cas 209747-05-7, Tolterodin hydrogen tartrate

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Computationally-Led Ligand Modification using Interplay between Theory and Experiments: Highly Active Chiral Rhodium Catalyst Controlled by Electronic Effects and CH–π Interactions
A chiral ligand for the rhodium-catalyzed asymmetric 1,4-addition of an arylboronic acid to a coumarin substrate that could markedly reduce catalyst loading was developed using interplay between theoretical and experimental approaches. Evaluation of the transition states for insertion and for hydrolysis of intermediate complexes (which were emphasized in response to the experimental results) using DFT calculations at the B97D/6-31G(d) level with the LANL2DZ basis set for rhodium revealed that: (i) the electron-poor nature of the ligands and (ii) CH–π interactions between the ligand and coumarin substrates played significant roles in both acceleration of insertion and inhibition of ArB(OH)2 decomposition (protodeboronation). The computationally-designed ligand, incorporating the above information, enabled a decrease in the catalyst loading to 0.025 mol% (S/C=4,000), which is less than one one-hundredth relative to past catalyst loadings of typically 3 mol%, with almost complete enantioselectivity. Furthermore, the gram-scale synthesis of the urological drug, (R)-tolterodine (l)-tartrate, was demonstrated without the need of intermediate purification. (Figure presented.).
Korenaga, Toshinobu,Sasaki, Ryo,Takemoto, Toshihide,Yasuda, Toshihisa,Watanabe, Masahito
supporting information
p. 322 - 333
(2018/01/22)

Ligand-Phospholipid Conjugation: A Versatile Strategy for Developing Long-Acting Ligands That Bind to Membrane Proteins by Restricting the Subcellular Localization of the Ligand
We hypothesized that if drug localization can be restricted to a particular subcellular domain where their target proteins reside, the drugs could bind to their target proteins without being metabolized and/or excreted, which would significantly extend the half-life of the corresponding drug-target complex. Thus, we designed ligand-phospholipid conjugates in which the ligand is conjugated with a phospholipid through a polyethylene glycol linker to restrict the subcellular localization of the ligand in the vicinity of the lipid bilayer. Here, we present the design, synthesis, pharmacological activity, and binding mode analysis of ligand-phospholipid conjugates with muscarinic acetylcholine receptors as the target proteins. These results demonstrate that ligand-phospholipid conjugation can be a versatile strategy for developing long-acting ligands that bind to membrane proteins in drug discovery.
Kawamura, Shuhei,Ito, Yoshihiko,Hirokawa, Takatsugu,Hikiyama, Eriko,Yamada, Shizuo,Shuto, Satoshi
p. 4020 - 4029
(2018/05/07)

PROCESS FOR THE PREPARATION OF (R)-2-(3-DIISOPROPYLAMINO)-1-PHENYLPROPYL)-4METHYLPHENOL AND SALTS THEREOF
The present invention relates to an improved process for the preparation of Tolterodine or salts thereof, which comprises the use of 3-(2-methoxy-5-methylphenyl)-3-phenylpropyl methane sulfonate.
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(2012/03/08)

Chiral separation of tolterodine tartrate using amylosed base immobilized stationary phase in LC method
High-performance liquid chromatographic method was developed and validated for chiral separation of tolterodine tartrate. It was achieved on Chiral pack IA (immobilized amylosed based polysaccharides stationary phase) using a mobile phase of hexane: 2-propanol: triethylamine: trifluroacetic acid (91:9:0.2:0.1 v/v) at a flow rate 1.1 mL/min. Resolution between S-tolterodine tartrate and R-tolterodine tartrate was found to be 2.9. Developed LC method was used for the quantification of S-tolterodine tartrate as chiral impurity in Rtolterodine tartrate. The developed method was extensively validated and proved to be robust. The calibration curve for S-tolterodine tartrate showed an excellent linearity over the concentrations range 0.1 to 10 μg/mL. The limit of detection and limit of quantification for S-tolterodine tartrate were 0.11 μg/mL and 0.34 μg/mL respectively. Average recovery of S-isomer was in the range of 97.30 to 101.59 %. S-tolterodine tartrate and R-tolterodine tartrate solutions in mobile phase were found to be stable for 48 h. The proposed method was short runtime, precise and accurate for quantitative determination of S-isomer in R-tolterodine tartrate in API and its solid oral dosage form.
Ahirrao, V. K.,Patil, C. S.,Bembalkar, S. R.,Katariya, M. V.,Ubale, S. B.,Pawar, R. P.,Marathe, R. P.
p. 5708 - 5710,3
(2020/09/15)

PROCESS FOR THE PREPARATION OF N,N-DIISOPROPYL-3-(2-HYDROXY-5-METHYLPHENYL)- 3-PHENYL PROPYLAMINE AND ITS SALTS STARTING FROM A NOVEL INTERMEDIATE
The invention concerns an improved process for the preparation of tolterodine (N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propyl amine) and its salts, in particular for the preparation of the tartrate salt, and more particularly for the (+)-(R) enantiomer of tolterodine L-tartrate, starting from a novel intermediate, N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3- phenyl-2-propenamide, which can be used as pure Z or E isomer or as a mixture of Z and E isomers. When the target is the preparation of the enantiomer (R)-(+)-(N,N- diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine) and diastereomeric crystallization of suitable compound is applied, the present invention covers also the use of racemisation of undesired (S)-(-)- (N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3 -phenyl propylamine) enantiomer and its recycle in the process.
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(2012/08/07)

Process for the preparation of N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)- 3-phenyl propylamine and its salts starting from a novel intermediate
The invention concerns an improved process for the preparation of tolterodine (N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propylamine) and its salts, in particular for the preparation of the tartrate salt, and more in particular for the (+)-(R) enantiomer of tolterodine L-tartrate, starting from a novel intermediate, N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl-2-propenamide which can be used as pure Z or E isomer or as a mixture of Z and E isomers.
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Page/Page column 11

(2012/07/28)

PROCESS FOR PREPARING TOLTERODINE AND THE L-TARTRATE THEREOF
The present invention relates to a process for preparing tolterodine and the L-tartrate thereof. The preparation consists of the following steps: A) ammonolysis reaction between diisopropylamine and compound 2 (3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-
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Page/Page column 4

(2012/01/03)

A PROCESS FOR THE PREPARATION OF TOLTERODINE TARTRATE
The present invention relates to provide an improved process for the preparation of tolterodine or salt thereof, comprises a step of reducing 3-(2-methoxy-5-methylphenyl) -3-phenyl propionic acid of formula (III) in the presence of a reducing agent, an acidic reagent and a solvent to obtain 3-(2-methoxy-5-methylphenyl) -3-phenyl propanol of formula (IV).
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Page/Page column 19-20; 10

(2010/05/13)

IMPROVED PROCESS FOR THE PREPARATION OF (R)-2-(3-DIISOPROPYLAMINO)-1-PHENYLPROPYL)-4METHYLPHENOL AND SALTS THEREOF
The present invention relates to an improved process for the preparation of Tolterodine or salts thereof, which comprises the use of 3-(2-methoxy-5-methylphenyl)-3-phenylpropyl methane sulfonate.
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Page/Page column 8

(2010/09/17)

A PROCESS FOR THE PREPARATION OF TOLTERODINE TARTRATE
The present invention relates to provide a process for the preparation of (+)-(R)-Tolterodine-L-tartrate, comprises a step of aminating hydroxyl protected 3-(2-methoxy-5-methylphenyl)-3-phenyl propanol of formula (V) with diisopropylamine in the presence of water to obtain N, N-diisopropyl-3-(2-methoxy-5-methylphenyl)-3-phenylpropyl amine of formula (VI).
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Paragraph 213-222

(2010/09/03)

CRYSTALLINE TOLTERODINE TARTARATE AND A PHARMACEUTICAL COMPOSITION CONTAINING THE SAME
A crystalline salt of 2-[(1R)-3-[bis(l-methylethyl)amino]-1-ρhenylρropyl]-4-methyl-phenol with (2R,3R)-2,3-dihydroxybutanedioic acid, known under the name R-tolterodine tartarate, wherein: a) at least 90 % of all crystals are present in a size smaller than 30 μm, b) at least 40 % of crystalline matter are smaller than 250 μm, c) the maximum size of crystals does not exceed 800 μm, d) the salt contains less than 0.1 weight % of the undesirable enantiomer S-tolterodine tartarate, e) analytical test for sulfate ashes (Pharm. Eur.) provides a value lower than 0.1%. The method of its preparation involves at least one crystallization from water. A pharmaceutical composition containing tolterodine or its pharmaceutically acceptable salts further contains a filler, a disintegrant and a lubricant, said composition being free of ions of alkaline earth metals.
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Page/Page column 18-20

(2008/06/13)

PROCESS FOR THE PRODUCTION OF BENZOPYRAN-2-OL DERIVATIVES
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 11-12; 13-14

(2008/06/13)

Process for producing tolterodine
The present invention provides a process for producing tolterodine of the formula (1) or its salt, which comprises a step reacting a compound of the formula (2) with a base to obtain a reaction product; a step reacting the reaction product with a compound
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Page/Page column 10-11

(2010/11/28)

A process for the purification of tolterodine
Process for the purification of tolterodine comprising reacting racemic tolterodine with sulfuric acid to obtain an addition salt and racemic tolterodine acid sulfate in the crystalline form.
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Page/Page column 3

(2010/11/28)

PROCESS FOR PREPARING 3,3-DIARYLPROPYLAMINES
Described is a process of preparing a pure solid or crystalline racemic 3,3- diarylpropylamine compound and the compounds formed thereof. The solid and crystalline forms of racemic 3,3-diarylpropylamine compound are especially suitable for producing highl
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Page/Page column 12-13; 13-14

(2008/06/13)

PROCESS FOR PREPARATION OF 3-(2-HYDROXY-5-SUBSTITUTED PHENYL)-N-ALKYL-3-PHENYLPROPYLAMINES
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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(2008/06/13)

Reduction of ethyl benzoylacetate and selective protection of 2-(3-hydroxy-1-pheny|propyl)4-methylphenol: A new and facile synthesis of tolterodine
A new and facile synthesis of tolterodine using ethyl benzoylacetate as the starting material was developed. Reduction using sodium borohydride in methanol followed by Friedel-Crafts alkylation utilizing FeCl3 ·6H2O as catalyst lead to the known 2-(3-hydroxyl- phenylpropyl)-4-methylphenol intermediate. Consecutive protection of phenolic OH withp-toluenesulfonyl chloride via two-phase reaction and conversion of aliphatic OH using p-nitrobenzenesulfonyl chloride facilitates direct substitution of duesopropylamine. After simultaneous deprotection of the tosyl group, optically pure (R)-tolterodine·L-tartrate was obtained by resolution using L-tartaric acid with 99.99% purity.
De Castro, Kathlia A.,Jungnam, Ko,Daejong, Park,Sungdae, Park,Hakjune, Rhee
p. 918 - 921
(2012/12/30)

SUBSTANTIALLY PURE TOLTERODINE TARTRATE AND PROCESS FOR PREPARING THEREOF
The present invention provides substantially pure Tolterodine.
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Page/Page column 16-18

(2008/06/13)

METHOD OF OBTAINING TOLTERODINE
The process comprises reacting a compound of formula (II), where R is a hydroxyl protecting group, and the asterisk indicates an asymmetric carbon atom, with diisopropylamine in the presence of a reducing agent; optionally converting the resulting intermediate into a salt and, if so desired, isolating it; removing the hydroxyl protecting group; and if so desired, separating the desired (R) or (S) enantiomer, or the mixture of enantiomers and/or converting the obtained compound into a pharmaceutically acceptable salt thereof. Tolterodine is a muscarinic receptor antagonist useful in treating urinary incontinence and other symptoms of urinary bladder hyperactivity.
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Page/Page column 10

(2008/06/13)

PROCESS FOR PREPARATION OF 3-(2-HYDROXY-5-METHYLPHENYL)-N,N-DIISOPROPYL-3-PHENYLPROPYLAMINE
A new process for preparation of 3-(2-hydroxy-5-methylphenyl)-N,N-diisopropyl-3-phenylpropylamine from 3,4-dihydro-6-methyl-4-phenyl-2-benzopyran-2-one is characterized by intermediates such as 3-(2-hydroxy-5-methyl phenyl)-3- phenylpropanol and its sulph
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Page/Page column 25

(2008/06/13)

Process for preparing tolterodine
A process for preparing tolterodine with high purity.
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Page/Page column 7

(2010/11/08)

TOLTERODINE, COMPOSITIONS AND USES THEREOF, AND PREPARATION OF THE SAME
Racemic tolterodine free base in crystalline form, tolterodine with improved purity, compositions and uses thereof, and processes of preparing the same.
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Page/Page column 16

(2008/06/13)

An improved, scalable, and impurity-free process for tolterodine tartrate
Tolterodine tartrate is an anticholinergic muscle relaxant used to treat urinary frequency, urinary urgency, and incontinence in people with unstable bladders. An improved, cost-effective, and impurity-free process for tolterodine tartrate suitable for la
Srinivas, Keesari,Srinivasan, Neti,Reddy, Kikkuru Srirami,Ramakrishna, Muddasani,Reddy, Chinta Raveendra,Arunagiri, Muthulingam,Kumari, Routhu Lalitha,Venkataraman, Sundaram,Mathad, Vijayavitthal T.
p. 314 - 318
(2012/12/24)

ENANTIOSELECTIVE SYNTHESIS OF ENANTIOMERICALLY ENRICHED COMPOUNDS
Method of preparing an enantiomerically enriched compound of formula (II) comprising enantioselective hydrogenation of a compound of general formula (I): where W, X and Z have the meanings indicated in the description, to give a compound of general formula (II): where W, Y, T and C* have the meanings indicated in the description, in the presence of a catalyst or its suitable precursor based on Rh, Ru or Ir, having an oxidation state of 0, +1 or +2, and containing at least one enantiomerically enriched chiral ligand.
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Page/Page column 13

(2010/02/10)

3,3-DIARYLPROPYLAMINE DERIVATIVES AND PROCESSES FOR ISOLATION THEREOF
The invention relates to 3,3-diarylpropylamines derivatives and processes for producing them. More particularly, it relates to the preparation of pure tolterodine or a pharmaceutically acceptable salt thereof and pharmaceutical compositions that include t
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Page 9 - 12

(2010/02/08)

PROCESS TO PREPARE TOLTERODINE
Disclosed is a novel intermediate, 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-ol (IV) and an improved process for the preparation of tolterodine.
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(2008/06/13)

Process to prepare tolterodine
Disclosed is a novel intermediate, 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-ol (IV) STR1 and an improved process for the preparation of tolterodine.
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(2008/06/13)

3,3-DIPHENYLPROPYLAMINES AND PHARMACEUTICAL COMPOSITIONS THEREOF
Novel 3,3-diphenylpropylamines of formula (I) wherein R1 signifies hydrogen or methyl, R2, R3 and R4 independently signify hydrogen, methyl, methoxy, hydroxy, carbamoyl, sulphanoyl or halogen, and X represents a tertiary amino group -NR5, R6, wherein R5 and R6 signify non-aromatic hydrocarbyl groups, which may be the same or different and which together contain at least three carbon atoms, and which may form a ring together with the amine nitrogen, their salts with physiologically acceptable acids and, when the compounds can be in the form of optical isomers, the racemic mixture and the individual enantiomers, their use as drugs, especially as anticholinergic agents, their use for preparing an anticholinergic drug, pharmaceutical compositions containing the novel amines, and methods for preparing the same
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(2008/06/13)