Method for preparing tiotropium bromide

Abstract

The invention relates to the application of microwave and ultrasonic technologies in synthesizing tiotropium bromide anhydride, in particular to a method for preparing the refined product of a finished product, namely, tiotropium bromide anhydride through crystallization and recrystallization processes by using a crude product of tiotropium bromide prepared through bromization reaction after hydrolytic reaction of scopolamine hydrobromide under microwave function, substitution and coupling reaction of bromothiophene, magnesium, and oxalic acid dimethyl ester under the microwave function, and condensation reaction of scopine and thiophen methyl glycollate under the microwave function. Using the invention to prepare tiotropium bromide anhydride, not only the reaction time is short, the side reaction is less, and the yield rate is high in the room temperature condition, but also the product quality is stable, controllable, safe and effective.

Description

technical field [0001] The invention relates to the application of microwave and ultrasonic technology in the synthesis of tiotropium bromide anhydrous, in particular to the hydrolysis reaction of scopolamine hydrobromide under the action of microwave, the substitution of bromothiophene and magnesium with dimethyl oxalate under the action of ultrasonic The crude product of tiotropium bromide prepared by bromination reaction after coupling reaction, condensation reaction of scopolamine and methyl thiophene glycolate under the action of microwave is then crystallized and recrystallized to prepare the final product tiotropium bromide anhydrous The method of the product. Background technique [0002] Tiotropium bromide (Tiotropium Bromide) was approved for listing in the Netherlands in November 2001 for the treatment of chronic obstructive pulmonary disease (COPD). Its basic patent is EP418716, which was proposed on September 12, 1990 by the German BoehringerIngelheim company ,...

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Problems solved by technology

After retrieval, the current methods for preparing tiotropium bromide are all traditional synthetic techniques, which have the problems of long reaction time, many by-products, and low yield. For example, Liu Xianhua et al. It is reported in the literature: "Using natural scopolamine as a raw material to synthesize and hydrolyzing it with ammonia water takes a long time and has many side reactions, mainly obtaining isoscopolamine; the laboratory uses barium hydroxide to hydrolyze scopolamine for 140 minutes, and a yield of 42% can be obtained. scopolamine, but the reaction time must be extended when the production is enlarged, and the longer the time in the alkaline environment, the higher the ratio of scopolamine to isoscopolamine [Proceedings of the First Academic Annual Conference of Shandong Pharmaceutical Association (Part II), 2005]"

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