- Study on synthesis and biological effects of a series of 3,4-dihydroisoquinoline-2(1H)-carboxamide derivatives
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In this paper, we have reported the synthesis and biological evaluation of nineteen (S)-N-substituted-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide derivatives as novel candidate antidepressant and anticonvulsant agents. Compounds 2h, 2k, 2r, and 2s exhibited better potent antidepressant activity and displayed the antidepressant effects in a dose-dependent manner from 10 to 30 mg/kg in the FST and TST. And, we found that the best antidepressant effect of compounds 2r and 2s are likely mediated by an increase in central nervous system 5-HT and NE. In addition, compounds 2r and 2s also exhibited the anticonvulsant activity against MES-induced seizures. Thus, compounds 2r and 2s may be a useful antidepressant adjunct therapy for treating depression in patients with epilepsy. In addition, compounds 2r and 2s showed the anti-inflammatory activity and the excellent analgesic activity. Several scholars have postulated the anti-inflammatory and analgesic effects of antidepressant drugs, suggesting that they may be possess a similar mechanism of action.
- Fu, Zhi-Yang,Jin, Qing-Hao,Xia, Ya-Nan,Jiang, Hai-Ying,Guan, Li-Ping
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- Synthesis, potential anti-inflammatory and analgesic activities study of (S)-N-substituted-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamides
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A series of (S)-N-substitued-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide derivatives were designed, synthesized and evaluated for their anti-inflammatory and analgesic effects in vivo. Among the synthesized compounds 2a and 2n showed the best anti-inflammatory activity (inhibition rate: 95% and 92.7%, respectively) and analgesic effect (inhibition rate: 100% and 100%, respectively), which was greater than that or nearly equivalent to that of indomethacin. Compounds 2a and 2n were selected to test their inhibitory effects against ovine COX-1 and COX-2 using the cyclooxygenase inhibition assay in vitro. Compounds 2a and 2n are weak inhibitors of COX-1 isozyme but displayed moderate COX-2 isozyme inhibitory effects (IC50?=?0.47?μM and 1.63?μM, respectively) and COX-2 selectivity indexes (SI?=?11.5 and 4.8). Furthermore, compound 2a was more inhibitors of COX-2 isozyme active than the reference drug celecoxib.
- Guan, Li-Ping,Xia, Ya-Nan,Jin, Qing-Hao,Liu, Bing-Yu,Wang, Si-Hong
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- Asymmetric synthesis method for preparation of solifenacin
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The invention relates to an asymmetric synthesis method for preparation of solifenacin and specifically, discloses a preparation method of solifenacin. The method comprises that ortho-substituted aldehyde as a raw material undergoes a reaction under catalysis of rhodium and a chiral sulfoxide-olefin ligand to produce a key intermediate for high enantioselective addition, and the intermediate is further functionalized and cyclized to form solifenacin. The method is easy to operate, needs mild reaction conditions and has high efficiency and high selectivity.
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- Preparation method and application of solifenacin derivative
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The invention relates to a preparation method of a solifenacin derivative. The preparation method includes the steps of: (a) using a solifenacin EP impurity A shown as formula 1, adding chlorine dioxide shown as formula 2 in the presence of potassium carb
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Paragraph 0015; 0016; 0019; 0022
(2018/09/08)
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- Highly Enantioselective Arylation of N,N-Dimethylsulfamoyl-Protected Aldimines Using Simple Sulfur-Olefin Ligands: Access to Solifenacin and (S)-(+)-Cryptostyline II
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With the use of a simple sulfur-olefin ligand, a highly enantioselective rhodium-catalyzed addition of arylboroxines to N,N-dimethylsulfamoyl-protected aldimines has been achieved, allowing access to a broad range of chiral diarylmethylamines in high yields (up to 98%) with uniformly excellent enantioselectivities (up to 99% ee). This catalyst system is also applicable to the arylation of N-tosyl arylimines. By utilizing this method, some biologically active molecules possessing a chiral 1-aryl-1,2,3,4-tetrahydroisoquinoline core such as Solifenacin and (S)-(+)-Cryptostyline II are facilely constructed.
- Jiang, Tao,Chen, Wen-Wen,Xu, Ming-Hua
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p. 2138 - 2141
(2017/04/27)
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- A process for the preparation of new thorley that succinic acid
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The invention relates to a method for preparing a solifenacin succinate ((3R)-1-azabicyclo [2.2.2] octane-3-yl (1S)-1-phenyl-3,4-dihydroisoquinoline-2-(1H)-carboxylate succinate). The method comprises the following steps: 1) preparing a compound (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline carboxylic acid ethyl ester of formula III from a compound (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline, serving as a raw material, of formula IV; 2) synthesizing a compound (3R)-1-azabicyclo [2.2.2] octane-3-yl (1S)-1-phenyl-3,4-dihydroisoquinoline-2-(1H)-carboxylate of formula II in an ionic liquid by using the compound (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline carboxylic acid ethyl ester of formula III; and 3) salifying the compound (3R)-1-azabicyclo [2.2.2] octane-3-yl (1S)-1-phenyl-3,4-dihydroisoquinoline-2-(1H)-carboxylate of formula II in an organic solvent to obtain the compound solifenacin succinate ((3R)-1-azabicyclo [2.2.2] octane-3-yl (1S)-1-phenyl-3,4-dihydroisoquinoline-2-(1H)-carboxylate succinate) of formula I. The preparation method has the advantages that the process is simple, the method is suitable for industrialized production, the yield of the product is high and the purity of the product is high.
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Paragraph 0053
(2016/10/07)
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- PROCESS FOR PREPARING (1S)-1-PHENYL-3,4-DIHYDRO-2(1H)-ISOQUINOLINE-CARBOXYLATE
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A process for preparation of (1S)-1-phenyl-3,4-dihydro-2(1H)-isoquinoline-carboxylate (Formula I), comprising reacting (1S)-1-phenyl-3,4-dihydro-2(1H)isoquinoline (Formula II) with carbon dioxide and an alkylating agent R-LG in the presence of a base to obtain the compound of Formula I in an organic solvent. In Formula I and II, R is an alkyl or a substituted alkyl; LG is a leaving group.
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Paragraph 0034
(2015/09/22)
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- Stereoselective Total Syntheses of Solifenacin and N -Acetyl-1-(4-chloro-phenyl)-6,7-dimethoxytetrahydroisoquinoline
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A highly stereoselective synthesis of 1-aryl-1,2,3,4-tetrahydroisoquinoline drugs such as solefinacin (muscarinic acetylcholine receptor antagonist) and N-acetyl-1-(4-chlorophenyl)-6,7-dimethoxytetrahydroisoquinoline (AMPA receptor antagonist) has been accomplished using (R)-tert-butanesulfinamide as a chiral source. Chiral tetrahydroisoquinolines have been prepared through the aryl Grignard addition to chiral N-sulfinylimines followed by haloamide cyclization.
- Babu, R. Anji,Reddy, N. Siva Senkar,Reddy, B. Jagan Mohan,Reddy, B. V. Subba
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p. 2794 - 2798
(2015/11/02)
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- An improved process for the preparation of highly pure solifenacin succinate via resolution through diastereomeric crystallisation
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An improved process for the preparation of solifenacin succinate (1) involving resolution through diastereomeric crystallization is described. (1S)-IQL derivative (5) is esterified to form (1S)-ethoxycarbonyl IQL derivative (6) which is condensed with (RS)-3-quinuclidinol (7) to form a solifenacin diastereomeric mixture (8); this is subjected to resolution through diastereomeric crystallization to produce solifenacin succinate (1), which is used for the treatment of an overactive bladder.
- Trinadhachari, Ganala Naga,Kamat, Anand Gopalkrishna,Venkata Balaji, Boddu,Prabahar, Koilpillai Joseph,Naidu, Kolukuluru Mohan,Babu, Korupolu Raghu,Sanasi, Paul Douglas
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p. 934 - 940
(2014/10/15)
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- Enantioselective iridium-catalyzed hydrogenation of 1- and 3-substituted isoquinolinium salts
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Asymmetric hydrogenation: The title reaction provides an efficient and rapid access to chiral 1- and 3-substituted 1,2,3,4-tetrahydroisoquinolines with excellent enantioselectivity (see scheme; L=ligand). A preliminary mechanistic study indicates that the 1,2-hydride addition might be the initial step in the reaction. The method has been used in the synthesis of urinary antispasmodic drug (+)-solifenacin. Copyright
- Ye, Zhi-Shi,Guo, Ran-Ning,Cai, Xian-Feng,Chen, Mu-Wang,Shi, Lei,Zhou, Yong-Gui
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p. 3685 - 3689
(2013/04/24)
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- NOVEL PROCESS FOR THE PREPARATION OF SOLIFENACIN SUCCINATE
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The present invention relates to a process for the preparation of Solifenacin succinate by condensing a compound of formula (IVb) with (RS)-3-quinuclidinol, wherein, R represents methyl, ethyl, isopropyl; to produce a diastereomeric mixture of (1S)-3,4-dihydro-1-phenyl-2(1H)-isoquinolinecarboxylic acid (3RS)-1-azabicyclo[2.2.2]oct-3-yl ester, which is treated with succinic acid in a solvent or mixture of solvents to produce optically pure Solifenacin succinate, Formula (X).
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Paragraph 0032; 0033
(2013/05/22)
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- Enantioselective synthesis of 1-aryl-tetrahydroisoquinolines through iridium catalyzed asymmetric hydrogenation
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Asymmetric hydrogenation of 1-aryl-3,4-dihydroisoquinolines using the [IrCODCl]2/(R)-3,5-diMe-Synphos catalyst is reported. Under mild reaction conditions, this atom-economical process provides easy access to a variety of enantioenriched 1-aryl-1,2,3,4-tetrahydroisoquinoline derivatives, which are important pharmacophores found in several pharmaceutical drug candidates, in high yields and enantiomeric excesses up to 99% after a single crystallization.
- Berhal, Farouk,Wu, Zi,Zhang, Zhaoguo,Ayad, Tahar,Ratovelomanana-Vidal, Virginie
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supporting information; experimental part
p. 3308 - 3311
(2012/08/28)
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- SOLIFENACIN SALTS
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The invention concerns fumarate salts of solifenacin, as well as pharmaceutical compositions comprising fumarate salts of solifenacin. The invention furthermore concerns a process for preparing solifenacin and salts thereof. The fumarate salt provides improved properties over the known solifenacin salts, especially in terms of its stability. The novel process for its preparation is furthermore improved over known processes for preparing solifenacin in that it provides a higher yield and recovers a greater amount of starting material.
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Page/Page column 17-18
(2012/02/01)
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- NOVEL PROCESS FOR THE PREPARATION OF SOLIFENACIN SUCCINATE
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The present invention relates to a process for the preparation of Solifenacin succinate by condensing a compound of formula (IVb) with (RS)-3-quinuclidinol, wherein, R represents methyl, ethyl, isopropyl; to produce a diastereomeric mixture of ( 1S)-3,4-dihydro- 1 -phenyl-2( 1 H)-isoquinolinecarboxylic acid (3RS)- 1 - azabicyclo[2.2.2]oct-3-yl ester, which is treated with succinic acid in a solvent or mixture of solvents to produce optically pure Solifenacin succinate, Formula (X).
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Page/Page column 8-9
(2012/01/14)
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- PROCESSES FOR THE PREPARATION OF SOLIFENACIN OR A SALT THEREOF
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The present invention describes recovery and racemization of (1R)-Phenyl- 1,2,3,4-tetrahydroisoquinoline of compound of formula (III) to obtain racemic 1- phenyl-1, 2,3,4-tetrahydroisoquinoline of compound of formula (I) and its further resolution to get ( IS)-1-phenyl-1, 2, 3, 4-tetrahydroisoquinoline (intermediate B) in high chemical and chiral purity, which is the key intermediate for the preparation of (3R)-azabicyclo[2.2.2]oct-3-yl (1S)-1-phenyl-3,4-dihydroisoquinoline-2-(1H)- carboxylate.
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- A PROCESS FOR THE PREPARATION OF SOLIFENACIN SALTS AND THEIR INCLUSION INTO PHARMACEUTICAL DOSAGE FORMS
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The invention relates to the synthesis of solifenacin, the preparation of its salts and their inclusion into pharmaceutically acceptable dosage forms.
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Page/Page column 32
(2010/04/03)
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- PROCESSES FOR SOLIFENACIN PREPARATION
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Processes for preparing solifenacin comprising distilling ethanol and organic solvent from a reaction mixture and recycling the organic solvent are described. The ethanol is removed using a Dean-Stark apparatus. Also described are processes for reducing solifenacin diastereomeric and enantiomeric impurities.
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Page/Page column 22-23
(2009/03/07)
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- PROCESS FOR PREPARING CHEMICALLY AND CHIRALLY PURE SOLIFENACIN BASE AND ITS SALTS
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The present invention provides improved processes for preparing chemically and chirally pure Solifenacin base. The present invention also provides for a composition comprising of a salt of Solifenacin having at least 98 % purity. The present invention also disclose certain new salts of Solifenacin as well as well as new polymorphic forms of Solifenacin hydrochloride and Solifenacin oxalate, in pure form.
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Page/Page column 31-32
(2009/09/04)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF SOLIFENACIN AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
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The present invention relates to an improved process for the preparation of solifenacin compound of formula (1) and its succinate salt compound of formula (1a), comprising the condensation of (R)-3- quinuclidinol with (S)-ethyl- 1 -phenyl- 1,2,3,4-tetrahy
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Page/Page column 15-16
(2009/12/23)
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- SOLIFENACIN COMPOSITIONS
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Compositions and/or formulations comprising solifenacin or a salt thereof and processes for preparing the same. Certain compositions and formulations contain a stable amorphous form of solifenacin succinate.
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- PROCESS FOR PREPARING SOLIFENACIN AND ITS SALTS
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The present invention relates to solifenacin in solid form and a process for its preparation and to a process for the preparation of (1S)-1-Phenyl-1,2,3,4-tetrahydro-isoquinoline, a key intermediate in the synthesis of solifenacin and its salts.
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Page/Page column 21
(2008/06/13)
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- COMPOSITION CONTAINING SOLIFENACIN SUCCINATE
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A solifenacin succinate-containing composition with less impurities which can be used as a bulk for pharmaceutical is provided. The solifenacin succinate-containing compostiion of the present invention has a reduced content of especially its optical isomers in comparison with the known compositions containing an acid addition salt of solifenacin, so that it can be used for production of a therapeutic agent containing solifenacin succinate. In addition, the above-described solifenacin succinate-containing composition can be easily produced in accordance with the production method of the present invention.
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Page/Page column 9; 10
(2008/06/13)
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- Synthesis and antimuscarinic properties of quinuclidin-3-yl 1,2,3,4-tetrahydroisoquinoline-2-carboxylate derivatives as novel muscarinic receptor antagonists
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In the course of continuing efforts to develop potent and bladder-selective muscarinic M3 receptor antagonists, quinuclidin-3-yl 1-aryl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate derivatives and related compounds were designed as conformationally restricted analogues of quinuclidin-3-yl benzhydrylcarbamate (8). Binding assays with rat muscarinic receptor subtypes revealed that the quinuclidin-3-yl 1-aryl-1,2,3,4- tetrahydroisoquinoline-2-carboxylate derivatives showed high affinities for the M3 receptor, and selectivity for the M3 receptor over the M2 receptor. Of these derivatives, (+)-(1S,3'R)-quinuclidin-3'-yl 1-phenyl-l,2,3,4-tetrahydroisoquinoline-2-carboxylate monohydrochloride (9b) exhibited almost the same inhibitory activity against bladder contraction to that of oxybutynin (1), and more than 10-fold selectivity for bladder contraction versus salivary secretion, demonstrating that 9b may be useful for the treatment of symptoms associated with overactive bladder without having side effects such as dry mouth.
- Naito, Ryo,Yonetoku, Yasuhiro,Okamoto, Yoshinori,Toyoshima, Akira,Ikeda, Ken,Takeuchi, Makoto
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p. 6597 - 6606
(2007/10/03)
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