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...

Examples

Embodiment Construction

[0029] 1, the preparation of scopolamine (intermediate I)

[0030] Under controlled anhydrous and anaerobic conditions, use a special bottom valve and a multifunctional reactor as a reactor, and use a special filter as a refining device, take 5.7g (0.013mol) of scopolamine hydrobromide, add 60% dehydrated alcohol ~80ml, alkalized to pH8~9 with ammonia gas. Add about 5.1 g (0.1353 mol) of sodium borohydride in portions, stir the reaction at 10-20°C, follow the reaction with TLC, and the reaction time is about 10-12 hours. Hydrogen chloride was acidified to pH 1~2, diluted with 70~130ml of anhydrous ether, and filtered. Add 50-70ml of dichloromethane to the filter cake, and alkalinize it with ammonia gas to pH 7-8. Suction filter, wash with 30-50ml dichloromethane in 3 times. The filtrates were combined and evaporated to dryness under reduced pressure below 25°C to obtain Intermediate I as a white solid with a yield of about 83%.

[0031] 2, the preparation of two (2-thienyl...

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...

Examples

Embodiment Construction

[0029] 1, the preparation of scopolamine (intermediate I)

[0030] Under controlled anhydrous and anaerobic conditions, use a special bottom valve and a multifunctional reactor as a reactor, and use a special filter as a refining device, take 5.7g (0.013mol) of scopolamine hydrobromide, add 60% dehydrated alcohol ~80ml, alkalized to pH8~9 with ammonia gas. Add about 5.1 g (0.1353 mol) of sodium borohydride in portions, stir the reaction at 10-20°C, follow the reaction with TLC, and the reaction time is about 10-12 hours. Hydrogen chloride was acidified to pH 1~2, diluted with 70~130ml of anhydrous ether, and filtered. Add 50-70ml of dichloromethane to the filter cake, and alkalinize it with ammonia gas to pH 7-8. Suction filter, wash with 30-50ml dichloromethane in 3 times. The filtrates were combined and evaporated to dryness under reduced pressure below 25°C to obtain Intermediate I as a white solid with a yield of about 83%.

[0031] 2, the preparation of two (2-thienyl...

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