Tiotropium bromide anhydride and preparation method thereof

Abstract

The invention discloses a method for preparing tiotropium bromide anhydride, which comprises the steps of: under the anhydrous and anaerobic condition, preparing an intermediate I by taking a special kettle bottom valve and a multi-functional reaction kettle as a reactor, taking a special filter as refining equipment and taking hydrobromic scopolamine as an initial raw material through reduction hydrogenation reaction; preparing an intermediate II by performing addition reaction of Grignard reagent and dimethyl oxalate in tetrahydrofuran, wherein the Grignard reagent is prepared from bromothiophene by taking tetrahydrofuran as a medium through iodine catalysis; preparing an intermediate III by performing ester exchange condensation reaction of the intermediate I and the intermediate II under the action of sodium; preparing an intermediate IV from the intermediate III through methylation bromination reaction; and preparing the tiotropium bromide anhydride by performing the activated carbon decoloration and recrystallization on the intermediate IV by using aqueous solution and acetonitrile methanol isopropyl ether solution. Compared with those in the prior art, reaction products of the method have the advantages of good quality, high yield, controlled reaction process, safe production and good environmental protection effect.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, in particular to a tiotropium bromide anhydrate and a preparation method thereof. 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 , its invention name is "Thienylcarboxylic acid ester of aminoalcohols, their quaternary products, their preparation and use of the compounds", what the patent claims is tiotropium bromide monohydrate and its synthetic route with bromothiophene as the starting material and Uses for the treatment of COPD, etc. [0003] The invention patent for the preparation method of tiotropium bromide anhydrate (patent number: ZL2006100548666) discloses a method of preparing scopolamine (intermediate I) by hydro...

AI Technical Summary

Problems solved by technology

The reaction of preparing scopolamine (intermediate I) through hydrolysis reaction disclosed in this invention patent is a process of hydrolysis from ester group to hydroxyl group with scopolamine hydrobromide as the starting raw material. If the reaction conditions are not well controlled, it is easy to make scopolamine Hydrolysis produces isoscopolamine by-products; the Grignard reagent prepared in ether from the bromothiophene disclosed in the invention patent and dimethyl oxalate undergoes an addition reaction in ether, and if the reaction makes the ketone ester Once separated, it can be added with another molecule of Grignard reagent immediately, and the quality of the produced alcohol ester is high. The reaction conditions such as reaction temperature and solvent are the key factors affecting the quality of the reaction. If the reaction conditions are not well controlled, the intermediates will be affected. Quality and yield of II; The quality of intermediate I and intermediate II directly affects the quality of final product tiotropium bromide anhydrate

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