- 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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- 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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- A PROCESS FOR PREPARING TIOTROPIUM BROMIDE AND INTERMEDIATES THEREOF
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Provided herein is a process for synthesis of tiotropium bromide and a process for synthesis of scopine starting from a dimethyl tartarate compound. The synthetic sequence comprises a double Mannich reaction (Robinson-Schopf reaction).
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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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- ELECTROPHILIC ALKYLATING REAGENTS, THEIR PREPARATION AND USE
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The present invention provides electrophilic alkylating reagents of formula II, wherein is an aryl group, R2 is an alkyl group, R3 is a substituted phenyl group, wherein the number of substituents (n) is greater than 2 and R4 is an anion, and salts thereof, methods for their preparation and methods for the preparation of alkylated biologically active compounds using such reagents.
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Paragraph 0099
(2014/06/25)
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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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- METHODS FOR THE SYNTHESIS OF TIOTROPIUM BROMIDE
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Present invention relates to methods for preparing (1α, 2β, 4β, 5α, 7β)-7-[(hydroxidi-2-thienllacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonane-bromide.
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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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- 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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- 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 16; 17; 18
(2013/04/13)
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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 00034
(2013/08/28)
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- MIXED SOLVATE OF TIOTROPIUM BROMIDE AND A METHOD OF ITS PREPARATION
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Mixed solvate of propyleneglycol/ethanol solvate of tiotropium bromide of formula V contains ethanol in the range of 3,000 to 40,000 ppm and propyleneglycol in the range of 3,000 to 40,000 ppm. An additional solution provides a method of preparing the solvate of tiotropium bromide, wherein a form of tiotropium bromide, selected from an anhydrous form, hydrate, solvate, or mixed solvate, is dissolved in a mixture of propyleneglycol and ethanol at a temperature in the range of from 40°C to the boiling point of the solvent, the formed solution is cooled down and the precipitated solvate is isolated. The solvate of tiotropium bromide is used in preparing an inhalation therapeutic formulation.
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Page/Page column 10-11
(2013/06/27)
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- Manufacturing process for tiotropium bromide
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The present invention relates to a novel manufacturing process of pharmaceutically active compound of formula I used as a long-acting anticholinergic bronchodilator. Starting from oxalic acid derivative of formula III the invention describes preparation of a novel cyclic anhydride of formula II which is very efficient precursor in the synthesis of Tiotropium bromide (compound of formula I).
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Page/Page column 3
(2012/05/21)
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- ANHYDRATE OT TIOTROPIUM BROMIDE
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Novel Anhydrate The present invention relates to a novel form of anhydrous tiotropium bromide, processes for the preparation of anhydrous tiotropium bromide, pharmaceutical compositions comprising anhydrous tiotropium bromide and uses of the compositions.
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Page/Page column 5
(2012/06/18)
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- TIOTROPIUM BROMIDE PREPARATION PROCESS
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Present invention relates to a novel process for preparing (1α, 2β, 4β, 5α, 7β)-7-[(hydroxidi-2-thienllacety)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.0 2,4]nonan-bromide.
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Page/Page column 11
(2011/10/13)
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- SYNTHESIS METHOD FOR PRODUCING TIOTROPIUM BROMIDE
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The present invention relates to a new method for producing ((1α, 2β, 4β, 7β)-7-[(hydroxidi- 2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9- azoniatricyclo[3.3.1.02,4]nonane-bromide.
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Page/Page column 10
(2011/10/13)
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- DICHLOROMETHANE SOLVATE OF TIOTROPIUM BROMIDE AND ITS USE
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The present invention relates to a novel solvate of tiotropiumbromide, a process to prepare this solvate and the use of this and other solvates in processes for the preparation of anhydrous tiotropium bromide. The present invention also relates to pharmaceutical compositions comprising anhydrous tiotropium bromide and uses of the compositions.
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Page/Page column 15
(2011/02/24)
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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 16
(2011/02/24)
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- NOVEL ANHYDRATE
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Novel Anhydrate The present invention relates to a novel form of anhydrous tiotropium bromide, processes for the preparation of anhydrous tiotropium bromide, pharmaceutical compositions comprising anhydrous tiotropium bromide and uses of the compositions.
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Page/Page column 14-16
(2011/02/24)
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- METHOD FOR PRODUCING AMMONIUM HEXAFLUOROPHOSPHATES
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The invention relates to a method for producing ammonium hexafluorophosphates of general formula (1) wherein R1, R2, R3 and R4 are defined as in the claims and in the description, said novel ammonium hexafluorophosphates and to the use thereof for producing pharmaceutically active compounds.
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Page/Page column 6
(2010/04/23)
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- METHOD FOR PRODUCING SCOPINIUM SALTS
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The invention relates to a new method of preparing scopinium salts of general formula 1 wherein Y? may have the meanings given in the claims and in the specification.
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Page/Page column 5-6
(2010/05/13)
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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 14
(2009/09/04)
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- PURE AND STABLE TIOTROPIUM BROMIDE
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This invention relates to solvates of tiotropium bromide having a purity of at least 99%, process for preparing such pure solvates, and their use in pharmaceutical, formulations. This invention also provides tiotropium bromide solvates containing less than about 0.15% area by HPLC of 2,2-dithienyl glycolic acid.
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Page/Page column 28
(2008/06/13)
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- New Process for the Production of Tiotropium Salts
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The invention relates to a new process for preparing tiotropium salts of general formula 1 wherein X? may have the meanings given in the claims and in the specification.
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Page/Page column 4-5
(2008/06/13)
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- Novel Crystalline Forms of Tiotropium Bromide
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The invention relates to new crystalline forms of tiotropium bromide, processes for preparing them and their use for preparing a pharmaceutical composition for the treatment of respiratory complaints, particularly for the treatment of COPD (chronic obstructive pulmonary disease) and asthma.
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Page/Page column 4
(2008/06/13)
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- NOVEL CRYSTALLINE FORMS OF TIOTROPIUM BROMIDE
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The invention relates to a new crystalline forms of tiotropium bromide, processes for preparing them and their use for preparing a pharmaceutical composition for the treatment of respiratory complaints, particularly for the treatment of COPD (chronic obstructive pulmonary disease) and asthma.
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Page/Page column 12
(2008/06/13)
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- New method for preparing tiotropium salts
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The invention relates to a new process for preparing tiotropium salts of general formula 1 wherein X? may have the meanings given in the claims and in the specification.
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Page/Page column 4-5
(2008/06/13)
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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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