- Asymmetric Hydroesterification of Diarylmethyl Carbinols
-
An efficient asymmetric hydroesterfication of diarylmethyl carbinols is developed for the first time with a Pd-WingPhos catalyst, resulting in a series of chiral 4-aryl-3,4-dihydrocoumarins in excellent enantioselectivities and good yields. The method features mild reaction conditions, a broad substrate scope, use of easily accessible starting materials, and low palladium loadings. A plausible stereochemical model is also proposed with the Pd-WingPhos catalyst. This method has enabled a 4-step asymmetric synthesis of (R)-tolterodine from readily available starting materials.
- Tian, Duanshuai,Xu, Ronghua,Zhu, Jinbin,Huang, Jianxun,Dong, Wei,Claverie, Jerome,Tang, Wenjun
-
p. 6305 - 6309
(2021/02/09)
-
- Chiral Fe(ii) complex catalyzed enantioselective [1,3] O-to-C rearrangement of alkyl vinyl ethers and synthesis of chromanols and beyond
-
A highly efficient enantioselective [1,3] O-to-C rearrangement of racemic vinyl ethers that operates under mild conditions was developed. This method with chiral ferrous complex catalyst provided an efficient access to a wide range of chromanols with high yields and excellent enantioselectivities. In addition, an important urological drug (R)-tolterodine and others were easily obtained after simple transformations.
- Dong, Shunxi,Feng, Xiaoming,Lin, Qianchi,Liu, Xiaohua,Wang, Lifeng,Zhou, Pengfei
-
p. 10101 - 10106
(2020/10/19)
-
- Metal-free annulative hydrosulfonation of propiolate esters: synthesis of 4-sulfonates of coumarins and butenolides
-
An efficient metal-free and cost-effective method for the synthesis of coumarin and butenolide 4-sulfonates (46 examples) has been developed. The reaction involves addition of sulfonic acids to ethyl propiolates followed by lactonization, resulting in direct formation of coumarin and butenolide 4-sulfonates. This methodology has been elaborated to Sonogashira and Suzuki coupling including the synthesis of rac-tolterodine.
- Fernandes, Rodney A.,Gangani, Ashvin J.,Kunkalkar, Rupesh A.
-
p. 3970 - 3984
(2020/03/19)
-
- Rh-Catalyzed Asymmetric Conjugate Addition of Arylboronic Acids to 3-Arylpropenoates: Enantioselective Synthesis of (R)-Tolterodine
-
A highly enantioselective conjugate addition of arylboronic acids to 3-arylpropenoates is presented. The rhodium complexes obtained from deoxycholic acid derived binaphthyl phosphites showed good activity as well as very high enantioselectivity (ee up to 99 %) in the conjugate addition to different ethyl-3-arylpropenoates, allowing to obtain useful chiral building blocks for the synthesis of active pharmaceutical ingredients. The method was applied to the enantioselective synthesis of the antimuscarinic drug (R)-tolterodine.
- Zullo, Valerio,Iuliano, Anna
-
p. 1377 - 1384
(2019/01/04)
-
- Catalytic asymmetric synthesis of chiral phenols in ethanol with recyclable rhodium catalyst
-
A general method to access diverse chiral phenols by rhodium-catalyzed asymmetric conjugate arylation using hydroxylated arylboronic acids in ethanol was developed. Recycling of the rhodium catalyst by flash chromatography on silica gel was feasible in this system. The synthetic utility of the strategy was demonstrated by efficient synthesis of chiral drug tolterodine.
- Yao, Jian,Liu, Na,Yin, Long,Xing, Junhao,Lu, Tao,Dou, Xiaowei
-
p. 4946 - 4950
(2019/09/30)
-
- Synthesis method of tolterodine and enantiomers thereof
-
Belonging to the field of chemical synthesis, the invention discloses a synthesis method of tolterodine and enantiomers thereof. The method includes: taking cinnamaldehyde as the raw material for asymmetric arylation reaction with (2-hydroxy-5-methylphenyl)boric acid under the action of a rhodium catalyst to obtain a hemiacetal intermediate, and subjecting the hemiacetal intermediate directly to reductive amination reaction without purification, thus obtaining high optically pure tolterodine. 2-hydroxyl-5-methyl cinnamaldehyde and phenylboronic acid are taken as the starting raw materials, andthe same synthesis method and operation steps are employed to prepare high optically pure tolterodine enantiomers. The method reported by the invention has the characteristics of short route, high total yield, good stereoselectivity and the like, and the ee values of the two synthesized configuration products are both greater than 99%.
- -
-
Paragraph 0086-0099
(2019/10/01)
-
- 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)
-
- Palladium-catalyzed diastereoselective synthesis of β,β-diarylpropionic acid derivatives and its application to the total synthesis of (R)-tolterodine and the enantiomer of a key intermediate for MK-8718
-
Palladium-catalyzed diastereoselective synthesis of optically active β,β-diarylpropionic acid derivatives employing 4-(tert-butyl)oxazolidin-2-one as the chiral auxiliary under an air atmosphere in excellent yields with high diastereoselectivity is reported. The catalytic system is applied to the total synthesis of (R)-tolterodine and the enantiomer of a key intermediate for MK-8718.
- Zhi, Wubin,Li, Jingya,Zou, Dapeng,Wu, Yangjie,Wu, Yusheng
-
p. 537 - 540
(2018/01/17)
-
- Chiral Inductive Diastereoconvergent Allylation Reactions of Allyltrimethylsilane and Diastereomixtures of Diarylmethanols Catalyzed by FeCl3
-
We report the chiral-auxiliary-controlled diastereoconvergent allylation reactions of allyltrimethylsilane with diastereomeric mixtures of diarylmethanols in the presence of FeCl3 as a Lewis acid catalyst. This reaction was successfully applied to a variety of substrates; it proceeded irrespective of the substituent on the aromatic ring of the substrate. The present method was used as the key step in synthesizing (R)-tolterodine.
- Fujihara, Rina,Nakata, Kenya
-
p. 6566 - 6573
(2018/11/10)
-
- 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)
-
- 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
-
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.
- -
-
Page/Page column 22; 23
(2017/09/05)
-
- PHOSPHOLIPID CONJUGATE
-
PROBLEM TO BE SOLVED: To provide a compound that suitably interacts with a receptor existing on a cell surface to regulate its activity, to provide a pharmaceutical composition containing the compound, and to provide a method for treating a disease using the compound, and the like. SOLUTION: The above mentioned object is achieved by providing a compound represented by general formula: P-S-L (where, P is a phospholipid moiety; S is a spacer moiety which includes a structure represented by -(PEG)n- wherein n is an integer equal or greater than 5; L is a ligand moiety of a cytoplasmic membrane receptor). SELECTED DRAWING: Figure 3 COPYRIGHT: (C)2016,JPOandINPIT
- -
-
Paragraph 0056
(2017/02/28)
-
- An efficient synthesis of racemic tolterodine
-
The efficient and cost effective of the synthesis of (±)-tolterodine (1), a precursor of (+)-(R)-tolterodine was efficiently performed from 6-methyl-4-chroman-2-one (2) via 4 steps in high yield. This process is suitable for large-scale commercial production by avoiding hazardous reagents and high pressure of hydrogen gas.
- Rao, K.Sudarshan,Rao, K.Nageswara,Muralikrishna,Jayashree
-
p. 2813 - 2814
(2014/06/09)
-
- Enantioselective synthesis of (R)-tolterodine using lithiation/borylation- protodeboronation methodology
-
The synthesis of the pharmaceutical (R)-tolterodine is reported using lithiation/borylation-protodeboronation of a homoallyl carbamate as the key step. This step was tested with two permutations: an electron-neutral aryl Li-carbamate reacting with an electron-rich boronic ester and an electron-rich aryl Li-carbamate reacting with an electron-neutral boronic ester. It was found that the latter arrangement was considerably better than the former. Further improvements were achieved using magnesium bromide in methanol leading to a process that gave high yield and high enantioselectivity in the lithiation/borylation reaction. The key step was used in an efficient synthesis of (R)-tolterodine in a total of eight steps in a 30% overall yield and 90% ee.
- Roesner, Stefan,Aggarwal, Varinder K.
-
p. 965 - 974
(2013/02/22)
-
- Coumarins from free ortho -hydroxy cinnamates by Heck-Matsuda arylations: A scalable total synthesis of (R)-tolterodine
-
Free ortho-hydroxy cinnamate ester derivatives are evaluated in the synthesis of structurally diverse 4-aryl-coumarins via a tandem Heck-Matsuda cyclization reaction. Free phenolic groups were considered incompatible with such a reaction, which usually provide the corresponding diazo dyes. A concise and scalable route employing a ligand-free, Pd-catalyzed Heck-Matsuda arylation under aerobic conditions for the preparation of (R)-Tolterodine in high overall yield and ee is also presented.
- Barancelli, Daniela A.,Salles, Airton G.,Taylor, Jason G.,Correia, Carlos Roque D.
-
p. 6036 - 6039
(2013/02/23)
-
- 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.
- -
-
Page/Page column 5
(2012/03/08)
-
- The lactol route to fesoterodine: An amine-promoted Friedel-Crafts alkylation on commercial scale
-
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
-
p. 1010 - 1017
(2011/12/16)
-
- Highly enantioselective hydrogenation of styrenes directed by 2′-hydroxyl groups
-
A new synthetic strategy that turns styrene-type olefins into excellent substrates for Rh-catalyzed asymmetric hydrogenation by installing a 2′-hydroxyl substituent is described. This methodology accommodates trisubstituted olefinic substrates in various E/Z mixtures, leading to valuable benzylic chiral compounds including (R)-tolterodine. It is also demonstrated that the 2′-hydroxyl groups could be readily removed in high yield without loss of ee from the products. Thus, this technology represents an attractive alternative to the Ir(P-N) catalyst system for the asymmetric hydrogenation of unfunctionalized olefins.
- Wang, Xiang,Guram, Anil,Caille, Seb,Hu, Jack,Preston,Ronk, Michael,Walker, Shawn
-
p. 1881 - 1883
(2011/05/15)
-
- Rearrangement of ethers: A new route to tolterodine
-
The rearrangement of benzyl phenolic ether in the presence of an acid or AlCl3 is utilized to produce biphenyl methane compounds in very good yields. The synthesis of muscarine receptor antagonist tolterodine is described.
- Arava, Veera Reddy,Bandatmakuru, Sreenivasula Reddy,Malreddy, Sashibhushan,Golla, Narayanaswamy
-
p. 1565 - 1571
(2011/06/27)
-
- 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-
- -
-
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).
- -
-
Page/Page column 19; 10
(2010/05/13)
-
- A process for the rapid removal of dialkylamino-substituents from aromatic rings. Application to the expedient synthesis of (R)-tolterodine
-
A range of N,N-dialkylanilines have been successfully converted to the parent substituted benzenes by a novel two-step pathway. The products are obtained in good yields and optical purity of adjacent stereocenters is maintained. This technology has been applied toward the synthesis of (R)-tolterodine.
- Paras, Nick A.,Simmons, Bryon,MacMillan, David W.C.
-
experimental part
p. 3232 - 3238
(2009/08/15)
-
- Asymmetrie Conjugate reductions of coumarins. A new route to tolterodine and related coumarin derivatives
-
"Chemical Equation Presented" The combination of catalytic amounts of [(R)-DTBM-SEGPHOS]CUH In the presence of stoichiometric DEMS (dlethoxymethylsllane) In toluene at room temperature leads to asymmetric reductions of 4-substituted coumarins. Several targets or their known precursors can be prepared In high yields and ee's, Including the muscarine receptor antagonist (R)-tolterodine.
- Gallagher, Brian D.,Taft, Benjamin R.,Lipshutz, Bruce H.
-
supporting information; experimental part
p. 5374 - 5377
(2010/02/28)
-
- Enantioselective synthesis of (R)-tolterodine via CuH-catalyzed asymmetric conjugate reduction
-
(Chemical Equation Presented) An efficient and highly enantioselective method for the preparation of (R)-tolterodine is described. The synthesis was performed by CuH-catalyzed asymmetric conjugate reduction of a β,β-diaryl-substituted unsaturated nitrile
- Yoo, Kihyun,Kim, Hyohyun,Yun, Jaesook
-
supporting information; experimental part
p. 4232 - 4235
(2009/09/25)
-
- Co-catalyzed mild and chemoselective reduction of phenyl esters with NaBH4: a practical synthesis of (R)-tolterodine
-
CoCl2 catalyzes effectively the chemoselective reduction of phenyl carboxylic esters to the corresponding saturated alcohols in high yields using NaBH4 at ambient conditions. By employing this methodology, the synthesis of (R)-tolterodine, a muscarinic receptor antagonist, has been achieved in high yield and optical purity.
- Jagdale, Arun R.,Sudalai, Arumugam
-
p. 3790 - 3793
(2008/09/21)
-
- Rhodium/chiral diene-catalyzed asymmetric 1,4-addition of arylboronic acids to arylmethylene cyanoacetates
-
Asymmetric 1,4-addition of arylboronic acids to (£)-methyl 2-cyano-3-arylpropenoates proceeded in the presence of a rhodium catalyst (3 mol %) coordinated with a chiral diene ligand, (R,R)-Ph-bod*, to give high yields of the corresponding methyl 3,3-diaryl-2-cyanopropanoates with high enantioselectivity (up to 99% ee). This catalytic asymmetric transformation was applied to the asymmetric synthesis of (R)-tolterodine. American Chemical Society.
- Soegel, Sebastian,Tokunaga, Norihito,Sasaki, Keigo,Okamoto, Kazuhiro,Hayashi, Tamio
-
p. 589 - 592
(2008/04/12)
-
- METHOD OF OBTAINING 3,3-DIPHENYLPROPYLAMINES
-
The invention relates to a method of obtaining 3,3-diphenylpropylamines (I), wherein R1 is H, alkyl, haloalkyl or alkoxyalkyl, R2 is alkyl, alkoxy, halogen, NO2, CN, CHO, which may be free or protected, CH2OH or COOR6, and R3 and R4 are selected independently from H and alkyl or together with the nitrogen to which they are bound form a ring having 3 to 7 members. The inventive method consists in reacting a propylenephenylamine and a disubstituted aromatic hydrocarbon and, if necessary, separating the desired enantiomer or the mixture of enantiomers, and/or converting the compound (I) into a salt. Compounds (I) are muscarinic receptor antagonists which can be used in the treatment of urinary incontinence and other symptoms of urinary bladder hyperactivity. Said compounds include tolterodine.
- -
-
Page/Page column 10
(2008/12/05)
-
- 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.
- -
-
Page/Page column 18-20
(2008/06/13)
-
- Selective nosylation of 1-phenylpropane-1,3-diol and perchloric acid mediated Friedel-Crafts alkylation: Key steps for the new and straightforward synthesis of tolterodine
-
We have developed a new and straightforward synthesis of racemic tolterodine [N,N-diisopropyl-3-(2-hydroxy-5-methyl-phenyl)-3-phenylpropanamine]. The synthesis involves selective nosylation on the primary alcohol of 1-phenylpropane-1,3-diol using 4-nitrob
- De Castro, Kathlia A.,Rhee, Hakjune
-
experimental part
p. 1841 - 1844
(2009/04/04)
-
- 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.
- -
-
Page/Page column 11
(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.
- -
-
Page/Page column 11-12; 13-14
(2008/06/13)
-
- Enantioselective synthesis of (S)- and (R)-tolterodine by asymmetric hydrogenation of a coumarin derivative obtained by a Heck reaction
-
(Chemical Equation Presented) An efficient and short enantioselective synthesis of (S)- and (R)-tolterodine was performed by asymmetric hydrogenation of a coumarin intermediate, easily obtained by a Heck reaction from inexpensive and commercially available starting materials.
- Ulgheri, Fausta,Marchetti, Mauro,Piccolo, Oreste
-
p. 6056 - 6059
(2008/02/10)
-
- PROCESS FOR PREPARING TOLTERODINE OR ITS SALT AND SYNTHETIC INTERMEDIATE
-
Provided is a process for preparing tolterodine or its salt, which comprises: (a) reacting 2-[3-(p-nitrobenzenesulfonyloxy)-1-phenylpropyl]-4-methyl-(p-nitrobenzenesulfonyloxy or p-toluenesulfonyloxy)benzene with diisopropylamine to obtain 2-[3-(N,N-diiso
- -
-
Page/Page column 8
(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
- -
-
Page/Page column 10
(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.
- -
-
Page/Page column 3-4
(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
- -
-
Page/Page column 12
(2008/06/13)
-
- NOVEL PROCESS FOR THE PREPARATION OF TOLTERODINE
-
The present invention relates to a novel and improved process for the preparation of tolterodine of formula I. Key steps involved in the process are a vinyl Grignard reaction on a benzophenone derivative of formula XXI to get the vinyl carbinol derivative
- -
-
Page/Page column 17-18
(2010/11/26)
-
- A process for the preparation of tolterodine
-
A novel process for the preparation of tolterodine (I), i.e. (R)-N,N-diisopropyI-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine, in the racemic form, as well as intermediates useful for its preparation.
- -
-
Page/Page column 8
(2010/11/23)
-
- 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.
- -
-
Page/Page column 10
(2008/06/13)
-
- Process for the preparation of tolterodine
-
A novel process for the preparation of tolterodine, i.e. (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine, in the racemic form, as well as intermediates useful for its preparation.
- -
-
Page/Page column 5
(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
- -
-
Page/Page column 24; 25
(2008/06/13)
-
- Rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to coumarins: Asymmetric synthesis of (R)-tolterodine
-
(Chemical Equation Presented) Rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to coumarins proceeded with high enantioselectivity in the presence of a rhodium catalyst (3 mol %) generated from Rh(acac)(C 2H4)2 and (R)-Segphos to give the corresponding (R)-4-arylchroman-2-ones in over 99% ee. This asymmetric reaction was applied to the synthesis of (R)-tolterodine.
- Chen, Gang,Tokunaga, Norihito,Hayashi, Tamio
-
p. 2285 - 2288
(2007/10/03)
-
- 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.
- -
-
Page/Page column 11; 12
(2010/02/10)
-
- 4 against the first quaternary ammonium compounds and their use as muscarine
-
The compound 2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-(trifluoromethyl) phenol may be used to prepare the compound (3R)-3-[2-hydroxy-5-(trifluoromethyl)phenyl]-N,N-diisopropyl-N-methyl-3-phenylpropan-1-aminium bromide by reaction with methyl bromide.
- -
-
Page/Page column 17
(2008/06/13)
-
- Catalytic asymmetric total synthesis of the muscarinic receptor antagonist (R)-tolterodine
-
A convenient and high yielding method for the preparation of (R)-tolterodine, utilizing a catalytic asymmetric Me-CBS reduction was developed. Highly enantioenriched (A)-6-methyl-4-phenyl-3,4-dihydrochromen-2-one (94% ee) was recrystallized to yield practically enantiopure material (ee >99%) and converted to (R)-tolterodine in a four-step procedure. The configuration of the crucial stereocenter was preserved during the synthesis and the obtained product was identified by chiral HPLC to be the (R)-tolterodine enantiomer.
- Hedberg, Christian,Andersson, Pher G.
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p. 662 - 666
(2007/10/03)
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- TOLTERODINE, COMPOSITIONS AND USES THEREOF, AND PREPARATION OF THE SAME
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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)
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- Combination therapies
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The invention is directed to methods of treating asthma, COPD, allergic rhinitis, and infectious rhinitis by administering a first pharmaceutical agent including one or more compounds selected from the quarternary ammonium compounds of formulae I-V and a second pharmaceutical agent including one or more pharmaceutical agents selected from Adenosine A2a Receptor Agonists, D2-Dopamine Receptor Agonists, Phosphodiesterase Inhibitors (PDE's), corticosteroids, norepinephrine reuptake inhibitors, 4-hydroxy-7-[2-[2-[3-[2-phenylethoxy]-propylsulphonyl]ethylamino]ethyl]-1,3-benzothiazol-2(3H)-one, and pharmaceutically acceptable salts thereof, and non-quarternized antimuscarinic compounds.
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- Quaternary ammonium compounds
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Novel quaternary ammonium compounds of the formula and any stereoisomers thereof, wherein R1, R2 and R3 independently represent C1-C6 alkyl, optionally substituted with phenyl or hydroxyl, or both, and wherein any two of R1, R2 and R3 may form a ring together with the quaternary ammonium nitrogen; R4 represents —H, —CH3, or —CO—R4-1,wherein R4-1 represents —(C1-C4 alkyl), —(C1-C4 alkoxy), or —NR4-2R4-3, wherein R4-2 and R4-3 independently represent —H or —(C1-C4 alkyl); R5, R6 and R7 independently represent —H, —OCH3, —OH, —CONH2, —SO2NH2, —F, —Cl, —Br, —I, —CF3, or —(C1-C4 alkyl), optionally substituted with one or two —OH, —(C1-C4 alkoxy), —COOH, or —CO—O—(C1-C3 alkyl); and X? represents an anion of a pharmaceutically acceptable acid, the compounds for use as medicaments, use of the compounds for the manufacture of specific medicaments, and pharmaceutical compositions comprising the compounds. The present invention also concerns a method of treatment involving administration of the compounds.
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- A new efficient route to Tolterodine
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Tolterodine, an important urological drug, can be conveniently prepared starting from 1-[2-hydroxy-5-methyl)phenyl]-1-phenylethylene, accessible in high yield by alumina-promoted ortho alkenylation of p-cresol with phenylacetylene. The hydroformylation of this olefin, catalyzed by rhodium complexes both in homogeneous or in aqueous biphasic system, affords the desired linear aldehyde in about 80-90% yield. The reductive amination of this aldehyde, in the presence of HN-(iPr)2 and Pd/C (5%) as the catalytic precursor at 4 atm H2 and 48°C, produces directly tolterodine in more than 90% yield. Some experiments of enantioselective hydroformylation of 1-[2-hydroxy-5-methyl)phenyl]-1-phenylethylene catalyzed by Rh(CO)2acac/(S,R)-Binaphos and other enantiopure ferrocenyldiphosphines afforded only low yields of the expected chiral aldehyde; unfortunately, the achieved ee did not exceed 8%.
- Botteghi, Carlo,Corrias, Tatiana,Marchetti, Mauro,Paganelli, Stefano,Piccolo, Oreste
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p. 379 - 383
(2013/09/06)
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