A kind of preparation method of topagliflozin monohydrate

Abstract

The invention relates to a preparation method of Tofogliflozin monohydrate. In the route, p-Hydroxybenzoic acid used as a starting material is subjected to acylation, iodination, Friedel-Crafts and reduction reaction to obtain an iodinated diphenylmethane framework; by means of the characteristic that an iodinated substance is reactive, the splicing the diphenylmethane framework and a saccharide ring is realized under mild conditions through the effect of isopropyl magnesium chloride lithium chloride; and the eleven-step total yield is 22%. The route is high in yield, favorable in selectivity, low in production cost and mild in reaction conditions, does not use flammable, explosive or high-toxicity reagent, obtains products and intermediate compounds which are easy to purify, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a new preparation method of topagliflozin monohydrate, which belongs to the field of medicine and chemical industry. Background technique [0002] Topagliflozin monohydrate was jointly developed by Chugai Pharmaceutical, Sanofi-Aventis and Japan Kowa, and was launched in Japan in 2014. The advantage of this new type of SGLT2 inhibitor is that the drug is more selective, and it can reduce blood sugar while reducing body weight, and there are no obvious side effects. [0003] At present, the published literature on synthesis is all published by Chugai Pharmaceutical Co., Ltd., as follows: [0004] (1) Japan's Chugai Pharmaceutical Co., Ltd. announced the synthesis route of topagliflozin (EP1852439A1) for the first time in 2006. The route uses 2-bromoterephthalic acid as the starting material, and undergoes reduction, hydroxyl protection, addition, ring closure, Oxidation, addition, reduction, and hydrogenolysis are eight steps ...

AI Technical Summary

Problems solved by technology

This technical route mainly has the following disadvantages: 1. the yield is low, the yields of the second and fifth steps are only 18% and 33%, and the total yield is only 1.6%; 2. all intermediates and products need to be subjected to column chromatography Purification is not suitable for industrialized production; ③ palladium carbon is used in the reaction, which is not only expensive but also belongs to a class of metals, which is not conducive to product quality control; ④ the third step of gluconolactone derivatives and benzene ring addition uses butyl Lithium requires a reaction temperature of -78°C. It is an ultra-low temperature reaction with harsh conditions, and butyllithium is extremely flammable, posing a major safety hazard; ⑤The boron trifluoride used in the reaction will decompose into highly toxic fluoride in the air Smoke, not conducive to labor protection

However, the metal-halogen exchange reaction in this route still needs to be carried out at -78°C, and it is not easy to scale up the production process. At the same time, 2,4-dibromobenzyl alcohol is expensive and the use of noble metals such as Pd / C leads to higher production costs. , so it is not suitable for industrial production

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