- Electrochemical oxidation of 5-hydroxymethyl tolterodine and identification of its oxidation products using liquid chromatography and mass spectrometry
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The electrochemical behavior of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of antimuscarinic drugs tolterodine and fesoterodine used to treat urge incontinence and overactive bladder, was investigated using cyclic and differential pulse voltammetry at glassy carbon electrode. Electrooxidation of 5-HMT proceeds as a complex pH-dependent process. Controlled potential electrolysis of 5-HMT solutions was performed at platinum gauze electrode in aqueous-methanolic media. Electrolyzed solutions were analyzed using ultra performance liquid chromatography with electrospray ionization quadrupole time-of-flight mass spectrometry. Two main oxidation centers of the studied molecule were located: the p-hydroxybenzyl alcohol group and the tertiary amino group. Oxidation of the first center proceeds in several steps leading to the formation of 5-formyl tolterodine, p-benzoquinone derivative and several dimeric, hydroxylated and methoxylated products depending on pH of the solution and electrode potential. The second center is oxidized preferentially in alkaline media at higher potentials under the hydrolytic cleavage of diisopropylamine and formation of corresponding aldehydes. Mechanism of the electrochemical oxidation of 5-HMT has been proposed.
- Ku?erová, Pavla,Skopalová, Jana,Ku?era, Luká?,Táborsky, Jakub,?vecová, Hana,Lemr, Karel,Canka?, Petr,Barták, Petr
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Read Online
- NOVEL (R) AND RAC 3-(2-(ALLYLOXY)-5-METHYLPHENYL)-N,N-DIISOPROPYL-3- PHENYLPROPAN-1-AMINE AND ITS USE FOR SYNTHESIS OF (R) AND RAC-2-(3- (DIISOPROPYLAMINO)-1-PHENYLPROPYL)-4-(HYDROXYMETHYL)PHENOL
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The present invention relates to novel chiral 3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine (5) and racemic 3-(2-(allyloxy)-5-methylphenyl)-N,N-diisopropyl-3-phenylpropan-1-amine () and its use in improved and industrially advantageous process for preparation of chiral and racemic form of 2-(3-(diisopropylamino)-1-phenylpropyl)-4-(hydroxymethyl)phenol. Further, present invention relates to preparation of the same.
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- Formal synthesis of fesoterodine by acid-facilitated aromatic alkylation
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The competitive muscarinic receptor antagonist fesoterodine is a congener of tolterodine and has better efficiency compared to tolterodine. In this study, we present an efficient synthesis of the fesoterodine intermediate 3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzaldehyde from ethyl benzoylacetate by Friedel-Crafts alkylation in the presence of an acid as a key reaction step. The synthesis is carried out by the reduction of the ketoester to a 1,3-diol, diisopropylamine substitution, and Friedel-Crafts alkylation, followed by reduction and chiral resolution.
- Lee, Youngeun,Shabbir, Saira,Jeong, Yuri,Ban, Jaeyoung,Rhee, Hakjune
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p. 2885 - 2889
(2016/02/05)
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- Iridium-Catalyzed Enantioselective Allylic Substitution of Enol Silanes from Vinylogous Esters and Amides
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The enol silanes of vinylogous esters and amides are classic dienes for Diels-Alder reactions. Here, we report their reactivity as nucleophiles in Ir-catalyzed, enantioselective allylic substitution reactions. A variety of allylic carbonates react with these nucleophiles to give allylated products in good yields with high enantioselectivities and excellent branched-to-linear ratios. These reactions occur with KF or alkoxide as the additive, but mechanistic studies suggest that these additives do not activate the enol silanes. Instead, they serve as bases to promote the cyclometalation to generate the active Ir catalyst. The carbonate anion, which was generated from the oxidative addition of the allylic carbonate, likely activates the enol silanes to trigger their activity as nucleophiles for reactions with the allyliridium electrophile. The synthetic utility of this method was illustrated by the synthesis of the anti-muscarinic drug, fesoterodine.
- Chen, Ming,Hartwig, John F.
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supporting information
p. 13972 - 13979
(2016/01/15)
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- PROCESS FOR THE PREPARATION OF OPTICALLY PURE FESOTERODINE DERIVATIVES
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3,3-diphenylpropylamines of general formula (I), particularly Fesoterodine, as well as their enantiomers, solvates and salts, can be produced by treating a compound of formula (II) with a chiral alcohol to yield the diastereomeric esters of formula (IV) and (IV′), which can be further transformed into a compound of formula (I), or an enantiomer, solvate or salt thereof, wherein R1 is C1-C8 alkyl; and R2 and R3, independently of one another, represent H or C1-C6 alkyl, or together form a ring of 3 to 7 members with the nitrogen to which they are bound.
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- PROCESS FOR THE PREPARATION OF FESOTERODINE
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The present invention relates to an improved process for the preparation of Fesoterodine and pharmaceutically acceptable salts thereof. The present invention particularly relates to a process for the preparation of Fesoterodine from O-benzyl tolterodine.
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Paragraph 0032; 0049
(2015/01/07)
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- PROCESS FOR THE PREPARATION OF 2-HYDROXY-4-PHENYL-3,4-DIHYDRO-2H-CHROMEN-6-YL-METHANOL AND (R)-FESO-DEACYL
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The present invention regards an improved and industrially advantageous process for the preparation of the 2-hydroxy-4-phenyl-3,4-dihydro-2H-chromen-6-yl-methanol intermediates, also called “feso chromenyl” and (R)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenol, also called “(R)-feso deacyl”, which are in turn used in the synthesis of fesoterodine and in particular of fesoterodine fumarate. This process utilises reagents which are non-toxic and manageable at industrial level and enables obtaining a new stable and non-hygroscopic crystalline form of the key intermediate “(R)-feso deacyl”, called form B.
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- PROCESS FOR THE PREPARATION OF FESOTERODINE OR ITS SALTS
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The present invention relates to a process for the preparation of fesoterodine or its salts.
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Page/Page column 12
(2013/04/13)
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- DESFESOTERODINE SALTS
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The invention relates to substantially pure Desfesoterodine salts, Desfesoterodine salts, solid state forms thereof and pharmaceutical compositions comprising one or more of the Desfesoterodine salts and/or solid state forms thereof.
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Paragraph 0084
(2014/01/08)
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- PROCESS FOR THE PREPARATION OF OPTICALLY ACTIVE 3,3-DIPHENYLPROPYLAMINES
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The invention relates to a process for obtaining 3,3-diphenylpropylamines of general formula (I), particularly Fesoterodine, as well as their enantiomers, solvates and salts, comprising treating a compound of formula (II) with a chiral alcohol to yield the diastereomeric esters of formula (IV) and (IV'), which can be further transformed into a compound of formula (I), or an enantiomer, solvate or salt thereof, wherein R1 is C1-C8 alkyl; and R2 and R3, independently of one another, represent H or C1-C6 alkyl, or together form a ring of 3 to 7 members with the nitrogen to which they are bound.
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- PROCESS FOR THE PREPARATION OF MUSCARINIC RECEPTOR ANTAGONIST
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The present invention relates to novel and improved processes for the preparation of (r)-2-(3-(diisopropylamino)-1-phenylpropyl)-4-(hydroxymethyl)phenylisobutyrate represented by the following structural formula-1 and its pharmaceutically acceptable salts thereof.
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Page/Page column 60
(2012/08/07)
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- PROCESSES FOR THE PREPARATION OF FESOTERODINE
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The invention relates to improved process for the preparation of fesoterodine and its pharmaceutically acceptable salt, specifically fesoterodine fumarate of formula (1). The invention relates to solid state forms of a novel salt of fesoterodine and process for the preparation thereof. The invention also relates to highly pure fesoterodine fumarate substantially free of impurity X at RRT 1.37. The invention also provides solid particles of pure fesoterodine fumarate wherein 90 volume-percent of the particles (D90) have a size of higher than 200 microns.
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Page/Page column 33-34
(2012/03/26)
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- A PROCESS FOR PREPARING FESOTERODINE
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The present invention relates to an improved process for the preparation of Fesoterodine and pharmaceutically acceptable salts thereof. The present invention particularly relates to a process for the preparation of fesoterodine and pharmaceutically acceptable salts thereof which involves use and preparation of R(+) benzyl tolterodine and fumarate salt of R(+)-[4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-phenyl]-methanol.
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- PROCESS FOR THE PREPARATION OF 2 -HYDROXY- 4 -PHENYL -3, 4 -DIHYDRO-2H-CHROMEN- 6 -YL -METHANOL AND (R) - FESO - DEACYL
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The present invention regards an improved and industrially advantageous process for the preparation of the 2-hyaroxy-4-phenyl-3,4-dihydro-2H-chromen-6-yl-methanol intermediates, also called "feso chromenyl" and (R)-2-[3-(diisopropylamino)-l- phenylpropyl]-4-(hydroxymethyl)phenol, also called "(R)-feso deacyl", which are in turn used in the synthesis of fesoterodine and in particular of fesoterodine furnarate. This process utilises reagents which are non-toxic and manageable at industrial level and enables obtaining a new stable and non-hygroscopic crystalline form of the key intermediate "(R)-feso deacyl", called form B.
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- The lactol route to fesoterodine: An amine-promoted Friedel-Crafts alkylation on commercial scale
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We report the discovery and optimization of an amine-promoted Friedel-Crafts alkylation of cinnamaldehyde with 4-hydroxymethyl phenol. This reaction has been used successfully on commercial scale (200 kg) in the context of the manufacture of fesoterodine, a muscarinic antagonist used for the treatment of overactive bladder. Reductive aminations of diisopropylamine and lactol 4 are also discussed, as well as the resolution of the racemic amine rac-2 into its enantiomerically pure form.
- Dirat, Olivier,Bibb, Andrew J.,Burns, Colin M.,Checksfield, Graham D.,Dillon, Barry R.,Field, Stuart E.,Fussell, Steven J.,Green, Stuart P.,Mason, Clive,Mathew, Jinu,Mathew, Suju,Moses, Ian B.,Nikiforov, Petar I.,Pettman, Alan J.,Susanne, Flavien
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p. 1010 - 1017
(2011/12/16)
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- PREPARATION PROCESS OF FESOTERODINE AND INTERMEDIATES
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The present invention relates to a process of synthesis of 3,3 dipheylpropylamines, which may be used as pharmaceutical intermediates in the preparation of their pharmacologically active derivatives such as fesoterodine, tolterodine, their enantiomers, pharmaceutically acceptable salts and related compounds useful as antimuscarinic agents.
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- IMPROVED PROCESS FOR DIPHENYLPROPYLAMINE DERIVATIVES
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The present invention relates to an improved process for the preparation of biologically active diphenylpropylamine derivatives. The present invention specifically relates to an improved fesoterodine of formula (I) and its pharmaceutically acceptable salts.
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- Process for preparation of 3-(2-hydroxy-5-substituted phenyl)-3-phenylpropylamines, intermediates for making hydroxytolterodine
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A process is described for the preparation of 3-(5-formyl-2-hydroxyphenyl)-3-phenylpropylamine derivatives, intermediates which can be used for preparation of agents for urinary incontinence therapy, specifically to 2-(3-(diisopropylamino)-1-phenylpropyl)-4-(hydroxymethyl)phenol and its prodrugs.
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- SHORT SYNTHESIS OF TOLTERODINE, INTERMEDIATES AND METABOLITES
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A process is described for the preparation of intermediates which can be used for preparation of agents for urinary incontinence therapy, specifically to 2-(3-(diisopropylamino)- 1-phenylpropyl)-4-(hydroxymethyl)phenol and its prodrugs.
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- PROCESS FOR PREPARATION OF PHENOLIC MONOESTERS OF HYDROXYMETHYL PHENOLS
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Disclosed herein is an improved and efficient process for preparation of fesoterodine and its pharmaceutically acceptable salt. Disclosed also herein is novel intermediate of formula (III). Also disclosed are metal salts of formula (XII) and preparation thereof.
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- PROCESS FOR PREPARATION OF PHENOLIC MONOESTERS OF HYDROXYMETHYL PHENOLS
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A process for the preparation of phenolic monoesters of 2-(3-diisopropylamino-1-phenylpropyl)-4-(hydroxymethyl)phenol by converting (±)6-halo-4-phenylchroman-2-one to (±)4-halo-2-(3-hydroxy-1-phenylpropyl)phenol. The two hydroxyl groups are protected and the protected compound is reacted with diisopropylamine to give (±)[3-(2-benzyloxy-5-halophenyl)-3-phenylpropyl]diisopropylamine. The halo substituent on the benzene ring is converted to corresponding benzyl alcohol and then the protection is removed to give racemic 5-HMT. Racemic 5-HMT is converted R enantiomer and then it is esterified.
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- PROCESS FOR THE PREPARATION OF FESOTERODINE WITH LOW IMPURITIES CONTENT
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Disclosed is a process for the preparation of (R)-2-(3-diisopropylamino-1-phenylpropyl)-4-(hydroxymethyl)-phenol isobutyrate (Fesoterodine) or a pharmaceutically acceptable salt thereof having a low content of impurities such as tolterodine and tolterodine isobutyrate.
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Page/Page column 4-5
(2011/07/06)
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- A process for the preparation of fesoterodine with low impurities content
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Disclosed is a process for the preparation of (R)-2-(3-diisopropylamino-1-phenylpropyl)-4-(hydroxymethyl)-phenol isobutyrate (Fesoterodine) or a pharmaceutically acceptable salt thereof having a low content of impurities such as tolterodine and tolterodine isobutyrate.
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Page/Page column 8-9
(2011/07/09)
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- Process for the preparation of fesoterodine
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A process for the preparation of (R)-2-(3-diisopropylamino-1-phenylpropyl)-4-(hydroxymethyl)-phenol isobutyrate (Fesoterodine), its (S)-enantiomer, and novel intermediates useful in thei synthesis.
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Page/Page column 9-10
(2011/05/08)
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- SOLID STATE FORMS OF FESOTERODINE INTERMEDIATES
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Provided herein are novel solid state forms of fesoterodine intermediates, (R)-4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-benzoic acid and (R)-[4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-phenyl]-methanol, and processes for their preparation thereof. The solid state intermediates are useful for preparing fesoterodine or a pharmaceutically acceptable salt thereof in high purity.
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Page/Page column 8
(2011/06/19)
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- PROCESS FOR THE PREPARATION OF FESOTERODINE
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A process for the preparation of (R)-2-(3-diisopropylamino-1-phenylpropyl)-4-(hydroxymethyl)-phenol isobutyrate (Fesoterodine), its (S)-enantiomer, and novel intermediates useful in thei synthesis.
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Page/Page column 6
(2011/05/08)
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- Process for the Preparation of Fesoterodine
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Disclosed herein is an improved, commercially viable and industrially advantageous process for the preparation of Fesoterodine or a pharmaceutically acceptable salt thereof in high yield and purity. Disclosed also herein is an improved and industrially advantageous optical resolution method of racemic (±)-N,N-Diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropylamine and use thereof for the preparation of Fesoterodine.
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Page/Page column 10
(2010/09/05)
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- FESOTERODINE SUBSTANTIALLY FREE OF DEHYDROXY IMPURITY
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Provided herein is an impurity of fesoterodine, fesoterodine dehydroxy impurity, 2-[(lR)-3- [bis(l-methylethyl)amino]-l-phenylpropyl]-4-methylphenyl isobutyrate, and a process for preparing and isolating thereof. Provided further herein is a highly pure fesoterodine or a pharmaceutically acceptable salt thereof substantially free of fesoterodine dehydroxy impurity, process for the preparation thereof, and pharmaceutical compositions comprising highly pure fesoterodine or a pharmaceutically acceptable salt thereof substantially free of dehydroxy impurity. Provided also herein is a pharmaceutical composition comprising solid particles of pure fesoterodine fumarate substantially free of dehydroxy impurity, wherein 90 volume-percent of the particles (D90) have a size of less than about 200 microns.
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Page/Page column 8; 24
(2010/04/03)
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- PROCESS FOR PREPARATION OF 3-(2-HYDROXY-5-SUBSTITUTED PHENYL)-N-ALKYL-3-PHENYLPROPYLAMINES
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A new process for preparation of 3-(2-hydroxy-5-substituted phenyl)-N,alkyl-3- phenylpropylamiηes from cinamoyl chloride via N-alky-3-phenylprop-2-en-1 -amine has been developed.
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- PROCESS FOR THE PRODUCTION OF BENZOPYRAN-2-OL DERIVATIVES
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The invention provides a process for the production of a compound of formula (I), wherein Y is selected from CH3, CH2OH, CH2CH2OH, CH2Br and Br; comprising the steps of: (i) reacting a compound of formula (II), wherein OX is hydroxy or O- M+, in which M+ is a cation selected from Li+, Na+ and K+, and Y is as defined above; with trans-cinnamaldehyde (III), in the presence of a secondary amine compound; then (ii) treating the product of the preceding step with acid to afford the compound of formula (I). The above process may be used in the production of tolterodine and fesoterodine, which are useful in the treatment of overactive bladder.
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Page/Page column 26-27; 29
(2008/06/13)
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- A shortened synthesis of substituted hydroxymethyl phenols
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The present disclosure relates to a process for the preparation of 2-(3-diisopropylamino-1-phenylpropyl)-4-(hydroxymethyl)phenol or its phenolic monoesters or salts thereof, characterized by the steps of a) reacting a compound of formula (II) with a mixture of MeMgCl and Mg in a solvent, b) optionally reducing the temperature of the Grignard reagent to a lower temperature than in step a), and reacting the resulting Grignard reagent with an excess of a carbonate in a solvent, to obtain a compound of formula (III) wherein A is a C1-C6 alkyl group, and then further reacting the compound of formula (III) in a known manner to obtain the desired end product.
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Page/Page column 13-14
(2008/06/13)
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- SHORTENED SYNTHESIS USING PARAFORMALDEHYDE OR TRIOXANE
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The present disclosure relates to a process for the preparation of a compound of formula (I) wherein R is hydrogen, a formyl group, a straight, branched or cyclic C1-C6 alkylcarbonyl group or a phenylcarbonyl group, or a salt thereof, characterized by the steps of reacting a compound of formula (II) with a mixture of Grignard initiator and Mg in a solvent to form a Grignard reagent, reacting the Grignard reagent with paraformaldehyde or trioxane to obtain a compound of formula (III) and then further reacting the compound of formula (III) in a known manner to obtain a compound of formula (I) and optionally salt formation.
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Page/Page column 12; 14; 15; 16
(2008/06/13)
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- NEW CHIRAL INTERMEDIATE, PROCESS FOR PRODUCING THE SAME AND ITS USE IN THE MANUFACTURE OF TOLTERODINE, FESOTERODINE, OR THE ACTIVE METABOLITE THEREOF
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The compound of formula (I): is provided. It may be produced by subjecting a compound of formula (IV) to a reduction reaction wherein R represents hydrogen, straight or branched C1-C6 alkyl. This compound is a valuable intermediate which may be used in the synthesis of fesoterodine, tolterodine, its active metabolite, and related compounds.
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Page/Page column 21
(2008/06/13)
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- Shortened synthesis of 3,3-diarylpropylamine derivatives
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The invention relates to a method for producing derivatives of 3,3-diarylpropylamines of general formula (I) and sterically highly pure, stable intermediate products, and to their use for producing pharmaceutical compositions.
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Page/Page column 8
(2008/06/13)
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