- Discovery of sertraline and its derivatives able to combat drug-resistant gastric cancer cell via inducing apoptosis
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Resistance phenomena during chemotherapy of tumor has been severely hampering the applications of chemotherapeutics. Due to advantage of drug repurposing, discovery of new chemosensitizers based on approved drugs is an effect strategy to find new candidates. Herein, we found antidepressant drug – sertraline, could sensitize drug-resistant gastric cancer cell (SGC-7901/DDP) with the IC50 value of 18.73 μM. To understand the structure–activity relationship and improve the activity, 30 derivatives were synthesized and evaluated. The IC50 value of the best compound was improved to 5.2 μM. Moreover, we found apoptosis induction and cell cycle arrest was the reason for the cell death of the drug-resistant cells after treatment of sertraline and derivatives, and PI3K/Akt/mTOR pathway was involved.
- Mu, Chao,Peng, Rui-Kun,Guo, Chun-Ling,Li, Ao,Yang, Xiu-Ming,Zeng, Rong,Li, Yu-Long,Gu, Jing,Ouyang, Qin
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supporting information
(2021/04/12)
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- Sertraline side chain amino structure derivative as well as preparation method and application thereof
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The structural formula of the sertraline side chain amino structure derivative is shown as a formula I or a formula II, wherein R1 is H or cyclopropanyl, and R2 is selected from alkyl, naphthyl, alkylamine, cyclopropanyl, phenyl, or phenyl of which the No.3 position and/or the No.4 position is substituted by alkyl, methoxyalkyl, haloalkyl and halogen; and R3 is a hydrogen group or a 1-halogenated alkyl group. The invention also provides a preparation method of the sertraline derivative and application of the sertraline derivative in preparation of a medicine for treating gastric cancer. The sertraline derivative provided by the invention has an obvious sensitization effect on drug-resistant gastric cancer cells.
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Paragraph 0048-0049
(2021/04/17)
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- Titanium(IV)-Mediated Ring-Opening/Dehydroxylative Cross-Coupling of Diaryl-Substituted Methanols with Cyclopropanol Derivatives
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A titanium(IV)-mediated ring-opening/dehydroxylative cross-coupling of diaryl-substituted methanols with a cyclopropanol derivative was developed. The reactions proceeded efficiently to provide synthetically useful γ,γ-diaryl esters in moderate to good yields, which could be applied to the functionalization of complex molecules derived from bioactive fenofibrate and isoxepac and the synthesis of a precursor of Zoloft.
- Zhang, Si-Xuan,Ding, Yan,Wang, Jun-Jie,Shen, Chuanji,Zhou, Xiaocong,Chu, Xue-Qiang,Ma, Mengtao,Shen, Zhi-Liang
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p. 15753 - 15760
(2021/10/25)
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- Nickel-Catalyzed α-Carbonylalkylarylation of Vinylarenes: Expedient Access to γ,γ-Diarylcarbonyl and Aryltetralone Derivatives
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We report a Ni-catalyzed regioselective α-carbonylalkylarylation of vinylarenes with α-halocarbonyl compounds and arylzinc reagents. The reaction works with primary, secondary, and tertiary α-halocarbonyl molecules, and electronically varied arylzinc reagents. The reaction generates γ,γ-diarylcarbonyl derivatives with α-secondary, tertiary, and quaternary carbon centers. The products can be readily converted to aryltetralones, including a precursor to Zoloft, an antidepressant drug.
- Dhungana, Roshan K.,Giri, Ramesh,Khanal, Namrata,Shekhar, K. C.
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p. 8047 - 8051
(2020/04/30)
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- Method for preparing serrine hydrochloride intermediate and impurities
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The invention relates to a method for preparing a sertraline hydrochloride intermediate and an impurity. The invention provides a method for refining 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone. The content of the impurity 4-(2,3-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone in the obtained product is less than 0.1%. The invention also relates to a method for preparing the isomer impurity 4-(2,3-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone from the mother solution.
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Paragraph 0027-0032
(2020/12/31)
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- α,α-Diarylethylene Glycols as Valuable Precursor for Synthesis of 1,1-Diarylethenes and α,α-Diaryl Acetaldehydes
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Towards assembling of diarylmethine unit present in biologically important molecules, we have developed a new Weinreb Amide (WA) based building block derived from glycolic acid. The WA functionality present in this building block permits the sequential addition of various arylmagnesium bromide reagents in a controlled manner that enables assembly of a diarylmethine unit. The developed synthetic route provides easy access to important diarylethenes and α,α-diarylethylene glycols. The synthesized α,α-diarylethylene glycols provide access to synthetically important symmetrical and unsymmetrical α,α-diaryl acetaldehydes as valuable intermediates.
- Tiwari, Praveen Kumar,Sivaraman, Balasubramaniam,Aidhen, Indrapal Singh
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p. 3594 - 3605
(2017/07/22)
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- Synthesis of 1-Aryltetralins and 1-Arylnaphthalenes via (4 + 2) Annulation of β-Ketosulfones with Styryl Bromides
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A novel route has been developed for the synthesis of various substituted 1-aryltetralins 6 and 1-arylnaphthalenes 8 via (1) K2CO3-mediated α-styrylation of β-ketosulfones 3 with bromostyryl bromides 4 and (2) stereocontrolled NaBH4-promoted reduction of the resulting γ-alkenones 5, followed by BF3·OEt2-catalyzed intramolecular annulation of the corresponding γ-alkenols 7 under rt/5 h and reflux/10 h conditions, respectively. The key structures of 6 and 8 were confirmed by X-ray crystallographic analysis. A plausible mechanism has been proposed.
- Chang, Meng-Yang,Cheng, Yu-Chieh
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p. 1682 - 1685
(2016/04/26)
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- Sodium amalgam mediated desulfonylative reduction of α-functionalized β-ketosulfones
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Sodium amalgam mediated desulfonylative reduction of β-ketosulfones in MeOH at rt affords alcohols in good yields via radical desulfonylation of β-ketosulfones and sequential Bouveault-Blanc reduction of the resulting ketones.
- Chan, Chieh-Kai,Huang, Yi-Hsuan,Chang, Meng-Yang
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p. 5521 - 5529
(2016/08/04)
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- Sustainable flow oppenauer oxidation of secondary benzylic alcohols with a heterogeneous zirconia catalyst
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A flow chemistry process for the Oppenauer oxidation of benzylic secondary alcohols using partially hydrated zirconium oxide and a simple carbonyl containing oxidant such as acetone, cyclohexanone, and neopentanal is reported. The heterogeneous oxidative system could be applied to a wide range of functionalized alcohol substrates, allowing clean and fast delivery of ketone products within a few minutes between 40 and 100 C.
- Chorghade, Rajeev,Battilocchio, Claudio,Hawkins, Joel M.,Ley, Steven V.
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supporting information
p. 5698 - 5701
(2013/12/04)
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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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- Asymmetric hydrogenation of N-alkyl and N-aryl ketimines using chiral cationic Ru(diamine) complexes as catalysts: The counteranion and solvent effects, and substrate scope
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Asymmetric hydrogenation of N-alkyl and N-aryl ketimines catalyzed by chiral cationic η6-arene-(N-monosulfonylated diamine) Ru(II) complexes has been investigated. Strong counteranion and solvent effects on the enantioselectivity were observed. The ruthenium catalyst bearing non-coordinating BArF- anion was found to be particularly effective for the hydrogenation of acyclic and exocyclic N-alkyl ketimines in the presence of (Boc)2O in dichloromethane or even under solvent-free conditions, providing chiral amines with up to >99% ee and full conversions. Alternatively, the ruthenium catalyst bearing achiral phosphate anion together with corresponding phosphoric acid as the additive was also efficient for the hydrogenation of N-alkyl ketimines in the absence of (Boc)2O with excellent enantioselectivities and full conversions. For N-aryl ketimines lower enantiomeric excesses were observed by using the ruthenium catalyst bearing BArF- anion. This catalytic protocol thus provides a facile and practical access to optically active amines and has been successfully employed in the gram-scale synthesis of enantiomerically pure (+)-sertraline.
- Chen, Fei,Ding, Ziyuan,He, Yanmei,Qin, Jie,Wang, Tianli,Fan, Qing-Hua
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supporting information; experimental part
p. 5248 - 5257
(2012/08/08)
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- Stereoselective amination of chiral benzylic ethers using chlorosulfonyl isocyanate: Total synthesis of (+)-Sertraline
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The stereoselective amination of various chiral benzylic ethers using chlorosulfonyl isocyanate is developed, and the application of this method to the total synthesis of a potent antidepressant, (+)-sertraline, from readily available 1-naphthol is also described (Figure presented).
- Lee, Sang Hwi,Kim, In Su,Li, Qing Ri,Dong, Guang Ri,Jeong, Lak Shin,Jung, Young Hoon
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experimental part
p. 10011 - 10019
(2012/02/05)
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- Aerobic oxidation of secondary benzylic alcohols and direct oxidative amidation of aryl aldehydes promoted by sodium hydride
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We reported herein new reactivities and possible mechanistic implications of a simplest oxidant (NaH/air) uncovered on a broad range of useful transformations, including aerobic alcohol oxidations, allylic alcohol isomerizations and oxidations, cyclopropyl alcohol fragmentations, and direct aryl aldehyde oxidative amidations. These readily implementable transition-metal-free processes feature exceptional material accessibility, operational simplicity, and environmental compatibility, and add new dimensions to its synthetic utilities that are fairly robust yet had not previously been fully realized and systematically explored.
- Wang, Xinbo,Wang, David Zhigang
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supporting information; experimental part
p. 3406 - 3411
(2011/06/17)
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- Asymmetric hydrogenation of N-Alkyl ketimines with phosphine-free, chiral, cationic Ru-MsDPEN catalysts
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(Solvent) free and easy: A phosphine-free, chiral, cationic Ru-MsDPEN complex [(S,S)-1] is found to be an efficient catalyst for the enantioselective hydrogenation of a range of often-problematic N-alkyl ketimines (see scheme). This new method provides a more practical and greener synthetic approach to optically active amines, particularly N-alkyl amines, such as Sertraline.
- Chen, Fei,Wang, Tianli,He, Yanmei,Ding, Ziyuan,Li, Zhiwei,Xu, Lijin,Fan, Qing-Hua
-
supporting information; experimental part
p. 1109 - 1113
(2011/03/21)
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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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- IMPROVED MANUFACTURING PROCEDURE FOR THE PREPARATION OF POLYMORPHIC FORM II OF CIS-(1S)-N-METHYL-4-(3,4-DICHLOROPHENYL)-1,2,3,4-TETRAHYDRO-1-NAPTHLENEAMINE HYDROCHLORIDE (SERTRALINE HYDROCHLORIDE)
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The present invention relates to the improved, scalable and efficient manufacturing procedure for the preparation of the antidepressant Cis-(1S)-N-Methyl-4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydro-1-napthaleneamine hydro chloride, Sertraline Hydrochloride polymorphic form II. The present invention further relates to the improved and modified procedures for preparing, separating and isolating the key intermediates involved in the preparationof Sertraline Hydrochloride polymorphic form II. The present invention also further relates to the use of novel reagents or a combination thereof and new methodologies to prepare some o'f the key intermediates involved in the preparation of Polymorphic Form II of Sertraline Hydrochloride.
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Page/Page column 22
(2008/06/13)
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- Synthesis and X-ray crystal structure analysis of 4-(3,4-dichlorophenyl)-2- (3,4,5-trimethoxy-benzylidene)-3,4-dihydro-naphthalen-1(2H)-one: Sertraline key intermediate analog
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The novel bioactive compound 4-(3,4-dichlorophenyl)-2-(3,4,5-trimethoxy- benzylidene)-3,4-dihydro-naphthalen-1(2H)-one was synthesised in three different methods, namely, conventional, MW irradiation with solvent and MW irradiation without solvent. The synthesised compound was characterised by spectroscopic techniques and finally confirmed by X-ray crystal structure analysis.
- Kavitha, Chandagirikoppal V.,Mantelingu, Kempegowda,Sarala, Gangadaraiah,Naveen,Anandalwar, Sridhar M.,Prasad, Javaregowda Shashidhara,Rangappa, Kanchugarakoppal S.
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p. 730 - 732
(2007/10/03)
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- A new and simplified process for preparing N-[4-(3,4-dichlorophenyl)-3,4- dihydro-1(2H)-naphthalenylidene]methanamine and a telescoped process for the synthesis of (1S-cis)-4-(3,4-dichlorophenol)-1,2,3,4-tetrahydro-N-methyl-1- naphthalenamine mandelate: Key intermediates in the synthesis of sertraline hydrochloride
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N-[4-(3,4-Dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]-methanamine, sertraline imine (3), is an intermediate for the synthesis of Zoloft, sertraline hydrochloride (1). A cleaner, simpler, and more efficient alternative to the Schiff base-mediated formation of sertraline imine has been developed and is presented in this paper. The condensation reaction between 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalone, sertraline tetralone (2), and monomethylamine was carried out in ethanol, without the need for classical dehydrating agent, such as TiCl4, or more novel approaches, such as molecular sieves, both of which produce hazardous byproducts and solid wastes. The low solubility of the imine 3 in this type of solvent is exploited, such that the reaction equilibrium favorably enhances the imine formation. Furthermore, an improved and highly selective catalytic reduction of 3 with Pd/CaCO3 catalyst in ethanol as the reaction solvent, followed by the resolution of the racemic cis isomer (6) with D-(-)-mandelic acid results in a more efficient telescoped commercial process to (1S-cis)-4-(3,4-dichlorophenol)- 1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine mandelate, sertraline mandelate (4). This new process has been implemented commercially and eliminates the use of hazardous material such as TiCl4, significantly reduces undesirable byproducts, reduces the number of intermediate isolations, and improves the overall process yield and productivity on industrial scale.
- Taber, Geraldine P.,Pfisterer, David M.,Colberg, Juan C.
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p. 385 - 388
(2013/09/05)
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- HYDROGENATION OF IMINE INTERMEDIATES OF SERTRALINE WITH CATALYSTS
-
Provided are hydrogenation processes of sertraline imine intermediates with catalysts in various reactors.
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- PROCESS FOR THE MANUFACTURE OF SERTRALINE
-
Process for the preparation of sertraline by reductive amination of racemic 4-(3, 4-dichlorophenyl)-3, 4-dihydro-1-(2H)-naphthalenone, carried out as one- reaction-vessel process without isolation of intermediates, in the form of pure separated cis and trans isomers, the way of conversion of trans isomer to cis isomer and preparation of FII polymorph of 1S-cis isomer from any other polymorph.
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Page 3; 8-10
(2010/02/05)
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- DDQ as a versatile reagent for oxidative cleavage of tosylhydrazones and oximes
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2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) was found to be a very efficient oxidative reagent for the selective cleavage of tosylhydrazones and oximes of carbonyl compounds for the first time.
- Chandrasekhar,Reddy, Ch. Raji,Reddy, M. Venkat
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p. 430 - 431
(2007/10/03)
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- Process for preparing chiral tetralone
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A process for preparing the chiral (4S)-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone is disclosed wherein racemic 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone is asymmetrically reduced by contacting the racemic tetralone with an asymmetric reagent to produce a mixture of cis and trans alcohols, separating the cis from the trans alcohols, and oxidizing the (4S) enantiomer of the resulting cis and trans alcohols. Also disclosed are novel intermediates used in the synthesis of the above chiral tetralone.
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- Method of preparing 4-dichlorophenyl-1-tetralones
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Method of preparing 4-disubstituted phenyl-1-tetralones of formula STR1 in which X represents halogen, C1 -C4 alkyl or C1 -C4 alkoxy and Y, situated in position 2' or 3', represents halogen or C1 -C4 alkyl, this method being characterized in that it comprises the reaction, in the presence of an acid agent, of α-naphthol of formula (II) with a phenyl compound of formula (III): STR2 where X represents halogen, C1 -C4 alkyl or C1 -C4 alkoxy, and Y is situated in the ortho or meta position with respect to X and represents halogen or C1 -C4 alkyl.
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- Process for preparing sertraline intermediates
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A novel three-step process for preparing 4-(3,4-dichlorophenyl)-4-phenylbutanoic acid is disclosed, which involves (1) reducing 4-(3,4-dichlorophenyl)-4-ketobutanoic acid to 4-(3,4-dichlorophenyl)-4-hydroxybutanoic acid; (2) then converting the intermediate hydroxy acid formed in the first step to 5-(3,4-dichlorophenyl)-dihydro-2(3H)-furanone, and (3) thereafter reacting the resulting gamma-butyrolactone compound with benzene in a Friedel-Crafts type reaction to form the desired final product. The latter compound is known to be useful as an intermediate leading to 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone and ultimately, to cis-(1S)(4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalene amine (sertraline), which is known to be a preferred anti-depressant agent in the field of medicinal chemistry. The aforementioned 5-(3,4-dichlorophenyl)-dihydro-2(3H)-furanone and 4-(3,4-dichlorophenyl)-4-hydroxybutanoic acid are both novel compounds. There is also disclosed a novel process for converting 5-(3,4-dichlorophenyl)-dihydro-2(3H)-furanone directly to 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone, as well as an alternate novel process for converting 4-(3,4-dichlorophenyl)-4-hydroxybutanoic acid directly to this same key intermediate.
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- 6-phenyl-1,2-3,4,4a,5-6,10b-octahydrobenz(h)isoquinolines useful for treating depression
-
6-Phenyl-1,2,3,4,4a,5,6,10b-octahydrobenz(h)isoquinolines having anti-depressant activity and methods for their preparation.
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-
- Nontricyclic Antidepressant Agents Derived from cis- and trans-1-Amino-4-aryltetralins
-
The need for drugs that lack the obtrusive and limiting side effects of the tricyclic antidepressants has prompted the search for agents with greatly enhanced selectivity for specific mechanisms believed to be essential for antidepressant efficacy.The potential role of derangements of 5-HT pathways in the etiology of depression has long been suspected and has given impetus to the development of newer compounds that accentuate inhibition of serotonin reuptake.This paper presents structure-activity relationship for a series of cis-1-amino-4-(substituted-aryl)tetralins, which are surprisingly potent and selective inhibitors of serotonin uptake in in vitro models.These compounds are pharmacologically distinct from corresponding members of the trans series, which also potently block uptake of dopamine and norepinephrine.The activity in both cis and trans series is stereospecific, being restricted to the cis-(1S,4S) and the trans-(1R,4S) enantiomers.
- Welch, Willard M.,Kraska, Allen R.,Sarges, Reinhard,Koe, B. Kenneth
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p. 1508 - 1515
(2007/10/02)
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