- Discovery of sertraline and its derivatives able to combat drug-resistant gastric cancer cell via inducing apoptosis
-
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
-
supporting information
(2021/04/12)
-
- Sertraline side chain amino structure derivative as well as preparation method and application thereof
-
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.
- -
-
Paragraph 0048-0049
(2021/04/17)
-
- Copper-Catalyzed Enantioselective Arylation via Radical-Mediated C-C Bond Cleavage: Synthesis of Chiral ω,ω-Diaryl Alkyl Nitriles
-
The first example of copper-catalyzed ring-opening, enantioselective arylation of cyclic ketoxime esters to access ω,ω-diaryl alkyl nitriles has been developed in high yield (up to 92% yield) with excellent enantioselectivity (up to 91% ee). Side-arm bis(oxazoline) ligand plays a significant role in this asymmetric catalytic transformation, which provides an efficient route to construct diverse chiral ω,ω-diaryl alkyl nitriles. Synthetic utility has also been demonstrated in the further derivatization of the ω,ω-diaryl alkyl nitrile to the corresponding amide.
- Cui, Guo-Qing,Dai, Jing-Cheng,Li, Yan,Li, Yuan-Bo,Hu, Duo-Duo,Bian, Kang-Jie,Sheng, Jie,Wang, Xi-Sheng
-
supporting information
p. 7503 - 7507
(2021/10/02)
-
- Exploring the synthetic potential of a marine transaminase including discrimination at a remote stereocentre
-
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.
-
supporting information
p. 188 - 198
(2021/01/18)
-
- Titanium(IV)-Mediated Ring-Opening/Dehydroxylative Cross-Coupling of Diaryl-Substituted Methanols with Cyclopropanol Derivatives
-
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
-
p. 15753 - 15760
(2021/10/25)
-
- Method for preparing serrine hydrochloride intermediate and impurities
-
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.
- -
-
Paragraph 0027-0032
(2020/12/31)
-
- Chemoenzymatic Synthesis of Sertraline
-
A chemoenzymatic approach has been developed for the preparation of sertraline, an established anti-depressant drug. Ketoreductases (KREDs) were employed to yield a key chiral precursor. The bioreduction of the racemic tetralone exhibited excellent enantioselectivity (>99 % ee) and diastereomeric ratio (99:1) at 29 % conversion (the maximum theoretical yield is 50 %) after 7 hours. The resulting (S,S)-alcohol was efficiently oxidized to an enantiopure (S)-ketone, an immediate precursor of sertraline, by using sodium hypochlorite as oxidant and 2-azaadamantane N-oxyl (AZADO) as organocatalyst. Alternative routes aiming at the direct biocatalytic amination using imine reductases and transaminases were unsuccessful.
- Marx, Lisa,Ríos-Lombardía, Nicolás,Süss, Philipp,H?hne, Matthias,Morís, Francisco,González-Sabín, Javier,Berglund, Per
-
p. 510 - 513
(2020/01/25)
-
- Nickel-Catalyzed α-Carbonylalkylarylation of Vinylarenes: Expedient Access to γ,γ-Diarylcarbonyl and Aryltetralone Derivatives
-
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.
-
p. 8047 - 8051
(2020/04/30)
-
- Identification of an Esterase Isolated Using Metagenomic Technology which Displays an Unusual Substrate Scope and its Characterisation as an Enantioselective Biocatalyst
-
Evaluation of an esterase annotated as 26D isolated from a marine metagenomic library is described. Esterase 26D was found to have a unique substrate scope, including synthetic transformations which could not be readily effected in a synthetically useful manner using commercially available enzymes. Esterase 26D was more selective towards substrates which had larger, more sterically demanding substituents (i. e. iso-propyl or tert-butyl groups) on the β-carbon, which is in contrast to previously tested commercially available enzymes which displayed a preference for substrates with sterically less demanding substituents (e.g. methyl group) at the β-carbon. (Figure presented.).
- Gavin, Declan P.,Murphy, Edel J.,Foley, Aoife M.,Castilla, Ignacio Abreu,Reen, F. Jerry,Woods, David F.,Collins, Stuart G.,O'Gara, Fergal,Maguire, Anita R.
-
p. 2466 - 2474
(2019/03/11)
-
- Correction to: Nickel-catalyzed asymmetric reductive cross-coupling to access 1,1-diarylalkanes (Journal of the American Chemical Society (2017) 139 (5684-5687) DOI: 10.1021/jacs.7b01705)
-
Pages 5684 and 5685, Table of Contents, and Supporting Information. The stereochemistry of L1, depicted as the (S,S)- enantiomer in Figure 1, Table 1, the TOC graphic (identical to Figure 1), and the Supporting Information of the original publication, was incorrect. (R,R)-L1 was used in this study. The stereochemistry of (R,R)-L1 has been confirmed by singlecrystal X-ray diffraction; the X-ray diffraction data and CIF file for (R,R)-L1 have been added to the Supporting Information. The corrected TOC graphic/Figure 1 is shown here. (R,R)-L4 and (R,R)-L5 were also used in Table 1 and incorrectly depicted as (S,S)-L4 and (S,S)-L5 in the original publication. To reflect that different enantiomeric series of catalysts were used, Table 1 has been updated to indicate that entries 2, 3, and 6 produce (S)-3a. This correction does not change the stereochemical assignment of the diarylalkane products, or the conclusions of the Communication. The stereochemistry of the products was assigned by obtaining an X-ray structure of diarylalkane 3k, and the rest of the compounds were assigned by analogy. (Table Presented).
- Poremba, Kelsey E.,Kadunce, Nathaniel T.,Suzuki, Naoyuki,Cherney, Alan H.,Reisman, Sarah E.
-
supporting information
p. 7746 - 7746
(2018/06/26)
-
- α,α-Diarylethylene Glycols as Valuable Precursor for Synthesis of 1,1-Diarylethenes and α,α-Diaryl Acetaldehydes
-
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
-
supporting information
p. 3594 - 3605
(2017/07/22)
-
- Nickel-Catalyzed Asymmetric Reductive Cross-Coupling to Access 1,1-Diarylalkanes
-
An asymmetric Ni-catalyzed reductive cross-coupling of (hetero)aryl iodides and benzylic chlorides has been developed to prepare enantioenriched 1,1-diarylalkanes. As part of these studies, a new chiral bioxazoline ligand, 4-heptyl-BiOX (L1), was developed in order to obtain products in synthetically useful yield and enantioselectivity. The reaction tolerates a variety of heterocyclic coupling partners, including pyridines, pyrimidines, indoles, and piperidines.
- Poremba, Kelsey E.,Kadunce, Nathaniel T.,Suzuki, Naoyuki,Cherney, Alan H.,Reisman, Sarah E.
-
supporting information
p. 5684 - 5687
(2017/05/04)
-
- A step-wise reduction of nonracemic α-ketoamides to α-methine amides under mild conditions
-
A step-wise reductive method that converts nonracemic γ-chiral α-ketoamides into amide derivatives was developed under mild conditions. The method involves a highly efficient three-step transformation including NaBH4-reduction, bromination and Pd/C hydrogenation reactions. As a consequence, a variety of nonracemic γ-diaryl amides products were obtained in high overall yields with excellent enantiomeric specificity. The utility of the method is demonstrated through the concise formal synthesis of (+)-sertraline in good overall yield.
- Wang, Bing,Wang, Min,Jia, Tao,Lou, Yazhou,Liao, Jian,Cao, Peng
-
p. 2042 - 2047
(2016/04/05)
-
- DIPHENYLOXIRANES, PROCESS FOR PREPARATION THEREOF, AND ITS USE IN AN ENANTIOSELECTIVE SYNTHESIS OF (+)-SERTRALINE
-
The present invention discloses substituted diphenyloxiranes and process for synthesis thereof. The present invention also provides a process for production of enantiomerically pure anti-3,3'-diphenylmethyloxirane and anti-3,3'-diphenylpropan- 1,2-diol from racemic anti-3,3'-diphenylmethyloxirane using hydrolytic kinetic resolution. Further it provides a process for preparation of enantioselective (+)- Sertraline from anti-3,3'-diphenylpropan-1,2-diol.
- -
-
-
- Synthesis of 1-Aryltetralins and 1-Arylnaphthalenes via (4 + 2) Annulation of β-Ketosulfones with Styryl Bromides
-
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
-
p. 1682 - 1685
(2016/04/26)
-
- Sodium amalgam mediated desulfonylative reduction of α-functionalized β-ketosulfones
-
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
-
p. 5521 - 5529
(2016/08/04)
-
- Rhodium-catalyzed asymmetric arylation of β,γ-unsaturated α-ketoamides for the construction of nonracemic γ,γ- diarylcarbonyl compounds
-
A highly regio- and enantioselective rhodium-catalyzed 1,4-addition of arylboronic acids to β,γ-unsaturated α-ketoamides using a simple new chiral sulfinylphosphine ligand is described. This transformation provides an attractive approach to construct chiral nonracemic γ,γ-diarylsubstituted carbonyl compounds, as exemplified in the concise syntheses of sertraline and tetrahydroquinoline-2-carboxylamide. Constructing chiral carbonyls: A simple new chiral sulfinylphosphine ligand L was developed, which promoted excellent 1,4-selectivities and enantioselectivities in the rhodium-catalyzed conjugate addition of arylboronic acids to β,γ-unsaturated α-ketoamides. The desired γ,γ-diaryl-α-ketocarbonyl compounds were afforded with high yields and high optical purities.
- Wang, Juanjuan,Wang, Min,Cao, Peng,Jiang, Liyin,Chen, Guihua,Liao, Jian
-
supporting information
p. 6673 - 6677
(2014/07/08)
-
- Nickel/bis(oxazoline)-catalyzed asymmetric negishi arylations of racemic secondary benzylic electrophiles to generate enantioenriched 1,1-diarylalkanes
-
A tertiary stereogenic center that bears two different aryl substituents is found in a variety of bioactive compounds, including medicines such as Zoloft and Detrol. We have developed an efficient method for the synthesis of enantioenriched 1,1-diarylalkanes from readily available racemic benzylic alcohols. Formation of a benzylic mesylate (which is not isolated), followed by treatment with an arylzinc reagent, LiI, and a chiral nickel/bis(oxazoline) catalyst, furnishes the Negishi cross-coupling product in high ee and good yield. A wide array of functional groups (e.g., an aryl iodide, a thiophene, and an N-Boc-indole) are compatible with the mild reaction conditions. This method has been applied to a gram-scale synthesis of a precursor to Zoloft.
- Do, Hien-Quang,Chandrashekar,Fu, Gregory C.
-
p. 16288 - 16291
(2013/12/04)
-
- Sustainable flow oppenauer oxidation of secondary benzylic alcohols with a heterogeneous zirconia catalyst
-
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.
-
supporting information
p. 5698 - 5701
(2013/12/04)
-
- AROMATIC KETONE SYNTHESIS WITH AMIDE REAGENTS AND RELATED REACTIONS
-
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.
- -
-
Paragraph 0038; 0040
(2013/10/22)
-
- 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
-
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
-
p. 5248 - 5257
(2012/08/08)
-
- Friedel-crafts acylation with amides
-
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.
-
experimental part
p. 5788 - 5793
(2012/07/30)
-
- Stereoselective amination of chiral benzylic ethers using chlorosulfonyl isocyanate: Total synthesis of (+)-Sertraline
-
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
-
experimental part
p. 10011 - 10019
(2012/02/05)
-
- Asymmetric hydrogenation of N-Alkyl ketimines with phosphine-free, chiral, cationic Ru-MsDPEN catalysts
-
(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
-
p. 1109 - 1113
(2011/03/21)
-
- Enantioselective syntheses of (+)-sertraline and (+)-indatraline using lithiation/borylation-protodeboronation methodology
-
The lithiation/borylation-protodeboronation of a homoallyl carbamate was applied to the synthesis of (+)-sertraline and (+)-indatraline. Due to the presence of the alkene, significant modifications of the methodology were required (use of 12-crown-4, TMSCl, H2O), or a solvent switch to CHCl3, to achieve high yields and high selectivities.
- Roesner, Stefan,Casatejada, Javier Mansilla,Elford, Tim G.,Sonawane, Ravindra P.,Aggarwal, Varinder K.
-
supporting information; experimental part
p. 5740 - 5743
(2011/12/22)
-
- Aerobic oxidation of secondary benzylic alcohols and direct oxidative amidation of aryl aldehydes promoted by sodium hydride
-
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
-
supporting information; experimental part
p. 3406 - 3411
(2011/06/17)
-
- Palladium-catalyzed γ-selective and stereospecific allyl-aryl coupling between acyclic allylic esters and arylboronic acids
-
Reactions between acyclic (E)-allylic acetates and arylboronic acids in the presence of a palladium catalyst prepared from Pd(OAc)2, phenanthroline (or bipyridine), and AgSbF6 (1:1.2:1) proceeded with excellent γ-selectivity to afford allyl-aryl coupling products with E-configuration. The reactions of α-chiral allylic acetates took place with excellent α-to-γ chirality transfer with syn stereochemistry to give allylated arenes with a stereogenic center at the benzylic position. The reaction tolerated a broad range of functional groups in both the allylic acetates and the arylboronic acids. Furthermore, γ-arylation of cinnamyl alcohol derivatives afforded gem-diarylalkane derivatives containing an unconjugated alkenic substituent. The synthetic utility of this method was demonstrated by its utilization in an efficient synthesis of (+)-sertraline, an antidepressant agent. The observed γ-regioselectivity and E-1,3-syn stereochemistry were rationalized based on a Pd(II) mechanism involving transmetalation between a cationic mono(acyloxo)palladium(II) complex and arylboronic acid, and directed carbopalladation followed by syn-β-acyloxy elimination. The results of stoichiometric reactions of palladium complexes related to possible intermediates were fully consistent with the proposed mechanism.
- Ohmiya, Hirohisa,Makida, Yusuke,Li, Dong,Tanabe, Masahito,Sawamura, Masaya
-
supporting information; experimental part
p. 879 - 889
(2010/03/25)
-
- Remarkable electronic effect on the diastereoselectivity of the Heck reaction of methyl cinnamate with arenediazonium salts: Formal total synthesis of (±)-indatraline and (±)-sertraline
-
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
-
supporting information; experimental part
p. 1217 - 1223
(2009/12/24)
-
- COMBINATIONS OF ESZOPICLONE AND TRANS 4-(3,4-DICHLOROPHENYL)-1,2,3,4-TETRAHYDRO-N-METHYL-1-NAPTHALENAMINE OR TRANS 4-(3,4-DICHLOROPHENYL)-1,2,3,4-TETRAHYDRO-1-NAPTHALENAMINE, AND METHODS OF TREATMENT OF MENOPAUSE AND MOOD, ANXIETY, AND COGNITIVE DISORDERS
-
One aspect of the present invention relates to pharmaceutical compositions containing two or more active agents that when taken together can be used to treat, e.g., menopause, mood disorders, anxiety disorders, or cognitive disorders. The first component of the pharmaceutical composition is a sedative eszopiclone. The second component of the pharmaceutical composition is trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine or trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine. The present invention also relates to a method of treating menopause, perimenopause, mood disorders, anxiety disorders, and cognitive disorders.
- -
-
Page/Page column 20; 22; 26; 28
(2008/06/13)
-
- TREATMENT OF PAIN DISORDERS WITH trans 4-(3,4-DICHLOROPHENYL)-1,2,3,4-TETRAHYDRO-1-NAPHTHALENAMINE AND ITS FORMAMIDE
-
Treatment of pain disorders with (1R,4S)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine; and (1S,4R)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine is disclosed. A process for preparing 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine is also disclosed. The process includes the preparation of all four isomers of N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide, which are also useful in treatment of pain disorders.
- -
-
Page/Page column 9
(2008/06/13)
-
- 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)
-
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.
- -
-
Page/Page column 22
(2008/06/13)
-
- 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
-
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.
-
p. 730 - 732
(2007/10/03)
-
- Asymmetric reduction of substituted indanones and tetralones catalyzed by chiral dendrimer and its application to the synthesis of (+)-sertraline
-
A recoverable dendrimeric supported prolinol was used as a catalyst in the asymmetric reduction of indanones and tetralones to give separable cis and trans isomers up to 97% ee. This method was also applied in the enantioselective synthesis of the antidepressant drug (+)-sertraline.
- Wang, Guangyin,Zheng, Changwu,Zhao, Gang
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p. 2074 - 2081
(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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- TREATMENT OF CNS DISORDERS WITH TRANS 4-(3,4-DICHLOROPHENYL)-1,2,3,4-TETRAHYDRO-1-NAPTHALENAMINE AND ITS FORMAMIDE
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Treatment of CNS disorders with (1R,4S)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine; and (1S,4R)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine is disclosed. A process for preparing 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine is also disclosed. The process includes the preparation of all four isomers of N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide, which are also useful.
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- HYDROGENATION OF IMINE INTERMEDIATES OF SERTRALINE WITH CATALYSTS
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Provided are hydrogenation processes of sertraline imine intermediates with catalysts in various reactors.
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- PROCESS FOR THE MANUFACTURE OF SERTRALINE
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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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- Asymmetric hydrogenation of a 4,4-diaryl-3-butenoate; a novel approach to sertraline.
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The asymmetric hydrogenation of a selectively crystallised (E)-4,4-diaryl-3-butenoate with a rhodium-PhanePhos catalyst is described, providing an intermediate to the antidepressant sertraline.
- Boulton, Lee T,Lennon, Ian C,McCague, Raymond
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p. 1094 - 1096
(2007/10/03)
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- Efficient kinetic resolution in the asymmetric hydrosilylation of imines of 3-substituted indanones and 4-substituted tetralones
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Kinetic resolution of the N-methyl imines of 3-substituted indanones and 4-substituted tetralones could be accomplished by hydrosilylation with a chiral titanocene catalyst. N-Methyl imines of 4-substituted tetralones were resolved to yield, after hydrolysis of the unreacted starting materials, ketones with high ee's and the amine products with high diastereomeric and enantiomeric purity. The utility of this process was demonstrated in the synthesis of sertraline.
- Yun, Jaesook,Buchwald, Stephen L.
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p. 767 - 774
(2007/10/03)
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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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- Catalytic asymmetric synthesis of diarylacetates and 4,4-diarylbutanoates. A formal asymmetric synthesis of (+)-sertraline
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(equation presented) The intermolecular C-H insertion chemistry of phenyldiazoacetates catalyzed by dirhodium tetrakis((S)-N-(dodecylbenzenesulfonyl)prolinate) (Rh2(S-DOSP)4) can be effectively carried out on cyclohexadienes, leading to the asymmetric synthesis of diarylacetates. The reaction of vinyldiazoacetates with cyclohexadienes results in an unprecedented carbenoid reaction that is formally a combined C-H insertion/Cope rearrangement. The synthetic utility of this novel transformation was demonstrated by its utilization in a formal asymmetric synthesis of (+)-sertraline.
- Davies, Huw M. L.,Stafford, Douglas G.,Hansen, Tore
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p. 233 - 236
(2008/02/12)
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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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- A Catalytic Enantioselective Synthetic Route to the Important Antidepressant Sertraline
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An efficient catalytic enantioselective synthesis of the important antidepressant sertraline is described.
- Corey, E. J.,Gant, Thomas, G.
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p. 5373 - 5376
(2007/10/02)
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- Synthesis of 4(S)-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone by SN2 cuprate displacement of an activated chiral benzylic alcohol
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Two routes for the preparation of 4(S)-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone are reported. The most efficient route generates a chiral benzylic alcohol by catalytic asymmetric oxazaborolidine reduction of a γ-ketoester that is subsequently activated and displaced in an SN2 manner with a higher order cuprate. Intramolecular Friedel-Crafts cyclization of the resulting t-butylester affords the title compound.
- Quallich,Woodall
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p. 10239 - 10248
(2007/10/02)
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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
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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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