Method for continuously preparing canagliflozin by using microreactor one-pot method

Abstract

The invention discloses a method for continuously preparing canagliflozin by using a microreactor one-pot method. The method is used for continuously preparing the canagliflozin by using the microreactor one-pot method, and microreactors are divided into a unit A, a unit B, a unit C and a unit D. The method comprises the steps of mixing a solution of M1 with n-butyl lithium in the unit A for carrying out a reaction; after the reaction is finished, enabling the reaction product to enter the unit B together with a solution of M3, and carrying out a reaction at the temperature of -15 to -5 DEG C to obtain an intermediate A; enabling reaction liquid containing the intermediate A to enter the unit C together with a methanol solution of methane sulfonic acid, and carrying out a reaction to obtain an intermediate B; enabling reaction liquid containing the intermediate B to directly react with boron trifluoride and triethyl silicane in the unit D to obtain the canagliflozin. The method greatly simplifies the operation steps, shortens the reaction time, greatly reduces the use of various solvents, lowers the production cost, improves the production safety, can realize continuous and automatic production, and is high in product purity and yield, thus being suitable for industrial production.

Description

technical field [0001] The invention relates to a method for preparing canagliflozin by using a microreactor one-pot continuous flow method, which belongs to the technical field of medicine. Background technique [0002] Canagliflozin, also known as canagliflozin, Chinese chemical name: (1S)-1,5-dehydro-1-{3-[(5-(4-fluorophenyl)-2-thienyl)methyl base]-4-methylphenyl}-D-glucitol, the structural formula is as follows: [0003] [0004] Canagliflozin is a novel SGLT-2 inhibitor for the treatment of type 2 diabetes in adult patients. Jointly developed by Mitsubishi Tanabe Pharmaceuticals and Johnson & Johnson Pharmaceuticals. On March 29, 2013, the U.S. Food and Drug Administration (FDA) approved canagliflozin for improving blood sugar control in adults with type II diabetes. This product is the first SGLT-2 inhibitor approved by the FDA. In November 2013 On March 25, it was approved by the European Commission (EC) for the treatment of adults with type 2 diabetes to improv...

AI Technical Summary

Problems solved by technology

The advantage of this route is that the reaction is simple and the idea of ​​constructing the skeleton is ingenious; the disadvantage is that the Grignard reagent needs to be self-made, and the use of butyllithium requires low temperature, which requires harsh operation and a high risk factor for the reaction.

[0022] The above several routes all have their own advantages, but the reaction characteristics of this key intermediate (compound 3 in route 1) have determined that there are certain potential safety hazards in the enlarged production process utilizing common reactors, which are difficult to amplify, and the steps The cumbersome and frequent post-processing has resulted in the generation of a large amount of waste water and waste liquid

Images