- Synthesis of 3-aryl-1-indanamines
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The present invention is a method of preparing a 3-aryl-1-indanamine represented by structural formula I: and physiologically acceptable salts thereof. In structure I, phenyl ring A can be unsubstituted or substituted with 1-4 substitutents. R1is an aromatic group which can be substituted or unsubstituted. R2and R3are each, independently, hydrogen, an aliphantic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, an aralkyl group, or a substituted aralkyl group. Alternatively, R2and R3, taken together with the nitrogen substitutent on the indan ring, form a non-aromatic ring system having 1-2 heteroatoms.
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- Slow-onset, long-duration 3-(3′,4′-dichlorophenyl)-1-indanamine monoamine reuptake blockers as potential medications to treat cocaine abuse
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A series of 3-(3′,4′-dichlorophenyl)-1-indanamine monoamine reuptake blockers have been synthesized in an effort to develop a compound that could be used as a maintenance therapy to treat cocaine abuse. Since the effects of cocaine on dopamine (DA) and serotonin (5HT) transporters are important components of its pharmacological activity, the focus was on nonselective inhibitors of monoamine transport. To reduce or eliminate the abuse potential of a DA reuptake blocker, the compounds were designed to be slow-onset, long-duration prodrugs whose N-demethylated metabolites would have increased activity over the parent compound with the ideal being a parent compound that has little or no activity. To achieve this, pairs of compounds with different groups on the amine nitrogen and with and without an additional N-methyl group were synthesized. All of the synthesized compounds were screened for binding and reuptake at the cloned human DA, 5HT, and norepinephrine (NE) transporters. As previously found, trans isomers are nonselective blockers of DA, 5HT, and NE reuptake, cis isomers with small N-alkyl groups are selective blockers of 5HT reuptake, and tertiary amines of the trans compounds are less potent than the corresponding N-demethylated secondary amines as blockers of DA reuptake. Larger N-alkyl groups in both the trans and cis series were found to reduce activity for the 5HT and NE transporters with less effect at DA transporters. Selected trans compounds were also screened for locomotor activity in mice and generalization to a cocaine-like profile in rats. With intraperitoneal administration, all of the trans isomers showed a slow onset of at least 20 min and an extremely long duration of action in the locomotor assays. Several of the trans compounds also fully generalized to a cocaine-like pharmacological profile. An initial lead compound, the N,N-dimethyl analogue trans-1b, was resolved into chirally pure enantiomers. Surprisingly, both enantiomers were found to have significant affinity for the DA transporter and to cause locomotor activation. This is in contrast to the N-methyl compound in which only the (+)-enantiomer had significant activity. The absolute configuration of the more active enantiomer was determined by X-ray crystallography to be 3R,1S.
- Froimowitz,Wu,Moussa,Haidar,Jurayj,George,Gardner
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p. 4981 - 4992
(2007/10/03)
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- Application of (2-Cyanoaryl)arylacetonitriles in Cyclization and Annulation Reactions. Preparation of 3-Arylindans, 4-Aryl-3,4-dihydronaphthalenes, 4-Arylisoquinolines, 1-Aminonaphthalenes, and Heterocyclic Analogues
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(2-Cyanoaryl)arylacetonitriles, obtained from o-halogen-substituted cyanoaromatics and arylacetonitriles may be alkylated with methyl chloroacetate.Subsequent abstraction of the proton adjacent to the ester group followed by attack of the anion at the aromatic cyano group gives rise to annulated 1-aminocyclopentenes by a Dieckmann-type reaction.The homologous esters similarly produce annulated 1-aminocyclohexenes.The generality of this annulation method is demonstrated by preparation of derivatives of 1-amino-1H-indene, 4-amino-6H-cyclopentathiophene, 5-amino-7H-pyrindine, 1-amino-3,4-dihydronaphthalene, and 5-amino-2,9-dihydro-1H-cyclopentisoquinoline.Hydrolysis and decarboxylation of these compounds leads to ketones as exemplified by synthesis of 3-arylindan-1-ones and 4-aryl-3,4-dihydro-1(2H)-naphthalen-1-ones.When treated with hydrogen bromide, the (2-cyanophenyl)phenylacetonitriles cyclize to -condensed 3-bromo-5-aryl-6-aminopyridines.Thus, derivatives of isoquinoline, thienopyridine, and 1,6-naphthyridine were prepared.
- Sommer, Michael Bech,Begtrup, Mikael,Boegesoe, Klaus Peter
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p. 4822 - 4827
(2007/10/02)
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- Neuroleptic activity and dopamine-uptake inhibition in 1-piperazino-3-phenylindans
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A series of 1-piperazino-3-phenylindans was synthesized and tested for neuroleptic and thymoleptic activity. Neuroleptic activity was found only in trans racemates and was associated with one of the enantiomers only. The potent and long-acting neuroleptic compound trans-4-[3-(4-fluorophenyl)-6-(trifluoromethyl)indan-1-yl]-1-piperazineeth anol (Lu 18-012, tefludazine) was developed by systematic variation of structural components. Thymoleptic activity was optimized, especially with respect to dopamine-uptake inhibition. No geometrical stereoselectivity was found with regard to dopamine-uptake inhibition, but a high enantioselectivity could be demonstrated for both cis and trans racemates. The most potent compounds were 1-piperazino-3-(3,4-dichlorophenyl)indans with IC50 values of about 2 nM for inhibition of dopamine uptake.
- Bogeso
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p. 935 - 947
(2007/10/02)
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