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Method for preparing tiotropium bromide

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

Active Publication Date: 2011-02-23
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, basify with saturated potassium bicarbonate solution to pH=8-10, and add 1.5 kg of sodium borohydride at 5-20℃ Reduce the reaction for 8-12 hours, adjust the pH to 1-2 with hydrogen chloride, add 15 liters of anhydrous acetone, freeze overnight, add ether to the filter cake, basify ammonia, filter with suction, and evaporate to dryness under reduced pressure at 15-20°C. 612 grams of viscous B, yield 76%.

[0021] In a 10 liter three-necked flask, add 5 liters of xylene to 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. Transesterification reaction occurs, the reaction temperature is controlled at 50℃, and the reaction is 2-3 hours. After the reaction, add dilute hydrochloric acid solution to adjust pH=1-3, add 10 liters of cold distilled water for washing, and adju...

Embodiment 2

[0025] Preparation of scopolitol and methyl 2,2-dithienyl glycolate The method of preparing scopolitol and methyl 2,2-dithienyl glycolate in patent 201010045804.5 was used to prepare scopolitol and 2,2-dithienyl ethanol. Methyl acid.

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

[0027] The preparation steps of crude tiotropium bromide are the same as in Example 1, except that the volume ratio of methanol and water is 1:0.5, and the total volume of methanol and water (ml) is the same ...

Embodiment 3

[0030] The preparation method is the same as in Example 1, except that the mass ratio of sodium and sodium methoxide is 1:1, the yield of 2-(2-thienyl)glycolate scopolamine is 80%, and the yield of 2-(2-thienyl) ) The content of scopolamine glycolate isomer 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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IPC IPC(8): C07D451/10
Inventor 许坤田玉花马玉霞
Owner ANHUI DEXINJIA BIOPHARM
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