136310-64-0

Basic information

• Product Name: Scopine-2,2-dithienyl glycolate
• Synonyms: SCOPINE-2,2-DITHIENYL GLYCOLATE;2-thiopheneacetic acid, a-hydroxy-a-2th ( Di(2-thienyl) Glycolate );N-DeMethyl TiotropiuM;α-Hydroxy-α-2-thienyl-2-thiopheneacetic Acid (1α,2β,4β,5α,7β)-9-Methyl-3-oxa-9-azatricyclo[3.3.1.02,4]non-7-yl Ester;Scopine di(2-thienyl)glycolate scopine-2-dithienyl glycolate;Tiotropium EP Impurity B;2-Thiopheneacetic acid, -hydroxy--2-thienyl-, (1,2,4,5,7);(1R,2R,4S,5S,7s)-9-Methyl-3-oxa-9-azatricyclo[3.3.1.02,4]nonan-7-yl 2-hydroxy-2,2-dithiophen-2-ylacetate
• CAS NO: 136310-64-0
• Molecular Formula: C₁₈H₁₉NO₄S₂
• Molecular Weight: 377.483
• EINECS: 1533716-785-6
• Product Categories: TIOTROPIUM BROMIDE;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Tiotropium Bromide Intermediates
• Mol File: 136310-64-0.mol

Chemical Properties

• Melting Point: 138-140°C
• Boiling Point: 542.3 ºC at 760 mmHg
• Flash Point: 281.7 ºC
• Appearance: /
• Density: 1.48 g/cm³
• Vapor Pressure: 1.37E-12mmHg at 25°C
• Refractive Index: 1.687
• Storage Temp.: -20°C Freezer
• PKA: 10.32±0.29(Predicted)
• CAS DataBase Reference: Scopine-2,2-dithienyl glycolate(CAS DataBase Reference)
• NIST Chemistry Reference: Scopine-2,2-dithienyl glycolate(136310-64-0)
• EPA Substance Registry System: Scopine-2,2-dithienyl glycolate(136310-64-0)

Safety Data

• Hazardous Substances Data: 136310-64-0(Hazardous Substances Data)

Usage

Uses

Scopine-2,2-dithienyl glycolate is primarily used as a precursor in the pharmaceutical industry for the production of tiotropium bromide, a highly effective anticholinergic agent. Tiotropium bromide is widely prescribed for the treatment of asthma and chronic obstructive pulmonary disease (COPD).
Used in Pharmaceutical Industry:
Scopine-2,2-dithienyl glycolate is used as a key intermediate for the synthesis of tiotropium bromide, which is an anticholinergic agent. The compound plays a vital role in the development of this medication due to its effectiveness in treating respiratory conditions such as asthma and COPD. Its use in the pharmaceutical industry is focused on improving the quality of life for patients suffering from these respiratory ailments by providing a more effective treatment option.

InChI:InChI=1/C18H19NO4S2/c1-19-11-8-10(9-12(19)16-15(11)23-16)22-17(20)18(21,13-4-2-6-24-13)14-5-3-7-25-14/h2-7,10-12,15-16,21H,8-9H2,1H3

Upstream product

• 136310-66-2 (1R,3S,5S)-2'-hydroxy-2',2'-di(thiophen-2''-yl)acetic acid 8-methyl-8-azabicyclo[3.2.1]oct-6-en-3-yl ester 
• 26447-85-8 hydroxy-di-thiophen-2-yl-acetic acid methyl ester 
• 498-45-3 scopine 
• 85700-55-6 6exo,7exo-epoxy-tropane-3endo-ol; scopine; hydrochloride 
• 1449372-70-6 (1α,2β,4β,5α,7β)-9-methyl-3-oxa-9-azatricyclo[3.3.1.0^2,4]nonan-7-ol oxalate 
• 1003-09-4 2-bromothiophene 
• 22143-95-9 tropenol 
• 51-34-3 scopolamine 
• 1454836-37-3 C₁₀H₁₂ClNO₄ 
• 5713-61-1 thiophen-2-yl magnesium bromide 
• 672-21-9 (+/-)-Scopolamine hydrobromide 
• 20513-09-1 (1R,3S,5S)-8-methyl-8-azabicyclo[3.2.1]oct-6-en-3-ol 
• 22150-33-0 (1R,3S,5S)-3'-hydroxy-2'-phenylpropionic acid 8-methyl-8-azabicyclo[3.2.1]oct-6-en-3-yl ester 

Downstream Products

• 139404-48-1 tiotropium bromide 
• 1256081-14-7 C₁₀H₁₅O₄S^(1-)*C₁₉H₂₂NO₄S₂⁽¹⁺⁾ 

Relevant articles and documents

Crystal Structures of Tiotropium Bromide and Its Monohydrate in View of Combined Solid-state Nuclear Magnetic Resonance and Gauge-Including Projector-Augmented Wave Studies

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.

Synthesis and radiolabelling of ipratropium and tiotropium for use as PET ligands in the study of inhaled drug deposition

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.

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

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.

Preparation method of tiotropium bromide

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.

AN IMPROVED PROCESS FOR PREPARATION OF SCOPINE HYDROBROMIDE

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.

PROCESS FOR SYNTHESIS OF TIOTROPIUM BROMIDE MONOHYDRATE

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.

A tiotropium bromide intermediate preparation method

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.

Discovery of Novel Potent Muscarinic M3 Receptor Antagonists with Proper Plasma Stability by Structural Recombination of Marketed M3 Antagonists

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.

CRYSTALLINE FORM OF TIOTROPIUM BROMIDE

A stable crystalline form of tiotropium bromide, and a process for its preparation with high purity.

IMPROVED PROCESS FOR ACYL TRANSFER REACTIONS

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.