- Crystal Structures of Tiotropium Bromide and Its Monohydrate in View of Combined Solid-state Nuclear Magnetic Resonance and Gauge-Including Projector-Augmented Wave Studies
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Tiotropium bromide is an anticholinergic bronchodilator used in the management of chronic obstructive pulmonary disease. The crystal structures of this compound and its monohydrate have been previously solved and published. However, in this paper, we showed that those structures contain some major errors. Our methodology based on combination of the solid-state nuclear magnetic resonance (NMR) spectroscopy and quantum mechanical gauge-including projector-augmented wave (GIPAW) calculations of NMR shielding constants enabled us to correct those errors and obtain reliable structures of the studied compounds. It has been proved that such approach can be used not only to perform the structural analysis of a drug substance and to identify its polymorphs, but also to verify and optimize already existing crystal structures.
- Pindelska, Edyta,Szeleszczuk, Lukasz,Pisklak, Dariusz Maciej,Majka, Zbigniew,Kolodziejski, Waclaw
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- Synthesis and radiolabelling of ipratropium and tiotropium for use as PET ligands in the study of inhaled drug deposition
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Ipratropium bromide [(1R,3r,5S,8r,2′RS)-3-(3′-hydroxy-2′- phenylpropionyloxy)-8-isopropyl-8-methyl-8-aza-bicyclo[3.2.1]octan-8-ium bromide] and tiotropium bromide [(1R,2R,4S,5S,7s)-7-[2′-hydroxy-2′, 2′-di(thiophen2″-yl)acetoxy]-9,9-dimethyl-9-aza-3-oxatricyclo[3.3.1. 02,4]nonan-9-ium bromide] are inhaled drugs used in the treatment of chronic obstructive pulmonary disease (COPD) and asthma. Tertiary amine precursors have been synthesized and radiolabelled with carbon-11 by N-alkylation with [11C]CH3I. The [11C] ipratropium and [11C]tiotropium positron emission tomography (PET) ligands are obtained with high radiochemical purity, in 0.3 and 0.5% non-decay corrected yields based on [11C]CO2 at end-of-synthesis and specific activities of 11 and 18 GBq μ mol-1, respectively, calculated at end-of-synthesis. These PET radioligands can be used in the study of inhaled drug deposition. CSIRO 2006.
- Issa, Fatiah,Kassiou, Michael,Chan, Hak-Kim,McLeod, Malcolm D.
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- NMR study on (1α, 2β, 4β, 5α, 7β)-7-[(hydroxydi-2-thienylacetyl) oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo [3.3.1.02,4] nonane bromide monohydrate
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The structure of (1α, 2β, 4β, 5α, 7β)-7-[(hydroxydi-2-thienylacetyl) oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo [3.3.1.02,4] nonane bromide monohydrate was studied using 1D and 2D NMR techniques. Complete NMR assignments of the compound were obtained using DEPT, H-H COSY, as well as HMQC and HMBC heteronuclear correlation techniques.
- Lin, Zhenguang,Mu, Yingdi,Liu, Yihui,Ren, Yeming,Lin, Jimao
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- Preparation method of tiotropium bromide
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The invention provides a preparation method of tiotropium bromide, which comprises the following steps: (1) reacting a compound of a formula I with a compound of a formula II with an alkaline compound to obtain a compound of a formula III, wherein R is methyl, ethyl, isopropyl or tert-butyl, (2) reacting a halogenating agent of the compound of the formula III with a catalyst to obtain a compound of a formula IV, reacting the compound of the formula IV with an alkali to obtain a compound V, wherein X is Cl, Br or I, and (3) reacting the compound of the formula V with methyl bromide to obtain the tiotropium bromide. According to the method, the defect that vanadium pentoxide and hydrogen peroxide-urea are used as epoxidation agents when tropine is used as a raw material to prepare tiotropium bromide in the prior art is overcome, the reaction safety is improved, and meanwhile, the yield of cyclized products is increased.
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Paragraph 0058-0062
(2021/08/19)
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- AN IMPROVED PROCESS FOR PREPARATION OF SCOPINE HYDROBROMIDE
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The present invention relates to an efficient and industrially advantageous process for the preparation of scopine free base or salts. Said compounds are important intermediates in the synthesis of tiotropium and pharmaceutically acceptable salts thereof. The method provided for preparing scopine free base or its salts has the advantages of a simple operation, high yield and low costs.
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Page/Page column 15
(2021/07/02)
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- A tiotropium bromide intermediate preparation method
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The invention relates to a preparation method of a tiotropium bromide intermediate, that is, scopine-2,2-di(2-thienyl)glycolate. The method is characterized in that Lewis acid is used as a catalyst, and scopine and 2,2-di(2-thienyl)methyl glycolate are stirred and react with each other in an organic solvent at the temperature of 50-120 DEG C to produce the scopine-2,2-di(2-thienyl)glycolate, wherein the organic solvent is selected from one or more of non-alcohol, non-carboxylic and non-ester organic solvents.
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Paragraph 0061-0103
(2018/04/02)
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- PROCESS FOR SYNTHESIS OF TIOTROPIUM BROMIDE MONOHYDRATE
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Provided herein is a process for synthesis of tiotropium bromide wherein the coupling of scopine with 2, 2-dithienyl glycolate is achieved by a two step process under mild conditions.
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- Discovery of Novel Potent Muscarinic M3 Receptor Antagonists with Proper Plasma Stability by Structural Recombination of Marketed M3 Antagonists
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The marketed long-acting M3 antagonists for treatment of chronic obstructive pulmonary disease have inappropriate plasma stability (either overstable or excessively unstable), which causes substantial systemic exposure or poor patient compliance. To discover novel M3 antagonists with proper plasma stability, we synthesized and biologically evaluated a series of chiral quaternary ammonium salts of pyrrolidinol esters, which were designed by structural recombination of the marketed M3 antagonists. As a result, two novel potent M3 antagonists, (R/S)-3-[2-hydroxy-2,2-di(thiophen-2-yl)acetoxy]-1,1-dimethylpyrrolidinium bromides (1 a: Ki=0.16 nm, IC50=0.38 nm, t1/2=9.34 min; 1 b: Ki=0.32 nm, IC50=1.01 nm, t1/2=19.2 min) with proper plasma stability were identified, which (particularly 1 a) hold great promise as clinical drug candidates to overcome the drawbacks caused by the inappropriate stability of the currently marketed M3 antagonists. In addition, structure–activity relationship studies revealed that the R configuration of the pyrrolidinyl C3 atom was clearly better than the S configuration.
- Xiang, Zuojuan,Liu, Jun,Sun, Hongbin,Wen, Xiaoan
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supporting information
p. 1173 - 1182
(2017/08/15)
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- IMPROVED PROCESS FOR ACYL TRANSFER REACTIONS
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The present invention relates to a novel process for the preparation of esters like Aclidinium, Atropin, Glycopyrroniunn, Tiotropium, Trospium and their respective precursors and derivatives, based on direct acyl transfer reactions.
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Page/Page column 12
(2014/09/29)
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- CRYSTALLINE FORM OF TIOTROPIUM BROMIDE
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A stable crystalline form of tiotropium bromide, and a process for its preparation with high purity.
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Paragraph 0038; 0039; 0040
(2014/10/16)
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- A METHOD OF PREPARING THE SCOPINE ESTER OF DI-(2-THIENYL)GLYCOLIC ACID, AN INTERMEDIATE IN THE SYNTHESIS OF TIOTROPIUM BROMIDE
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The present invention relates to a preparation method of tiotropium bromide of formula II, comprising the following steps: a) preparation of the scopine ester of formula I by transesterification of methyl di(2thienyl)glycolate of formula IV with scopine of formula III in the presence of a substoichiometric amount of a sterically hindered base selected from the group of alkali salts of branched C3 to C5 alkoxides in an inert solvent, b) isolation of the scopine ester of formula I, and c) quaternization of the scopine ester of formula I with methyl bromide.
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Page/Page column 18
(2013/10/21)
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- A METHOD OF PREPARING THE SCOPINE ESTER OF DI-(2-THIENYL)GLYCOLIC ACID, AN INTERMEDIATE IN THE SYNTHESIS OF TIOTROPIUM BROMIDE, AND ITS NEW FORM
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The invention relates to a preparation method of the scopine ester of di-(2- thienyl)glycolic acid of formula I. The scopine ester of formula I is an important intermediate in the synthesis of tiotropium bromide, the substance with the chemical name (1R,2R,4S,5S,7S)-7-(2-hydroxy-2,2-di(thiophen-2-yl)acetoxy)-9,9-dimethyl-3- oxa-9-azatricyclo[3.3.1.02'4]nonan-9-ium bromide of formula II. The method consists of the following steps, reaction of scopine of formula III with derivatives of oxalic acid of formula XIII, wherein X means F, CI, Br, I, and R is X or O-terf-butyl, O-methyl, A/-pyrrolidinyl, N-morpholinyl and /V-imidazolyl, in the presence of a weak base and a catalyst in an inert organic solvent, producing the derivative of formula XIV; reaction of the derivative of formula XIV with at least 2 equivalents of 2- thienylmagnesium bromide of formula XV; and isolating the resulting scopine ester of formula I is then and crystallization from a crystallization solvent.
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- PROCESS FOR PREPARING TIOTROPIUM BROMIDE
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The present invention relates to a novel process for the preparation of tiotropium bromide there is provided a process for preparing tiotropium bromide comprising (i) reacting scopine oxalate with diethylamine in an inert solvent to form scopine; (ii) reacting scopine and methyl di-(2-dithienyl)glycoIate (MDTG) in the presence of an inorganic base, and in an inert solvent to form N-demethyltiotropium; (iii) reacting N-demethyltiotropium with bromomethane in an inert solvent to form tiotropium bromide; (iv) crystallizing tiotropium bromide in a mixture of methanol and acetone, and optionally thereafter, (v) micronizing the tiotropium bromide so formed.
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Paragraph 00033
(2013/08/28)
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- PROCESS FOR THE PREPARATION OF SCOPINE ESTERS
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The present invention relates to a process for the preparation of scopine esters, as intermediates in the synthesis of tiotropium bromide. In particular, it relates to a transesterification process between scopine alcohol and an ester of a carboxyl acid in high yields and under conditions suitable for industrial use.
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Page/Page column 9; 10
(2013/04/13)
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- PROCESS TO PREPARE SCOPINE ESTERS
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The present invention relates to novel processes for the preparation of scopine esters and their quaternary salts. In particular, the present invention relates to a process for the preparation of tiotropium bromide, pharmaceutical compositions comprising tiotropium bromide and the use of such compositions in the treatment of respiratory disorders.
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Page/Page column 15-16
(2011/02/24)
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- NOVEL PROCESS FOR THE PREPARATION OF SCOPINE ESTERS
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The present invention relates to novel processes for the preparation of scopine esters and their quaternary salts. In particular, the present invention relates to a process for the preparation of tiotropium bromide, pharmaceutical compositions comprising tiotropium bromide and the use of such compositions in the treatment of respiratory disorders.
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Page/Page column 13
(2009/09/04)
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- TROPAN COMPOUND
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The conventional anticholinergic drugs for administration through inhalation have been considered to have the possibility of aggravating dysuria associated with prostatic hyperplasia mediated by blood, and it has been demanded that the conventional anticholinergic drugs for administration through inhalation will have to show reduced side effects or adverse ractions. The present invention relates to a compound represented by the general formula (I): (wherein A represents; and R1, R2, R3 and R1 each a hydrogen atom or a substituent; R5 is a substituent; X- is an anion;the symbol: denotes an exo-form or endo-form, or their mixture), its salt or solvation product thereof. They are useful as a prophylactic and/or therapeutic agent with reduced side effects or adverse reactions for the diseases mediated by the muscarinic receptor.
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Page/Page column 40; 45; 51
(2010/11/27)
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- Azabicycloalkane compounds
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This invention provides compounds of formula I: wherein R1, R2, R3, R4, R5, R6 and R7 are as defined in the specification, or a pharmaceutically acceptable salt or solvate or stereoisomer thereof. The compounds of this invention possess both β2 adrenergic receptor agonist and muscarinic receptor antagonist activity. Such compounds are useful for treating pulmonary disorders, such as chronic obstructive pulmonary disease and asthma.
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- Industrial process for preparing tropenol
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The invention relates to a new industrially useable process for preparing tropenol, optionally in the form of the acid addition salts thereof.
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