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A technology of tiotropium bromide and thiophene, which is applied in the field of preparation of tiotropium bromide, can solve the problems of long time, low yield, and many side reactions
Active Publication Date: 2008-07-30
HONGYI SCI & TECH CO LTD NANCHANG
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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 isoscop
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Embodiment 1
[0006] Preparation of Scopolamine (Intermediate 1)
[0007] Take scopolamine hydrobromide, methanol, and potassium carbonate, put them in a closed microwave normal pressure reactor with a wavelength of 0.1-100 cm, react quickly at room temperature, evaporate to dryness under reduced pressure, add dichloromethane, filter, filter cake with di Wash with methyl chloride three times, combine the filtrates, dry over anhydrous sodium sulfate, and evaporate to dryness under reduced pressure to obtain scopolamine oil (intermediate 1) with a yield of 99.3%.
Embodiment 2
[0009] Preparation of bis(2-thienyl)glycolic acid methyl ester (intermediate 2)
[0010] Take bromothiophene, magnesium chips, dimethyl oxalate, and ether, and place them in an ultrasonic reactor with a frequency of 20-300KHZ. After rapid reaction at room temperature, add dilute sulfuric acid dropwise to the reaction solution, separate the ether layer, Wash with sodium aqueous solution, wash with water, dry over anhydrous sodium sulfate, evaporate to dryness, and recrystallize with toluene to obtain bis(2-thienyl)glycolic acid methyl ester crystals (intermediate 2) with a yield of 96.7%.
Embodiment 3
[0012] Preparation of Scopolamine Bis(2-thienyl)glycolate (Intermediate 3)
[0013] Mix Intermediate 2 and Intermediate 1 with an equimolar molecular ratio, add sodium and place in a closed microwave normal pressure reactor with a wavelength of 0.1 to 100 cm. After rapid reaction at room temperature, add toluene to the reaction solution and continue the reaction. Dilute with ethyl acetate, wash the organic layer twice with water, dry over anhydrous sodium sulfate, filter, evaporate to dryness, and recrystallize with acetonitrile to obtain crystals of scopolamine bis(2-thienyl)glycolate (intermediate 3) , the yield was 98.3%.
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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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