Sotagliflozin preparing method and an intermediate thereof

Abstract

The invention provides a Sotagliflozin preparing method. The structure of an L-xylose derivative 1 is improved, the hydroxyl group is protected with a benzyl group or PMB group to obtain a compound 2,or series derivative reaction is conducted on the L-xylose derivative 1A to obtain the compound 2, the conditions of Grignard docking reaction of the compound 2 and 4-halogenated-1-chloro-2-(4-oxyethylbenzyl) benzene compound 3 are optimized, the reaction yield is increased to 85% or more, usage of excessive Grignard reagents or lithium reagents is avoided, material consumption is reduced, and the route efficiency is improved.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to a new method for preparing Sotagliflozin. Specifically, the present invention discloses a preparation method of Sotagliflozin, an SGLT1 / 2 dual inhibitor drug for treating diabetes, and an intermediate. Background technique [0002] Diabetes is clinically divided into two types: insulin-dependent diabetes (type I diabetes) and non-insulin-dependent diabetes (type II diabetes). The International Diabetes Federation (IDF) predicts that by 2035, the number of diabetic patients worldwide will reach 5.9 billion. Nearly 90% of them are type 2 diabetics. Sotagliflozin is a novel oral sodium-glucose cotransporter 1 and 2 (SGLT-1 and SGLT-2) dual inhibitor. Clinical studies have shown that sotagliflozin can reduce postprandial blood sugar and increase GLP by dually inhibiting the effects of SGLT1 and SGLT2 -1 and promote urinary sugar excretion, the drug is jointly developed b...

AI Technical Summary

Problems solved by technology

[0007] The synthetic method total yield of this Sotagliflozin is low, and process enlargement is difficult

Among them, the oxidation of L-xylose-derived alcohol intermediates needs to use Swern reaction, which needs to be reacted at a low temperature of -70°C. The scale-up production requires higher requirements for reaction equipment and operation, and the process cost is higher. In addition, the reaction produces a by-product dimethyl sulfide , waste gas treatment is troublesome; 4-bromo-1-chloro-2-(4-ethoxybenzyl) benzene forms lithium reagent under the effect of butyllithium and the aldehyde addition reaction of L-xylose derivative although relatively It is easy to carry out, but the reaction still needs a low temperature of -70°C, the experimental conditions are relatively high, the reaction selectivity is poor, the reaction yield is low, and the process is more difficult to scale up

[0008] PCT patent WO2009014970A improves the synthesis method of Sotagliflozin, and reacts Weinreb amide made of L-xylose derivatives with 4-iodo-1-chloro-2-(4-ethoxybenzyl)benzene to form a lithium reagent, Then the obtained intermediate carbonyl is reduced with sodium borohydride, although the selectivity of the reaction has been improved and the reaction yield has been improved by chiral induced reduction, but the exposed hydroxyl group of the Weinreb amide substrate needs to consume additional lithium reagents, which requires Using excessive 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene and n-butyllithium, the cost of process amplification is higher, and the efficiency is lower, and the synthetic route is:

Images