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Method for preparing tiotropium bromide

A technique for the preparation of tiotropium bromide, which is applied in the field of preparation of tiotropium bromide, can solve problems such as the content of isomers not meeting the requirements, and achieve the effects of reasonable reaction process design, safe reaction process, and high purity

Active Publication Date: 2013-06-05
ANHUI DEXINJIA BIOPHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The present invention aims at the problem that the 2-(2-thienyl) scopolamine glycolate isomer content in the existing tiotropium bromide process does not meet the requirements, and provides a preparation method of tiotropium bromide, the method The content of scopolamine isomers of 2-(2-thienyl) glycolate is between 0.05% and 0.08%, which is consistent with the content of scopolamine isomers of 2-(2-thienyl) glycolate in EP ≤ 0.1% Provisions

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Add 3 kg of scopolamine hydrobromide to a 50-liter three-necked flask, add 15 liters of anhydrous methanol, alkalinize with potassium bicarbonate saturated solution to pH=8-10, and add 1.5 kg of sodium borohydride at 5-20 °C Reduction reaction for 8-12 hours, adjust pH=1-2 with hydrogen chloride, add 15 liters of anhydrous acetone, freeze overnight, add diethyl ether to the filter cake, alkalinize with ammonia gas, filter with suction, and evaporate to dryness under reduced pressure at 15-20°C to obtain Viscous 612 grams of B, yield 76%.

[0021] In a 10-liter three-necked flask, add 5 liters of xylene, dissolve 612 grams of scopolamine and 1012 grams of methyl 2,2-dithienyl glycolate, add 20 grams of sodium and 60 grams of sodium methoxide at 50-60 ° C, A transesterification reaction occurs, the reaction temperature is controlled at 50°C, and the reaction takes 2-3 hours. After the reaction, add dilute hydrochloric acid solution dropwise to adjust the pH=1-3, add 10 li...

Embodiment 2

[0025] The preparation of scopolamine and methyl 2,2-dithienyl glycolate adopts the method for preparing scopolamine and methyl 2,2-dithienyl glycolate in patent 201010045804.5 to prepare scopolamine and 2,2-dithienyl ethanol acid methyl ester.

[0026] The preparation step of 2-(2-thienyl) scopolamine glycolate is the same as in Example 1, except that the mol ratio of scopolamine and 2,2-dithienyl glycolate methyl ester is 1:1.5, sodium and The mass ratio of sodium methoxide is 1:5, the amount of catalyst is 4wt% of the total amount of reactants, the mass sum (g) of scopolamine, 2,2-dithienyl glycolate methyl ester and catalyst and the volume of xylene (ml ) ratio is 1:5, the yield of 2-(2-thienyl)scopolamine glycolate is 75%, and the content of 2-(2-thienyl)scopolamine glycolate isomers is 0.07-0.08 %.

[0027] The preparation step of tiotropium bromide crude product is the same as embodiment 1, and difference is: methanol and water volume ratio are 1:0.5, and the total vo...

Embodiment 3

[0030] The preparation method is the same as in Example 1, except that the mass ratio of sodium and sodium methylate is 1:1, and the yield of 2-(2-thienyl) scopolamine glycolate is 80%, and 2-(2-thienyl ) The content of scopolamine glycolate isomers is 0.05-0.06%, the volume ratio of methanol to water is 1:1.5, the volume ratio of acetonitrile to methanol is 1:2.5, and the yield of tiotropium bromide is 80%.

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Abstract

The invention discloses a method for preparing tiotropium bromide, which comprises the following steps of: preparing scopine-2,2-dithienyl glycolate from scopine and methyl 2,2-dithienyl glycolate, reacting the scopine-2,2-dithienyl glycolate with methyl bromide to prepare a tiotropium bromide crude product, and refining the tiotropium bromide crude product to obtain a tiotropium bromide finishedproduct. The method is characterized in that: the scopine and the methyl 2,2-dithienyl glycolate undergo ester exchange reaction under the action of dimethylbenzene, and the mixed catalysts of sodiumand sodium methoxide, and after the reaction, reaction solution is post-treated to obtain the scopine-2,2-dithienyl glycolate. In the method, in the process of preparing the scopine-2,2-dithienyl glycolate, the sodium and the sodium methoxide are simultaneously taken as the catalysts, and scopine isomer content after the reaction is less than 0.1 percent which completely meets specifications in the trial standards of European pharmacopoeia; and the method solves a big problem for the conventional preparation of the tiotropium bromide and is easy to realize industrial production.

Description

technical field [0001] The invention relates to a preparation method of tiotropium bromide, in particular to a preparation method of tiotropium bromide whose scopolamine isomer is less than 0.1%, and belongs to the technical field of biopharmaceuticals. Background technique [0002] Tiotropium bromide is a specific and selective anticholinergic drug with a similar affinity to muscarinic receptor subtypes MI-M5. It produces bronchodilation by inhibiting smooth muscle M3 receptors. In preclinical in vitro and in vivo studies, tiotropium bromide has a dose-dependent inhibitory effect on methacholine-induced bronchoconstriction and can be maintained for more than 24 hours. Clinical studies It shows that the lung function can be significantly improved within 30 minutes of the first administration, and the pharmacodynamic steady state can be reached within 1 week. In addition, dyspnea can be significantly improved. [0003] The process of synthesizing tiotropium bromide is gener...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D451/10
Inventor 许坤田玉花马玉霞
Owner ANHUI DEXINJIA BIOPHARM
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