- 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
-
-
Read Online
- A new efficient route to Tolterodine
-
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
-
-
Read Online
- 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
-
-
Read Online
- 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)
-
- 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.
- -
-
Page/Page column 5
(2012/03/08)
-
- 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)
-
- 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)
-
- 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)
-
- 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 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)
-
- 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)
-
- 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)
-
- 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 9
(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)
-
- 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)
-
- 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.
- -
-
Page/Page column 16
(2008/06/13)
-